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Shah M, Rath S, Gulia S, Bhargava P, Sekar A, Rane S, Bajpai J, Shet T, Desai S, Sarin R, Pathak R, Popat P, Parab P, Kembhavi Y, Jethwa D, Dutta S, Patil A, Nair N, Rane P, Shetake A, Kolkur M, Joshi S, Badwe RA, Gupta S. Retrospective Study to Determine Factors Influencing Outcome in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Neoadjuvant Chemotherapy. JCO Glob Oncol 2025; 11:e2400365. [PMID: 40267382 DOI: 10.1200/go-24-00365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 02/01/2025] [Accepted: 03/13/2025] [Indexed: 04/25/2025] Open
Abstract
PURPOSE There are scant data on patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with neoadjuvant therapy (NAT) in real-world settings with limited access to HER2-targeted therapy. METHODS This was a retrospective analysis of patients with nonmetastatic, HER2-positive breast cancer treated with NAT between January 2014 and December 2018 to determine factors affecting pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS). RESULTS The cohort comprised 1,004 patients with a median age of 47 years, 533 (53.1%) with clinical T3/T4 tumors, 466 (46.4%) with clinical N2/3 status, and 527 (52.5%) with hormone receptor-positive disease. Trastuzumab was given to 528 (52.6%) patients in the neoadjuvant setting and 711 (70.8%) patients in neoadjuvant and/or postoperative settings. pCR was achieved in 226 (22.5%) patients; the 5-year EFS in the whole cohort, pCR group, and no-pCR group was 63.5% (95% CI, 60.36 to 66.63), 86.1% (95% CI, 81.59 to 90.60), and 57% ([95% CI, 53.47 to 60.52]; P < .001), respectively. In multivariable analysis in the full cohort, smaller tumor size (cT1/T2 v cT3/T4), higher grade (III v II), hormone receptor-negative status, and use of neoadjuvant HER2-targeted therapy were significantly associated with higher pCR, and smaller tumor size (cT1/T2 v cT3/T4), lower node involvement (cN0/N1 v cN2/N3), achievement of pCR, and receiving trastuzumab were significantly associated with higher EFS and OS. CONCLUSION In a setting with constrained access to HER2-targeted therapy, lower clinical tumor burden and receiving trastuzumab were significantly associated with increased pCR and survival in patients with HER2-positive breast cancer treated with NAT. Efforts should be made to enhance early diagnosis and access to HER2-targeted therapy worldwide.
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Affiliation(s)
- Minit Shah
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Sushmita Rath
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Seema Gulia
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Anbarasan Sekar
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Swapnil Rane
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Jyoti Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Tanuja Shet
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Sangeeta Desai
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Rajiv Sarin
- Department of Radiation Therapy, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Rima Pathak
- Department of Radiation Therapy, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Palak Popat
- Department of Radio-Diagnosis, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Pallavi Parab
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Yogesh Kembhavi
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Dinesh Jethwa
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Snigdha Dutta
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Asawari Patil
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Nita Nair
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Pallavi Rane
- Department of Biostatistics, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Ankush Shetake
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Manali Kolkur
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Shalaka Joshi
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Rajendra A Badwe
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India
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Khalaf BH, Suleiman AA, Suwaid MA. Exploring the Regulatory Roles of miR-21, miR-15, and miR-let-7 in ABC Transporter-Mediated Chemoresistance: Implications for Breast Cancer Etiology and Treatment. Mol Biotechnol 2025; 67:149-159. [PMID: 38133750 DOI: 10.1007/s12033-023-00990-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 11/13/2023] [Indexed: 12/23/2023]
Abstract
Breast cancer, a prevalent and aggressive malignancy among females worldwide, poses a significant challenge due to resistance to chemotherapy and tyrosine kinase inhibitors. In breast cancer, ABC transporters play a pivotal role by contributing to chemoresistance and drug efflux, a phenomenon observed also in various cancers. This study aims to elucidate the role of oncomiRs miR-15, miR-21, and miR-let-7 in breast cancer etiology and their impact on chemotherapy-resistant oncogenes ABCA1, ABCB1, and ABCC1. Blood samples from female breast cancer patients were analyzed to assess the expression levels of miRNAs and oncogenes by qPCR. Significantly, miR-21 exhibited a positive correlation with ABCA1 in newly diagnosed patients, while miR-15 and miR-let-7 displayed a positive correlation with ABCA1 in the metastasis group. Additionally, miR-let-7 demonstrated a negative correlation with ABCC1 in newly diagnosed patients. This study's findings provide valuable insights into the cancer etiology of these miRNAs and their interactions with ABCA1, ABCB1, and ABCC1. Targeting these interactions holds promise for mitigating drug efflux and chemoresistance in breast cancer, potentially enhancing current treatments and improving patient outcomes.
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Karci E, Bilici A, Bayram B, Celayir M, Ozyurt N, Uluc BO, Eken A, Basaran G, Demirci U, Kemal Y, Oruncu MB, Olmez OF, Selcukbiricik F, Korkmaz T, Erturk I, Bilgetekin I, Celik S, Turkel A, Alkan A, Sakin A, Can O, Gunaldi M, Esin E, Yildiz O. Neoadjuvant Pembrolizumab Plus Chemotherapy in Early-Stage Triple-Negative Breast Cancer: A Nationwide Retrospective Turkish Oncology Group Study. Cancers (Basel) 2024; 16:3389. [PMID: 39410009 PMCID: PMC11475936 DOI: 10.3390/cancers16193389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objectives: Following the results of the phase 3 KEYNOTE-522 trial, the U.S. Food and Drug Administration approved pembrolizumab, a humanized IgG4 kappa monoclonal antibody, in combination with neoadjuvant chemotherapy as a new standard of care for high-risk early-stage triple-negative breast cancer (TNBC). This retrospective, multicenter study in Türkiye assessed the real-world efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in early-stage TNBC. Methods: The study included 108 patients treated between 2021 and 2023 across 14 oncology centers. Three distinct neoadjuvant regimens incorporating pembrolizumab were administered at the discretion of the treating physicians. The primary outcomes were the pathological complete response (pCR) rate after neoadjuvant therapy and the 2-year event-free survival (EFS) and overall survival (OS) rates. Results: The observed pCR rate was 63.9%, closely mirroring the 64.8% reported in the KEYNOTE-522 trial. At the two-year mark, the EFS rate was 87.2% and the OS rate was 92.3%. Multivariable analysis identified pCR as the sole independent predictor of both EFS and OS. The safety profile was consistent with previous clinical trial data, with most adverse events being of grade 1-2 in severity. Conclusions: These findings provide valuable real-world confirmation of the efficacy and safety of neoadjuvant pembrolizumab-chemotherapy in early-stage TNBC, complementing evidence from randomized trials.
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Affiliation(s)
- Ebru Karci
- Department of Medical Oncology, Faculty of Medicine, İstanbul Medipol University, Istanbul 34214, Türkiye; (A.B.); (O.F.O.); (A.S.); (O.Y.)
| | - Ahmet Bilici
- Department of Medical Oncology, Faculty of Medicine, İstanbul Medipol University, Istanbul 34214, Türkiye; (A.B.); (O.F.O.); (A.S.); (O.Y.)
| | - Buket Bayram
- Department of Medical Oncology, Koc University Hospital, Istanbul 34010, Türkiye; (B.B.); (F.S.)
| | - Melisa Celayir
- Department of Medical Oncology, Faculty of Medicine, Mehmet Ali Aydınlar Acıbadem University, Istanbul 34752, Türkiye; (M.C.); (B.O.U.); (G.B.); (T.K.); (O.C.)
| | - Neslihan Ozyurt
- Department of Medical Oncology, Faculty of Medicine, Ordu University Training and Research Hospital, Ordu 52200, Türkiye;
| | - Başak Oyan Uluc
- Department of Medical Oncology, Faculty of Medicine, Mehmet Ali Aydınlar Acıbadem University, Istanbul 34752, Türkiye; (M.C.); (B.O.U.); (G.B.); (T.K.); (O.C.)
| | - Aynur Eken
- Department of Medical Oncology, Ozel Ortadogu Hospital, Adana 67055, Türkiye;
| | - Gul Basaran
- Department of Medical Oncology, Faculty of Medicine, Mehmet Ali Aydınlar Acıbadem University, Istanbul 34752, Türkiye; (M.C.); (B.O.U.); (G.B.); (T.K.); (O.C.)
| | - Umut Demirci
- Medical Oncology Unit, Memorial Ankara Hospital, Ankara 06520, Türkiye; (U.D.); (I.B.)
| | - Yasemin Kemal
- Department of Medical Oncology, Faculty of Medicine, Altınbas University, Istanbul 34147, Türkiye;
| | - Mehmet Berk Oruncu
- Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara 06100, Türkiye;
| | - Omer Fatih Olmez
- Department of Medical Oncology, Faculty of Medicine, İstanbul Medipol University, Istanbul 34214, Türkiye; (A.B.); (O.F.O.); (A.S.); (O.Y.)
| | - Fatih Selcukbiricik
- Department of Medical Oncology, Koc University Hospital, Istanbul 34010, Türkiye; (B.B.); (F.S.)
| | - Taner Korkmaz
- Department of Medical Oncology, Faculty of Medicine, Mehmet Ali Aydınlar Acıbadem University, Istanbul 34752, Türkiye; (M.C.); (B.O.U.); (G.B.); (T.K.); (O.C.)
| | - Ismail Erturk
- Ministry of Health Gülhane Training and Research Hospital, Ankara 06010, Türkiye;
| | - Irem Bilgetekin
- Medical Oncology Unit, Memorial Ankara Hospital, Ankara 06520, Türkiye; (U.D.); (I.B.)
| | - Serkan Celik
- Department of Medical Oncology, Yeditepe University, Istanbul 34755, Türkiye;
| | - Alper Turkel
- Department of Medical Oncology, Abdurrahman Yurtaslan Ankara Oncology Research and Training Hospital, Ankara 06200, Türkiye;
| | - Ali Alkan
- Department of Medical Oncology, School of Medicine, Mugla Sıtkı Kocman University, Mugla 48000, Türkiye;
| | - Abdullah Sakin
- Department of Medical Oncology, Faculty of Medicine, İstanbul Medipol University, Istanbul 34214, Türkiye; (A.B.); (O.F.O.); (A.S.); (O.Y.)
| | - Orcun Can
- Department of Medical Oncology, Faculty of Medicine, Mehmet Ali Aydınlar Acıbadem University, Istanbul 34752, Türkiye; (M.C.); (B.O.U.); (G.B.); (T.K.); (O.C.)
| | - Meral Gunaldi
- Department of Medical Oncology, Faculty of Medicine, Aydın University, Istanbul 34295, Türkiye;
| | - Ece Esin
- Department of Medical Oncology, Bayındır Hospital, Ankara 06250, Türkiye;
| | - Ozcan Yildiz
- Department of Medical Oncology, Faculty of Medicine, İstanbul Medipol University, Istanbul 34214, Türkiye; (A.B.); (O.F.O.); (A.S.); (O.Y.)
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Deng YX, Zhao YJ, Nong QH, Qiu HM, Guo QL, Hu H. Predictive Value of Pretreatment Neutrophil to Albumin Ratio in Response to Neoadjuvant Chemotherapy of Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2024; 16:393-402. [PMID: 39071809 PMCID: PMC11283269 DOI: 10.2147/bctt.s468239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/18/2024] [Indexed: 07/30/2024]
Abstract
Background The immune system appears to play a crucial role in how breast cancer responds to chemotherapy. In this study, we investigated a peripheral marker of immune and inflammation named the neutrophil to albumin ratio (NAR) to explore its potential relationship with pathological complete response (pCR) in locally advanced breast cancer patients who underwent neoadjuvant chemotherapy (NAC). Methods We conducted a retrospective analysis of 212 consecutive breast cancer patients who received NAC. The NAR was calculated by examining the complete blood cell count and albumin level in peripheral blood before starting NAC. Through ROC curve analysis, we determined the optimal cutoff value for NAR as 0.0877. We used Pearson's chi-square test or Fisher's exact test to evaluate the relationship between NAR and pCR, as well as other clinical and pathological characteristics. Logistic regression models were employed for univariate and multivariate analyses. Results The results of both univariate and multivariate logistic regression analyses showed that NAR was associated with tumor pathological regression. The NAR high group had a higher pCR rate compared to the NAR low group (OR 3.127 [95% CI 1.545-6.328]; p = 0.002). Conclusion According to this study, it was observed that patients with breast cancer who had high levels of NAR were more likely to achieve pCR when undergoing NAC.
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Affiliation(s)
- Yu-Xiang Deng
- Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China
| | - Yu-Jie Zhao
- Department of Radiotherapy, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China
| | - Qiao-Hong Nong
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China
| | - Hong-Mei Qiu
- Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China
| | - Qiao-Li Guo
- Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China
| | - Hui Hu
- Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China
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Wood SJ, Gao Y, Lee JH, Chen J, Wang Q, Meisel JL, Li X. High tumor infiltrating lymphocytes are significantly associated with pathological complete response in triple negative breast cancer treated with neoadjuvant KEYNOTE-522 chemoimmunotherapy. Breast Cancer Res Treat 2024; 205:193-199. [PMID: 38286889 DOI: 10.1007/s10549-023-07233-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 12/14/2023] [Indexed: 01/31/2024]
Abstract
INTRODUCTION For patients with locally advanced triple negative breast cancer (TNBC), the standard of care is to administer the KEYNOTE-522 (K522) regimen, including chemotherapy and immunotherapy (pembrolizumab) given in the neoadjuvant setting. Pathological complete response (pCR) is more likely in patients who receive the K522 regimen than in patients who receive standard chemotherapy. Studies have shown that pCR is a strong predictor of long-term disease-free survival. However, factors predicting pCR to K522 are not well understood and require further study in real-world populations. METHODS We evaluated 76 patients who were treated with the K522 regimen at our institution. Twenty-nine pre-treatment biopsy slides were available for pathology review. Nuclear grade, Nottingham histologic grade, Ki-67, lymphovascular invasion, and tumor infiltrating lymphocytes (TIL) were evaluated in these 29 cases. For the cases that did not have available slides for review from pre-treatment biopsies, these variables were retrieved from available pathology reports. In addition, clinical staging, race, and BMI at the time of biopsy were retrieved from all 76 patients' charts. Binary logistic regression models were used to correlate these variables with pCR. RESULTS At the current time, 64 of 76 patients have undergone surgery at our institution following completion of K522 and 31 (48.4%) of these achieved pCR. In univariate analysis, only TIL was significantly associated with pCR (p = 0.014) and this finding was also confirmed in multivariate analysis, whereas other variables including age, race, nuclear grade, Nottingham grade, Ki-67, lymphovascular invasion, BMI, pre-treatment tumor size, and lymph node status were not associated with pCR (p > 0.1). CONCLUSION Our real-world data demonstrates high TIL is significantly associated with pCR rate in the K522 regimen and may potentially serve as a biomarker to select optimal treatment. The pCR rate of 48.4% in our study is lower than that reported in K522, potentially due to the smaller size of our study; however, this may also indicate differences between real-world data and clinical trial results. Larger studies are warranted to further investigate the role of immune cells in TNBC response to K522 and other treatment regimens.
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Affiliation(s)
- Sarah J Wood
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
| | - Yuan Gao
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Ji-Hoon Lee
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA
- The Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Jessica Chen
- Emory College of Arts and Sciences, Emory University, Atlanta, GA, USA
| | - Qun Wang
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Jane L Meisel
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
| | - Xiaoxian Li
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
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Saleh T, Al Shboul S, Awad H, El-Sadoni M, Alhesa A, Alsharaiah E, Abu Shahin N, Alotaibi MR, Battah A, Azab B. Characterization of BCL-X L , MCL-1, and BAX Protein Expression in Response to Neoadjuvant Chemotherapy in Breast Cancer. Appl Immunohistochem Mol Morphol 2024; 32:189-199. [PMID: 38426376 DOI: 10.1097/pai.0000000000001189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 01/26/2024] [Indexed: 03/02/2024]
Abstract
The use of chemotherapy has improved the overall treatment of breast cancer, which is frequently administered in the form of neoadjuvant chemotherapy (NAC). Apoptosis is an established cell stress response to NAC in preclinical models; however, there is limited understanding of its role in clinical cancer, specifically, its contribution to favorable pathologic responses in breast cancer therapy. Here, we aimed to characterize the change in protein expression of 3 apoptosis-associated biomarkers, namely, BCL-X L , MCL-1, and BAX in breast cancer in response to NAC. For this, we utilized a set of 68 matched invasive breast cancer FFPE samples that were collected before (pre) and after (post) the exposure to NAC therapy that were characterized by incomplete pathologic response. Immunohistochemistry (IHC) analysis suggested that most of the samples show a decrease in the protein expression of all 3 markers following exposure to NAC as 90%, 69%, and 76% of the matched samples exhibited a decrease in expression for BCL-X L , MCL-1, and BAX, respectively. The median H-score of BCL-X L post-NAC was 150/300 compared with 225/300 pre-NAC ( P value <0.0001). The median H-score of MCL-1 declined from 200 pre-NAC to 160 post-NAC ( P value <0.0001). The median H-score of BAX protein expression decreased from 260 pre-NAC to 190 post-NAC ( P value <0.0001). There was no statistically significant association between the expression of these markers and stage, grade, and hormone receptor profiling (luminal status). Collectively, our data indicate that the expression of apoptosis regulatory proteins changes following exposure to NAC in breast cancer tissue, developing a partial pathologic response.
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Affiliation(s)
- Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa
| | - Sofian Al Shboul
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa
| | - Heyam Awad
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Mohammed El-Sadoni
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Ahmad Alhesa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Elham Alsharaiah
- Department of Pathology, King Hussein Medical Center, Royal Medical Service, Amman, Jordan
| | - Nisreen Abu Shahin
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Moureq R Alotaibi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - AbdelKader Battah
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
| | - Bilal Azab
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan
- Division of Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, AZ
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Kim EY, Lee KH, Yun JS, Park YL, Park CH, Jang SY, Ryu JM, Lee SK, Chae BJ, Lee JE, Kim SW, Nam SJ, Yu JH. Impact of residual microcalcifcations on prognosis after neoadjuvant chemotherapy in breast cancer patients. BMC Womens Health 2024; 24:187. [PMID: 38509531 PMCID: PMC10956337 DOI: 10.1186/s12905-024-02973-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 02/14/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC. METHODS A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCRw/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCRw/o mic group was breast non-pCR without residual microcalcifications. pCRw/mic group was breast pCR with residual microcalcifications. pCRw/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC. RESULTS There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCRw/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160-23.190) in non-pCRw/mic group and 5.970 (1.840-19.380) in non-pCRw/o mic group. Compared to pCRw/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130-34.090) in non-pCRw/mic group, 9.120 (2.850-29.200) in non-pCRw/o mic group. Compared to pCRw/o mic, the hazard ratio (95% CI) for distant metastasis in pCRw/mic group was 2.240 (0.230-21.500) without statistical significance (p = 0.486). CONCLUSIONS Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group.
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Affiliation(s)
- Eun Young Kim
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kwan Ho Lee
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ji-Sup Yun
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong Lai Park
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Chan Heun Park
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Yoon Jang
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Jai Min Ryu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Se Kyung Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Byung-Joo Chae
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Jeong Eon Lee
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Seok Won Kim
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Seok Jin Nam
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Jong Han Yu
- Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea.
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Dell'Aquila K, Vadlamani A, Maldjian T, Fineberg S, Eligulashvili A, Chung J, Adam R, Hodges L, Hou W, Makower D, Duong TQ. Machine learning prediction of pathological complete response and overall survival of breast cancer patients in an underserved inner-city population. Breast Cancer Res 2024; 26:7. [PMID: 38200586 PMCID: PMC10782738 DOI: 10.1186/s13058-023-01762-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Generalizability of predictive models for pathological complete response (pCR) and overall survival (OS) in breast cancer patients requires diverse datasets. This study employed four machine learning models to predict pCR and OS up to 7.5 years using data from a diverse and underserved inner-city population. METHODS Demographics, staging, tumor subtypes, income, insurance status, and data from radiology reports were obtained from 475 breast cancer patients on neoadjuvant chemotherapy in an inner-city health system (01/01/2012 to 12/31/2021). Logistic regression, Neural Network, Random Forest, and Gradient Boosted Regression models were used to predict outcomes (pCR and OS) with fivefold cross validation. RESULTS pCR was not associated with age, race, ethnicity, tumor staging, Nottingham grade, income, and insurance status (p > 0.05). ER-/HER2+ showed the highest pCR rate, followed by triple negative, ER+/HER2+, and ER+/HER2- (all p < 0.05), tumor size (p < 0.003) and background parenchymal enhancement (BPE) (p < 0.01). Machine learning models ranked ER+/HER2-, ER-/HER2+, tumor size, and BPE as top predictors of pCR (AUC = 0.74-0.76). OS was associated with race, pCR status, tumor subtype, and insurance status (p < 0.05), but not ethnicity and incomes (p > 0.05). Machine learning models ranked tumor stage, pCR, nodal stage, and triple-negative subtype as top predictors of OS (AUC = 0.83-0.85). When grouping race and ethnicity by tumor subtypes, neither OS nor pCR were different due to race and ethnicity for each tumor subtype (p > 0.05). CONCLUSION Tumor subtypes and imaging characteristics were top predictors of pCR in our inner-city population. Insurance status, race, tumor subtypes and pCR were associated with OS. Machine learning models accurately predicted pCR and OS.
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Affiliation(s)
- Kevin Dell'Aquila
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Abhinav Vadlamani
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Takouhie Maldjian
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Susan Fineberg
- Department of Pathology, Montefiore Health System and Albert Einstein College of Medicine, Bronx, NY, USA
| | - Anna Eligulashvili
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Julie Chung
- Department of Oncology, Montefiore Health System and Albert Einstein College of Medicine, Bronx, NY, USA
| | - Richard Adam
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Laura Hodges
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Wei Hou
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA
| | - Della Makower
- Department of Oncology, Montefiore Health System and Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tim Q Duong
- Department of Radiology, Montefiore Health System and Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY, 10467, USA.
- Center for Health Data Innovation, Montefiore Health System and Albert Einstein College of Medicine, Bronx, NY, USA.
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Dan J, Tan J, Huang J, Yuan Z, Guo Y. Early changes of platelet‑lymphocyte ratio correlate with neoadjuvant chemotherapy response and predict pathological complete response in breast cancer. Mol Clin Oncol 2023; 19:90. [PMID: 37854328 PMCID: PMC10580258 DOI: 10.3892/mco.2023.2686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 09/11/2023] [Indexed: 10/20/2023] Open
Abstract
Markers with inflammatory properties, such as the ratio of neutrophils to lymphocytes and the platelet-to-lymphocyte ratio (PLR), have been documented as potential indicators for predicting pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT) in cases of breast cancer. However, whether early changes of PLR (ΔPLR) during NACT can predict pCR has not been reported. A total of 257 breast cancer patients who underwent NACT were retrospectively analyzed. PLR was calculated by evaluating the complete blood cell counts prior to NACT and following two cycles of NACT. The analysis focused on the association between changes in PLR and the response to chemotherapy, as well as the association with pCR. Patients who stayed in or changed to the low PLR level subgroup after two cycles of NACT exhibited a superior response to chemotherapy, in contrast to those who stayed in or changed to the high PLR level subgroup. Of the 257 patients, 75 (29.1%) achieved a pCR after NACT. In the multivariate analysis, there was a significant association between ΔPLR and pCR, whereas pre-treatment and post-treatment PLR did not show any significant association. In multivariate analysis, patients who had a ΔPLR <0 had a notably higher rate of pCR compared with patients with a ΔPLR ≥0. It was concluded that ΔPLR, rather than pre-treatment or post-treatment PLR, is associated with pCR. This suggested that the early changes of PLR after two cycles of NACT might serve as a more accurate predictor for chemotherapy response and pCR in breast cancer.
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Affiliation(s)
- Jiaqiang Dan
- Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Department of Breast Surgery, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan 611137, P.R. China
| | - Jingya Tan
- Department of Rheumatology and Immunology, Wenjiang District People's Hospital of Chengdu City, Chengdu, Sichuan 611137, P.R. China
| | - Junhua Huang
- Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Department of Breast Surgery, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan 611137, P.R. China
| | - Zhiying Yuan
- Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Department of Breast Surgery, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan 611137, P.R. China
| | - Yao Guo
- Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Department of Breast Surgery, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan 611137, P.R. China
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10
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Al Shboul S, El-Sadoni M, Alhesa A, Abu Shahin N, Abuquteish D, Abu Al Karsaneh O, Alsharaiah E, Ismail MA, Tyutyunyk-Massey L, Alotaibi MR, Neely V, Harada H, Saleh T. NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy. Sci Rep 2023; 13:15903. [PMID: 37741850 PMCID: PMC10517932 DOI: 10.1038/s41598-023-42994-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 09/18/2023] [Indexed: 09/25/2023] Open
Abstract
Neoadjuvant chemotherapy (NAC) is a frequently utilized approach to treat locally advanced breast cancer, but, unfortunately, a subset of tumors fails to undergo complete pathological response. Apoptosis and therapy-induced senescence (TIS) are both cell stress mechanisms but their exact role in mediating the pathological response to NAC is not fully elucidated. We investigated the change in expression of PAMIP1, the gene encoding for the pro-apoptotic protein, NOXA, following NAC in two breast cancer gene datasets, and the change in NOXA protein expression in response to NAC in 55 matched patient samples (pre- and post-NAC). PAMIP1 expression significantly declined in post-NAC in the two sets, and in our cohort, 75% of the samples exhibited a downregulation in NOXA post-NAC. Matched samples that showed a decline in NOXA post-NAC were examined for TIS based on a signature of downregulated expression of Lamin-B1 and Ki-67 and increased p16INK4a, and the majority exhibited a decrease in Lamin B1 (66%) and Ki-67 (80%), and increased p16INK4a (49%). Since our cohort consisted of patients that did not develop complete pathological response, such findings have clinical implications on the role of TIS and NOXA downregulation in mediating suboptimal responses to the currently established NAC.
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Affiliation(s)
- Sofian Al Shboul
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Mohammed El-Sadoni
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, 11942, Jordan
| | - Ahmad Alhesa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, 11942, Jordan
| | - Nisreen Abu Shahin
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, 11942, Jordan
| | - Dua Abuquteish
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Ola Abu Al Karsaneh
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Elham Alsharaiah
- Department of Pathology, King Hussein Medical Center, Royal Medical Service, Amman, 11942, Jordan
| | | | | | - Moureq R Alotaibi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Victoria Neely
- Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Hisashi Harada
- Philips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan.
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11
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Zdanowski A, Sartor H, Feldt M, Skarping I. Mammographic density in relation to breast cancer recurrence and survival in women receiving neoadjuvant chemotherapy. Front Oncol 2023; 13:1177310. [PMID: 37388229 PMCID: PMC10304818 DOI: 10.3389/fonc.2023.1177310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/30/2023] [Indexed: 07/01/2023] Open
Abstract
Objective The association between mammographic density (MD) and breast cancer (BC) recurrence and survival remains unclear. Patients receiving neoadjuvant chemotherapy (NACT) are in a vulnerable situation with the tumor within the breast during treatment. This study evaluated the association between MD and recurrence/survival in BC patients treated with NACT. Methods Patients with BC treated with NACT in Sweden (2005-2016) were retrospectively included (N=302). Associations between MD (Breast Imaging-Reporting and Data System (BI-RADS) 5th Edition) and recurrence-free/BC-specific survival at follow-up (Q1 2022) were addressed. Hazard ratios (HRs) for recurrence/BC-specific survival (BI-RADS a/b/c vs. d) were estimated using Cox regression analysis and adjusted for age, estrogen receptor status, human epidermal growth factor receptor 2 status, axillary lymph node status, tumor size, and complete pathological response. Results A total of 86 recurrences and 64 deaths were recorded. The adjusted models showed that patients with BI-RADS d vs. BI-RADS a/b/c had an increased risk of recurrence (HR 1.96 (95% confidence interval (CI) 0.98-3.92)) and an increased risk of BC-specific death (HR 2.94 (95% CI 1.43-6.06)). Conclusion These findings raise questions regarding personalized follow-up for BC patients with extremely dense breasts (BI-RADS d) pre-NACT. More extensive studies are required to confirm our findings.
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Affiliation(s)
| | - Hanna Sartor
- Department of Translational Medicine, Diagnostic Radiology, Skåne University Hospital, Lund University, Lund/Malmö, Sweden
| | - Maria Feldt
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Ida Skarping
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Lund, Sweden
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12
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Plekhanov AA, Gubarkova EV, Sirotkina MA, Sovetsky AA, Vorontsov DA, Matveev LA, Kuznetsov SS, Bogomolova AY, Vorontsov AY, Matveyev AL, Gamayunov SV, Zagaynova EV, Zaitsev VY, Gladkova ND. Compression OCT-elastography combined with speckle-contrast analysis as an approach to the morphological assessment of breast cancer tissue. BIOMEDICAL OPTICS EXPRESS 2023; 14:3037-3056. [PMID: 37342703 PMCID: PMC10278614 DOI: 10.1364/boe.489021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 06/23/2023]
Abstract
Currently, optical biopsy technologies are being developed for rapid and label-free visualization of biological tissue with micrometer-level resolution. They can play an important role in breast-conserving surgery guidance, detection of residual cancer cells, and targeted histological analysis. For solving these problems, compression optical coherence elastography (C-OCE) demonstrated impressive results based on differences in the elasticity of different tissue constituents. However, sometimes straightforward C-OCE-based differentiation is insufficient because of the similar stiffness of certain tissue components. We present a new automated approach to the rapid morphological assessment of human breast cancer based on the combined usage of C-OCE and speckle-contrast (SC) analysis. Using the SC analysis of structural OCT images, the threshold value of the SC coefficient was established to enable the separation of areas of adipose cells from necrotic cancer cells, even if they are highly similar in elastic properties. Consequently, the boundaries of the tumor bed can be reliably identified. The joint analysis of structural and elastographic images enables automated morphological segmentation based on the characteristic ranges of stiffness (Young's modulus) and SC coefficient established for four morphological structures of breast-cancer samples from patients post neoadjuvant chemotherapy (residual cancer cells, cancer stroma, necrotic cancer cells, and mammary adipose cells). This enabled precise automated detection of residual cancer-cell zones within the tumor bed for grading cancer response to chemotherapy. The results of C-OCE/SC morphometry highly correlated with the histology-based results (r =0.96-0.98). The combined C-OCE/SC approach has the potential to be used intraoperatively for achieving clean resection margins in breast cancer surgery and for performing targeted histological analysis of samples, including the evaluation of the efficacy of cancer chemotherapy.
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Affiliation(s)
- Anton A. Plekhanov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Minin and Pozharsky sq. 10/1, 603950 Nizhny Novgorod, Russia
| | - Ekaterina V. Gubarkova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Minin and Pozharsky sq. 10/1, 603950 Nizhny Novgorod, Russia
| | - Marina A. Sirotkina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Minin and Pozharsky sq. 10/1, 603950 Nizhny Novgorod, Russia
| | - Alexander A. Sovetsky
- Institute of Applied Physics of the Russian Academy of Sciences, Ulyanova st. 46, 603950 Nizhny Novgorod, Russia
| | - Dmitry A. Vorontsov
- Nizhny Novgorod Regional Oncologic Hospital, Delovaya st. 11/1, 603093 Nizhny Novgorod, Russia
| | - Lev A. Matveev
- Institute of Applied Physics of the Russian Academy of Sciences, Ulyanova st. 46, 603950 Nizhny Novgorod, Russia
| | - Sergey S. Kuznetsov
- Nizhny Novgorod Regional Oncologic Hospital, Delovaya st. 11/1, 603093 Nizhny Novgorod, Russia
| | - Alexandra Y. Bogomolova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Minin and Pozharsky sq. 10/1, 603950 Nizhny Novgorod, Russia
- Lobachevsky State University, Gagarin Avenue 23, 603950 Nizhny Novgorod, Russia
| | - Alexey Y. Vorontsov
- Nizhny Novgorod Regional Oncologic Hospital, Delovaya st. 11/1, 603093 Nizhny Novgorod, Russia
| | - Alexander L. Matveyev
- Institute of Applied Physics of the Russian Academy of Sciences, Ulyanova st. 46, 603950 Nizhny Novgorod, Russia
| | - Sergey V. Gamayunov
- Nizhny Novgorod Regional Oncologic Hospital, Delovaya st. 11/1, 603093 Nizhny Novgorod, Russia
| | - Elena V. Zagaynova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Minin and Pozharsky sq. 10/1, 603950 Nizhny Novgorod, Russia
- Lobachevsky State University, Gagarin Avenue 23, 603950 Nizhny Novgorod, Russia
| | - Vladimir Y. Zaitsev
- Institute of Applied Physics of the Russian Academy of Sciences, Ulyanova st. 46, 603950 Nizhny Novgorod, Russia
| | - Natalia D. Gladkova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Minin and Pozharsky sq. 10/1, 603950 Nizhny Novgorod, Russia
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13
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Badiginchala R, Dattatreya PS, Suresh AVS, Nirni SS, Andra VV, Bunger D, Chaturvedi A. Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension (NDLS) versus Conventional Docetaxel as Neoadjuvant and Adjuvant Therapy for Primary Operable Breast Cancer. Onco Targets Ther 2023; 16:215-225. [PMID: 37033671 PMCID: PMC10075221 DOI: 10.2147/ott.s400824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/02/2023] [Indexed: 04/03/2023] Open
Abstract
Objective Nanosomal docetaxel lipid suspension (NDLS) is a novel formulation developed to overcome toxicity issues caused by excipients (polysorbate 80 and ethanol) present in commercially available docetaxel formulation. We conducted a prospective, observational study to compare the outcomes of nanosomal docetaxel lipid suspension (NDLS)-based versus conventional docetaxel-based chemotherapy in primary operable breast cancer. Methods Sixty adult women with newly diagnosed stage IIb-III breast cancer were included. Patients received NDLS-based (n=30) or docetaxel-based (n=30) chemotherapy. Patients received (1) four cycles of preoperative doxorubicin and cyclophosphamide (AC) followed by four cycles of NDLS or docetaxel (T) and surgery (neoadjuvant AC→NDLS [n=9], or neoadjuvant AC→T [n=10]), or (2) four cycles of preoperative AC followed by surgery and postoperative NDLS or T (neoadjuvant AC→adjuvant NDLS [n=14], or neoadjuvant AC→adjuvant T [n=15]), or (3) surgery followed by postoperative AC→NDLS or T (adjuvant AC→NDLS [n=7], or adjuvant AC→T [n=5]) regimens. The study outcomes were pathological complete response (pCR) rates, clinical overall response rates (ORR), disease-free survival (DFS), overall survival (OS), and adverse event (AE) profile. Results For neoadjuvant AC→T (n=10) vs neoadjuvant AC→NDLS (n=9), the pCR rates were 100% each, and the ORR were 100% vs 88.9% (p=1.0). All patients were alive at 6 months, and the median OS was not reached. Three patients had progressive disease (T: n=2, NDLS: n=1) with a DFS of 12 weeks in all three patients. Grade 3 infusion-related reactions were seen in five patients (16.7%) in T vs none in NDLS arms. Conclusion NDLS-based neo/adjuvant chemotherapy was efficacious in the treatment of primary operable breast cancer and showed comparable pCR, ORR, DFS and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.
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Affiliation(s)
- Revathi Badiginchala
- Medical Oncology, Omega Hospitals, Hyderabad, Telangana, India
- Correspondence: Revathi Badiginchala, Omega Hospitals, L/276A, Road Number 12, MLA Colony, Banjara Hills, Hyderabad, Telangana, 500034, India, Tel +8978698260, Email
| | | | | | | | | | - Deepak Bunger
- Medical Affairs, Intas Pharmaceuticals Limited, Ahmedabad, India
| | - Alok Chaturvedi
- Medical Affairs, Intas Pharmaceuticals Limited, Ahmedabad, India
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14
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Şeber ES, İriagac Y, Çavdar E, Karaboyun K, Avcı O, Yolcu A, Gürdal SÖ, Öznur M. A logarithmic model for hormone receptor-positive and breast cancer patients treated with neoadjuvant chemotherapy. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:434-439. [PMID: 36921198 PMCID: PMC10004284 DOI: 10.1590/1806-9282.20221255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/20/2022] [Indexed: 03/12/2023]
Abstract
OBJECTIVE The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population. METHODS Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics. RESULTS A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48-6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07-5.69, p=0.034). CONCLUSION In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.
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Affiliation(s)
- Erdoğan Selçuk Şeber
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Medical Oncology - Tekirdag, Turkey
| | - Yakup İriagac
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Medical Oncology - Tekirdag, Turkey
| | - Eyyup Çavdar
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Medical Oncology - Tekirdag, Turkey
| | - Kubilay Karaboyun
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Medical Oncology - Tekirdag, Turkey
| | - Okan Avcı
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Medical Oncology - Tekirdag, Turkey
| | - Ahmet Yolcu
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Radiation Oncology - Tekirdag, Turkey
| | - Sibel Özkan Gürdal
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Surgical Oncology - Tekirdag, Turkey
| | - Meltem Öznur
- Tekirdağ Namık Kemal University, Faculty of Medicine, Department of Pathology - Tekirdag, Turkey
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Vieira C, Borges A, Pereira FF, Antunes P, Redondo P, Antunes L, Lopes JM, Gonçalves FR, Borges M, Bento MJ. Pertuzumab in Combination with Trastuzumab and Docetaxel in the Neoadjuvant Treatment for HER2-Positive Breast Cancer. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2022; 6:1-9. [PMID: 36751658 PMCID: PMC9888519 DOI: 10.36401/jipo-22-12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 12/14/2022]
Abstract
Introduction This study aims to assess safety and effectiveness of pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant treatment (NeoT) of HER2-positive breast cancer. Methods Two consecutive retrospective cohorts (n = 94, 2012-2015 and 2015-2017) of adult women with HER2-positive breast cancer, receiving NeoT at the breast clinic in Portugal (IPO-Porto), were followed. All patients had surgery and received trastuzumab as adjuvant therapy. The 2012-2015 cohort received doxorubicin, cyclophosphamide, docetaxel plus trastuzumab, whereas the 2015-2017 cohort was treated with the same protocol plus pertuzumab. Results The 2012-2015 cohort was older (median 53 years), with locally advanced tumors (48.1%), mostly hormone receptor positive (59.3%). The 2015-2017 cohort was younger (median 43 years) with 60% operable tumors. Pathologic complete response (pCR) improved in the second cohort, while maintaining a good safety profile and tolerability. Clinical staging (p = 0.001) and hormone receptor (p = 0.003) were significant predictors of pCR, but not treatment regimen (p = 0.304). Conclusion Further research with larger samples and longer follow-up is needed to understand the clinical differences. Clinical effectiveness of treatment should also be measured through overall and progression-free survival.
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Affiliation(s)
- Cláudia Vieira
- Medical Oncology Department, Instituto Português de Oncologia do Porto, Porto, Portugal
,Molecular Oncology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Andreia Borges
- Outcomes Research Lab—IPO Porto, Instituto Português de Oncologia do Porto, Porto, Portugal
,Management, Outcomes Research, and Economics in Healthcare Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Filipa F. Pereira
- Medical Oncology Department, Instituto Português de Oncologia do Porto, Porto, Portugal
| | - Pedro Antunes
- Surgical Oncology Department, Instituto Português de Oncologia do Porto, Porto, Portugal
| | - Patrícia Redondo
- Outcomes Research Lab—IPO Porto, Instituto Português de Oncologia do Porto, Porto, Portugal
,Management, Outcomes Research, and Economics in Healthcare Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Luís Antunes
- Cancer Epidemiology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
,Department of Epidemiology, Instituto Português de Oncologia do Porto, Porto, Portugal
| | - José M. Lopes
- Medical Oncology Department, Instituto Português de Oncologia do Porto, Porto, Portugal
| | | | - Marina Borges
- Outcomes Research Lab—IPO Porto, Instituto Português de Oncologia do Porto, Porto, Portugal
,Management, Outcomes Research, and Economics in Healthcare Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Maria J. Bento
- Cancer Epidemiology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
,Department of Population Studies, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
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Liang X, Chen X, Yang Z, Liao Y, Wang M, Li Y, Fan W, Dai Z, Zhang Y. Early prediction of pathological complete response to neoadjuvant chemotherapy combining DCE-MRI and apparent diffusion coefficient values in breast Cancer. BMC Cancer 2022; 22:1250. [PMID: 36460972 PMCID: PMC9716688 DOI: 10.1186/s12885-022-10315-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 11/14/2022] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION Improving the early prediction of neoadjuvant chemotherapy (NAC) efficacy in breast cancer can lead to an improved prediction of the final prognosis of patients, which would be useful for promoting individualized treatment. This study aimed to explore the value of the combination of dynamic contrast-enhanced (DCE)-MRI parameters and apparent diffusion coefficient (ADC) values in the early prediction of pathological complete response (pCR) to NAC for breast cancer. METHODS A total of 119 (range, 28-69 years) patients with biopsy-proven breast cancer who received two cycles of NAC before breast surgery were retrospectively enrolled from our hospital database. Patients were divided into pCR and non pCR groups according to their pathological responses; a total of 24 patients achieved pCR, while 95 did not. The quantitative (Ktrans; Kep; Ve; IAUC) and semiquantitative parameters (W-in; W-out; TTP) of DCE-MRI that were significantly different between groups were combined with ADC values to explore their value in the early prediction of pCR to NAC for breast cancer. The independent T test was performed to compare the differences in DCE-MRI parameters and ADC values between the two groups. Receiver operating characteristic (ROC) curves were plotted, and the area under the ROC curve (AUC), sensitivity and specificity were calculated to evaluate the performance of the prediction. RESULTS The Ktrans, Kep, IAUC, ADC, W-in and TTP values were significantly different between the pCR and non pCR groups after NAC. The AUC (0.845) and specificity (95.79%) of the combined Ktrans, Kep, IAUC and ADC values were both higher than those of the individual parameters. The combination of W-in, TTP and ADC values had the highest AUC value (0.886) in predicting pCR, with a sensitivity and specificity of 87.5% and 82.11%, respectively. CONCLUSIONS The results suggested that the combination of ADC values and quantitative and semiquantitative DCE-MRI parameters, especially the combination of W-in, TTP, and ADC values, may improve the early prediction of pCR in breast cancer.
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Affiliation(s)
- Xinhong Liang
- grid.459766.fDepartment of Radiology, Meizhou People’s Hospital, Meizhou, 514031 China
| | - Xiaofeng Chen
- grid.459766.fDepartment of Radiology, Meizhou People’s Hospital, Meizhou, 514031 China
| | - Zhiqi Yang
- grid.459766.fDepartment of Radiology, Meizhou People’s Hospital, Meizhou, 514031 China
| | | | - Mengzhu Wang
- MR Scientific Marketing, Siemens Healthineers, Guangzhou, 510620 China
| | - Yulin Li
- grid.459766.fDepartment of Radiology, Meizhou People’s Hospital, Meizhou, 514031 China
| | - Weixiong Fan
- grid.459766.fDepartment of Radiology, Meizhou People’s Hospital, Meizhou, 514031 China
| | - Zhuozhi Dai
- grid.452734.3Department of Radiology, Shantou Central Hospital, Guangdong, 515041 China
| | - Yunuo Zhang
- grid.459766.fDepartment of Oncology, Meizhou People’s Hospital, Meizhou, 514031 China
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17
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Jin X, Wang K, Shao X, Huang J. Prognostic implications of the peripheral platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in predicting pathologic complete response after neoadjuvant chemotherapy in breast cancer patients. Gland Surg 2022; 11:1057-1066. [PMID: 35800742 PMCID: PMC9253186 DOI: 10.21037/gs-22-244] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/18/2022] [Indexed: 10/20/2023]
Abstract
BACKGROUND The inflammatory response is extremely important in tumor progression, and it is very difficult to identify prognostic indicators for neoadjuvant therapy in breast cancer patients. The aim of this study was to mine the potential prognostic significance of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer patients receiving anthracycline- or taxane-based neoadjuvant chemotherapy (NACT). METHODS A total of 67 women diagnosed with breast cancer who received neoadjuvant therapy were enrolled in the study. Before starting NACT, the PLR and NLR were calculated. The optimal cutoff value was calculated using receiver operating characteristic (ROC) curve analyses, which indicated that 106.3 and 2.464 were the best cutoff values for the PLR and NLR, respectively. The optimal cutoff values for them were used to divide patients into low and high NLR groups and low and high PLR groups. Independent prognostic biomarkers and the value of PLR and NLR were assessed. The connection between the NLR/PLR and pathologic complete response (pCR), together with other clinical/pathological factors was evaluated. RESULTS Logistic regression model analyses revealed that patients with a high PLR correlated remarkably with better pCR than those with a low PLR. The results indicated that by using the cutoff value of 106.3, PLR had prognostic significance. However, there was no significant difference in NLR if analyzed separately. By combining PLR and NLR, the NLRhigh and PLRhigh subgroups achieved a significantly higher rate of pCR than the NLRIow/PLRIow subgroup [odds ratio (OR) 0.153, 95% confidence interval (CI): 0.068 to 0.876, P=0.008]. Therefore, the combination of NLRhigh/PLRhigh was an independent prognostic factor different from others, such as PLR, Ki-67, and chemotherapy regimen. CONCLUSIONS The PLR may serve as a potential marker of the efficacy of neoadjuvant therapy in breast cancer, enabling oncologists to intervene earlier. Peripheral blood NLR and PLR can reflect the immune status of patients. Indicating that an immunogenic phenotype is a good predictor of chemotherapy response and that combined studies can better identify immunophenotypes in patients.
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Affiliation(s)
- Xiaoyan Jin
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Department of Surgical Oncology, Municipal Hospital Affiliated to Taizhou University, Taizhou, China
| | - Ke Wang
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xuan Shao
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Huang
- Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Todorova VK, Byrum SD, Gies AJ, Haynie C, Smith H, Reyna NS, Makhoul I. Circulating Exosomal microRNAs as Predictive Biomarkers of Neoadjuvant Chemotherapy Response in Breast Cancer. Curr Oncol 2022; 29:613-630. [PMID: 35200555 PMCID: PMC8870357 DOI: 10.3390/curroncol29020055] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Neoadjuvant chemotherapy (NACT) is an increasingly used approach for treatment of breast cancer. The pathological complete response (pCR) is considered a good predictor of disease-specific survival. This study investigated whether circulating exosomal microRNAs could predict pCR in breast cancer patients treated with NACT. Method: Plasma samples of 20 breast cancer patients treated with NACT were collected prior to and after the first cycle. RNA sequencing was used to determine microRNA profiling. The Cancer Genome Atlas (TCGA) was used to explore the expression patterns and survivability of the candidate miRNAs, and their potential targets based on the expression levels and copy number variation (CNV) data. Results: Three miRNAs before that NACT (miR-30b, miR-328 and miR-423) predicted pCR in all of the analyzed samples. Upregulation of miR-127 correlated with pCR in triple-negative breast cancer (TNBC). After the first NACT dose, pCR was predicted by exo-miR-141, while miR-34a, exo-miR182, and exo-miR-183 predicted non-pCR. A significant correlation between the candidate miRNAs and the overall survival, subtype, and metastasis in breast cancer, suggesting their potential role as predictive biomarkers of pCR. Conclusions: If the miRNAs identified in this study are validated in a large cohort of patients, they might serve as predictive non-invasive liquid biopsy biomarkers for monitoring pCR to NACT in breast cancer.
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Affiliation(s)
- Valentina K. Todorova
- Division of Medical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
- Correspondence:
| | - Stephanie D. Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.D.B.); (A.J.G.)
| | - Allen J. Gies
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (S.D.B.); (A.J.G.)
| | - Cade Haynie
- Biology Department, Ouachita Baptist University, Arkadelphia, AR 71998, USA; (C.H.); (H.S.); (N.S.R.)
| | - Hunter Smith
- Biology Department, Ouachita Baptist University, Arkadelphia, AR 71998, USA; (C.H.); (H.S.); (N.S.R.)
| | - Nathan S. Reyna
- Biology Department, Ouachita Baptist University, Arkadelphia, AR 71998, USA; (C.H.); (H.S.); (N.S.R.)
| | - Issam Makhoul
- Division of Medical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
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19
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Virostko J, Sorace AG, Slavkova KP, Kazerouni AS, Jarrett AM, DiCarlo JC, Woodard S, Avery S, Goodgame B, Patt D, Yankeelov TE. Quantitative multiparametric MRI predicts response to neoadjuvant therapy in the community setting. Breast Cancer Res 2021; 23:110. [PMID: 34838096 PMCID: PMC8627106 DOI: 10.1186/s13058-021-01489-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/17/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The purpose of this study was to determine whether advanced quantitative magnetic resonance imaging (MRI) can be deployed outside of large, research-oriented academic hospitals and into community care settings to predict eventual pathological complete response (pCR) to neoadjuvant therapy (NAT) in patients with locally advanced breast cancer. METHODS Patients with stage II/III breast cancer (N = 28) were enrolled in a multicenter study performed in community radiology settings. Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW)-MRI data were acquired at four time points during the course of NAT. Estimates of the vascular perfusion and permeability, as assessed by the volume transfer rate (Ktrans) using the Patlak model, were generated from the DCE-MRI data while estimates of cell density, as assessed by the apparent diffusion coefficient (ADC), were calculated from DW-MRI data. Tumor volume was calculated using semi-automatic segmentation and combined with Ktrans and ADC to yield bulk tumor blood flow and cellularity, respectively. The percent change in quantitative parameters at each MRI scan was calculated and compared to pathological response at the time of surgery. The predictive accuracy of each MRI parameter at different time points was quantified using receiver operating characteristic curves. RESULTS Tumor size and quantitative MRI parameters were similar at baseline between groups that achieved pCR (n = 8) and those that did not (n = 20). Patients achieving a pCR had a larger decline in volume and cellularity than those who did not achieve pCR after one cycle of NAT (p < 0.05). At the third and fourth MRI, changes in tumor volume, Ktrans, ADC, cellularity, and bulk tumor flow from baseline (pre-treatment) were all significantly greater (p < 0.05) in the cohort who achieved pCR compared to those patients with non-pCR. CONCLUSIONS Quantitative analysis of DCE-MRI and DW-MRI can be implemented in the community care setting to accurately predict the response of breast cancer to NAT. Dissemination of quantitative MRI into the community setting allows for the incorporation of these parameters into the standard of care and increases the number of clinical community sites able to participate in novel drug trials that require quantitative MRI.
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Affiliation(s)
- John Virostko
- Department of Diagnostic Medicine, University of Texas at Austin, Austin, TX, 78712, USA
- Livestrong Cancer Institutes, University of Texas at Austin, Austin, TX, USA
- Department of Oncology, University of Texas at Austin, Austin, TX, USA
- Oden Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA
| | - Anna G Sorace
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kalina P Slavkova
- Department of Physics, University of Texas at Austin, Austin, TX, USA
| | - Anum S Kazerouni
- Department of Radiology, University of Washington, Seattle, WA, USA
| | - Angela M Jarrett
- Oden Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA
| | - Julie C DiCarlo
- Livestrong Cancer Institutes, University of Texas at Austin, Austin, TX, USA
- Oden Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA
| | - Stefanie Woodard
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sarah Avery
- Austin Radiological Association, Austin, TX, USA
| | - Boone Goodgame
- Dell Seton Medical Center at the University of Texas, Austin, USA
| | | | - Thomas E Yankeelov
- Department of Diagnostic Medicine, University of Texas at Austin, Austin, TX, 78712, USA.
- Livestrong Cancer Institutes, University of Texas at Austin, Austin, TX, USA.
- Department of Oncology, University of Texas at Austin, Austin, TX, USA.
- Oden Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA.
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
- Department of Imaging Physics, MD Anderson Cancer Center, Houston, TX, USA.
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20
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Dhamija E, Singh R, Mishra S, Hari S. Image-Guided Breast Interventions: Biopsy and Beyond. Indian J Radiol Imaging 2021; 31:391-399. [PMID: 34556924 PMCID: PMC8448213 DOI: 10.1055/s-0041-1734223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Breast interventions primarily comprise of biopsy of the suspicious breast lesions to obtain accurate pathological diagnosis. Generally, image-guided breast biopsy is required for nonpalpable lesions, however, even in palpable lesions, image-guided biopsy should be performed as it improves the accuracy of diagnosis. Image-guided breast interventions have progressed well beyond biopsy, making the radiologist an important part of the multidisciplinary management of breast cancer. Preoperative localization of nonpalpable abnormalities guides optimal surgical excision to obtain negative margins without sacrificing the normal tissue. Ablative procedures for breast cancer treatment such as radiofrequency ablation (RFA) and high-intensity focused ultrasound ablation can sometimes replace surgery in older patients with comorbidities. This article enumerates and describes the expanding spectrum of image-guided interventions performed by breast radiologist.
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Affiliation(s)
- Ekta Dhamija
- Department of Radiodiagnosis, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Rashmi Singh
- Department of Radiodiagnosis, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Seema Mishra
- Department of Oncoanaesthesia & Palliative Medicine, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Smriti Hari
- Department of Radiodiagnosis, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
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21
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Kim R, Kin T. Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer. Cancers (Basel) 2021; 13:cancers13194756. [PMID: 34638242 PMCID: PMC8507525 DOI: 10.3390/cancers13194756] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary How a cure for primary breast cancer after (neo)adjuvant therapy can be achieved at the molecular level remains unclear. Immune activation by anticancer drugs may contribute to the eradication of residual tumor cells by postoperative (neo)adjuvant chemotherapy. In addition, chemotherapy-induced immunogenic cell death (ICD) may result in long-term immune activation by memory effector T cells, leading to the curing of primary breast cancer. In this review, we discuss the molecular mechanisms by which anticancer drugs induce ICD and immunogenic modifications for antitumor immunity and targeted therapy against damage-associated molecular patterns. Our aim was to gain a better understanding of how to eradicate residual tumor cells treated with anticancer drugs and cure primary breast cancer by enhancing antitumor immunity with immune checkpoint inhibitors and vaccines. Abstract How primary breast cancer can be cured after (neo)adjuvant therapy remains unclear at the molecular level. Immune activation by anticancer agents may contribute to residual tumor cell eradication with postsurgical (neo)adjuvant chemotherapy. Chemotherapy-induced immunogenic cell death (ICD) may result in long-term immune activation with memory effector T cells, leading to a primary breast cancer cure. Anthracycline and taxane treatments cause ICD and immunogenic modulations, resulting in the activation of antitumor immunity through damage-associated molecular patterns (DAMPs), such as adenosine triphosphate, calreticulin, high mobility group box 1, heat shock proteins 70/90, and annexin A1. This response may eradicate residual tumor cells after surgical treatment. Although DAMP release is also implicated in tumor progression, metastasis, and drug resistance, thereby representing a double-edged sword, robust immune activation by anticancer agents and the subsequent acquisition of long-term antitumor immune memory can be essential components of the primary breast cancer cure. This review discusses the molecular mechanisms by which anticancer drugs induce ICD and immunogenic modifications for antitumor immunity and targeted anti-DAMP therapy. Our aim was to improve the understanding of how to eradicate residual tumor cells treated with anticancer drugs and cure primary breast cancer by enhancing antitumor immunity with immune checkpoint inhibitors and vaccines.
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Affiliation(s)
- Ryungsa Kim
- Department of Breast Surgery, Hiroshima Mark Clinic, 1-4-3F, 2-Chome Ohte-machi, Naka-ku, Hiroshima 730-0051, Japan
- Correspondence:
| | - Takanori Kin
- Department of Breast Surgery, Hiroshima City Hospital, 7-33, Moto-machi, Naka-ku, Hiroshima 730-8518, Japan;
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22
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Oshi M, Gandhi S, Huyser MR, Tokumaru Y, Yan L, Yamada A, Matsuyama R, Endo I, Takabe K. MELK expression in breast cancer is associated with infiltration of immune cell and pathological compete response (pCR) after neoadjuvant chemotherapy. Am J Cancer Res 2021; 11:4421-4437. [PMID: 34659896 PMCID: PMC8493385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/20/2021] [Indexed: 06/13/2023] Open
Abstract
In experimental settings, maternal embryonic leucine zipper kinase (MELK), an apical member of the snf1/AMPK serine-threonine kinases family, plays a role in tumor growth. We investigated the clinical relevance of MELK expression by performing silico analyses of 7,135 breast cancer patients using multiple independent large cohorts. In triple negative breast cancer (TNBC) found that elevated MELK expression significantly correlates with Nottingham histologic grade and tumor growth according to American Joint Committee Cancer (AJCC) stage. High MELK tumor enriched cell proliferation-related gene sets as well as DNA repair, unfolded protein response, and MTORC signaling gene sets. In two independent cohorts a high mutation rate and worse survival was significantly associated with high MELK tumor. In immune-related gene sets including, allograft rejection, interferon (IFN)-α response, and IFN-γ response, high MELK tumor significantly enriched. Pro-cancer regulatory T cells, T helper type 2 cells and anti-cancer immune cells including CD4+ memory T cells, T helper type1 cells, CD8+ T cells, M1 macrophages, gamma-delta T cells, and dendritic cells with high levels of cytolytic activity (CYT) were highly infiltrated. MELK expression did not correlate with the responses to any of the drugs tested in cell lines. However, pathologic complete response was significantly associated with high MELK following NAC in both TNBC and ER-positive plus HER2-negative breast cancer. In conclusion, cell proliferation, immune response, and NAC breast cancer response was associated with MELK expression.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer CenterElm & Carlton Streets, Buffalo, NY 14263, USA
| | - Michelle R Huyser
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Akimitsu Yamada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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23
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Borges A, Pereira F, Redondo P, Antunes L, Vieira C, Antunes P, Bento MJ, Sousa S, Lopes JM, Rocha-Gonçalves F, de Sousa JA, Pereira DS, Borges M. The addition of neoadjuvant pertuzumab for the treatment of HER2+ breast cancer: a cost estimate with real-world data. HEALTH ECONOMICS REVIEW 2021; 11:33. [PMID: 34505956 PMCID: PMC8431932 DOI: 10.1186/s13561-021-00332-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 08/27/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Breast cancer (BC) is largely prevalent worldwide. HER2-positive BC account for roughly 20-25% of all BC cases and has an overall survival lower than other BC. Innovation on BC therapeutics is a constant, but novel therapies have higher costs. Therefore, cost-effectiveness research is essential to provide healthcare decision-makers with solid foundations for a resource allocation. This study aims to estimate the average direct medical costs/patient and cost-effectiveness of adding pertuzumab in neoadjuvant treatment (NeoT) for HER2-positive breast cancer (BC). METHODS Two retrospective real-world consecutive cohorts of ≥18yo female patients diagnosed with HER2-positive BC treated with NeoT at the Breast Clinic of IPO-Porto were studied. The AC-DH regimen (2012-2015) comprised 8 cycles of neoadjuvant therapy (4 cycles of doxorubicin + cyclosphosphamide followed by 4 cycles ofdocetaxel + trastuzumab), while the AC-DHP regimen (2015-2017) included also pertuzumab as NeoT. NeoT was followed by surgery and adjuvant trastuzumab. Micro-costing technique and a bottom-up approach was used comprising all medical direct costs from the hospital perspective. Unit costs were obtained from government official prices or from IPO-Porto costing system. Costs were adjusted to 2017 and are expressed in euros. Multivariable logistic regression models were used for effectiveness assessment, while generalized linear models with gamma distribution were used for costs. ICER was calculated using the pathological complete response (pCR) as the preferential measure of effectiveness. Sensitivity analysis was also performed. RESULTS AC-DHP (n = 40) and AC-DH (n = 54) cohorts had heterogenous patient profiles (median age 43y/53y; 67.5%/59.3% positive HR; 60.0%/27.8% operable; 25.0%/24.1% inflammatory, respectively). The AC-DHP average total cost/patient was 56,375€, with pertuzumab accounting for 13,978€ (24.79%) and increasing in 15,982€ the average cost/patient (p < 0.001). Clinical staging and hormone receptors (HR) were significantly associated with pCR. ICER was 1.370€ per percentage point of pCR. CONCLUSIONS ICER was more favourable in stage III HR negative BC patients compared to other patient profiles. Innovative treatments access is critical to deliver high-quality healthcare, but sustainability must be considered. These results suggest the importance of establishing a cost-effectiveness profile of Pertuzumab in NeoT for HER2-positive BC.
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Affiliation(s)
- Andreia Borges
- Outcomes Research Lab, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Management, Outcomes Research, and Economics in Healthcare Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Filipa Pereira
- Medical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Patrícia Redondo
- Outcomes Research Lab, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Management, Outcomes Research, and Economics in Healthcare Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Luís Antunes
- Department of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Cancer Epidemiology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Cláudia Vieira
- Medical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Molecular Oncology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Pedro Antunes
- Surgical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Maria José Bento
- Department of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Cancer Epidemiology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Department of Population Studies, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Susana Sousa
- Medical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - José Machado Lopes
- Outcomes Research Lab, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | | | - Joaquim Abreu de Sousa
- Surgical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Deolinda Sousa Pereira
- Medical Oncology Department, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Marina Borges
- Outcomes Research Lab, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
- Management, Outcomes Research, and Economics in Healthcare Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
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Khazindar AR, Hashem DAL, Abusanad A, Bakhsh SI, Bin Mahfouz A, El-Diasty MT. Diagnostic Accuracy of MRI in Evaluating Response After Neoadjuvant Systemic Therapy in Operable Breast Cancer. Cureus 2021; 13:e15516. [PMID: 34123680 PMCID: PMC8189538 DOI: 10.7759/cureus.15516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background Neoadjuvant chemotherapy (NAC) is an important step in the treatment of various types of breast cancer by downsizing the tumor to make it operable. Determining disease extent after NAC is essential for accurate surgical planning. MRI has been the gold standard for detecting tumors that are usually difficult to detect on ultrasound or mammography. However, the use of MRI after NAC is controversial. Therefore, we aimed to evaluate the diagnostic accuracy of post-NAC MRI in the detection of residual disease preoperatively and to investigate the factors associated with pathological complete response (pCR). Methodology This retrospective review study was approved by the institutional review board with waiving of the informed consent. A total of 90 charts between January 2016 and January 2019 were reviewed. Baseline lesion size was measured as the maximal diameter in a single dimension by pretreatment MRI. To assess the diagnostic accuracy of MRI in detecting residual disease, we used two different definitions of pCR in the breast. The first is the resolution of both invasive disease and ductal carcinoma in situ. The second is the resolution of the invasive disease only. As a secondary objective of the study, we assessed the association between different patients’ characteristics and both MRI and pathologic response using univariate and multivariate analysis. Results A total of 52 women (mean age: 47.4 years; range: 28-74) with 56 breast masses were eligible for the study. Complete MRI response was noted in 22 (39%) masses. pCR was achieved in 14 (25%) and 25 (44.6%) masses using the first and second pCR definitions, respectively. The negative predictive value (NPV) and overall accuracy of MRI for detecting residual disease were 50% and 75%, respectively, using the first pCR definition. With the second pCR definition, NPV and accuracy were 77.3% and 76.8%, respectively. Positive axillary lymph nodes were the only significant factor associated with incomplete MRI and pathological responses. Conclusions MRI NPV for residual disease was higher with the second pCR definition; however, overall accuracy was not different. MRI accuracy in detecting residual disease after NAC is not adequate to replace pathological assessment.
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Affiliation(s)
| | | | - Atlal Abusanad
- Department of Medicine, King Abdulaziz University, Jeddah, SAU
| | - Salwa I Bakhsh
- Department of Pathology, King Abdulaziz University, Jeddah, SAU
| | - Alya Bin Mahfouz
- Department of Radiology, King Abdulaziz University Hospital, Jeddah, SAU
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Prognostic Impact of Ki-67 Change in Locally Advanced and Early Breast Cancer after Neoadjuvant Chemotherapy: A Single Institution Experience. JOURNAL OF ONCOLOGY 2021; 2021:5548252. [PMID: 34054952 PMCID: PMC8112947 DOI: 10.1155/2021/5548252] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/26/2021] [Indexed: 02/05/2023]
Abstract
Systemic neoadjuvant chemotherapy (NCT) is a standard treatment for locally advanced breast cancer (LABC) and for selected early breast cancer (EBC). In these settings, the prognostic and predictive role of Ki-67 before and after NCT is unclear. The aim of our study was to investigate the prognostic role of Ki-67 change in patients not achieving pathological complete response (pCR). We retrospectively analyzed data of patients who did not achieve pCR assessing Ki-67 expression pre- and post-NCT. We stratified three groups: high reduction (>20%), low reduction (1–20%), and no reduction in Ki-67. These groups were correlated with clinical and pathological data by χ2 test. We estimated disease-free survival (DFS) and overall survival (OS) using Kaplan–Meier method, and we adopted univariate and multivariate Cox proportional hazard models. We selected 82 patients from a database of 143 patients, excluding those who were metastatic at diagnosis, achieved pCR, or lack data regarding Ki-67. Median age at diagnosis was 54 years (range 30–75); 51 patients were Luminal B, 10 human epidermal growth factor receptor 2 (HER-2) enriched, and 21 triple negative. A significant correlation between high Ki-67 reduction and luminal B HER-2-negative subtype was observed (p = 0,0035). The change in Ki-67 was significantly associated with DFS (p = 0,0596) and OS (p = 0,0120), also at multivariate analysis (p = 0,0256 for DFS; p = 0,0093 for OS). In particular, as compared to patients with low/no reduction of Ki-67, those with high Ki-67 reduction (>20%) after NCT showed better survival (60% vs. 56% vs. 83% after 5 years from diagnosis, respectively; p = 0.01). In conclusion, in our study, Ki-67 change showed a significant prognostic role in breast cancer patients treated with NCT who did not achieve pCR. Crucially, Ki-67 < 20% identifies a high-risk population that may be eligible for clinical trials with novel therapeutic interventions in adjuvant setting.
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Abd El Khalek S, Mohammed M, Hafez F. Predictive value of Ki67 for complete pathological response to neoadjuvant chemotherapy in patients with breast cancer. EGYPTIAN JOURNAL OF PATHOLOGY 2021; 41:194. [DOI: 10.4103/egjp.egjp_55_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Oshi M, Newman S, Murthy V, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K. ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer. Cancers (Basel) 2020; 12:E2758. [PMID: 32992708 PMCID: PMC7601042 DOI: 10.3390/cancers12102758] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/20/2020] [Accepted: 09/22/2020] [Indexed: 12/20/2022] Open
Abstract
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is a negative regulator of T cell activation, and reduction in ITPKC function is known to promote Kawasaki disease. Given the role of tumor infiltrating lymphocytes in NAC and since TNBC has the most abundant immune cell infiltration in breast cancer, we hypothesized that the ITPKC expression level is associated with NAC response and prognosis in TNBC. The ITPKC gene was expressed in the mammary gland, but its expression was highest in breast cancer cells among other stromal cells in a bulk tumor. ITPKC expression was highest in TNBC, associated with its survival, and was its independent prognostic factor. Although high ITPKC was not associated with immune function nor with any immune cell fraction, low ITPKC significantly enriched cell proliferation-related gene sets in TNBC. TNBC with low ITPKC achieved a significantly higher pCR rate after NAC. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in TNBC.
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Affiliation(s)
- Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (S.N.); (V.M.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Stephanie Newman
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (S.N.); (V.M.); (Y.T.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, NY 14263, USA
| | - Vijayashree Murthy
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (S.N.); (V.M.); (Y.T.)
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (S.N.); (V.M.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (S.N.); (V.M.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, New York, NY 14263, USA
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Woitek R, McLean MA, Gill AB, Grist JT, Provenzano E, Patterson AJ, Ursprung S, Torheim T, Zaccagna F, Locke M, Laurent MC, Hilborne S, Frary A, Beer L, Rundo L, Patterson I, Slough R, Kane J, Biggs H, Harrison E, Lanz T, Basu B, Baird R, Sala E, Graves MJ, Gilbert FJ, Abraham JE, Caldas C, Brindle KM, Gallagher FA. Hyperpolarized 13C MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer. Radiol Imaging Cancer 2020; 2:e200017. [PMID: 32803167 PMCID: PMC7398116 DOI: 10.1148/rycan.2020200017] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/24/2020] [Accepted: 04/15/2020] [Indexed: 04/12/2023]
Abstract
Purpose To compare hyperpolarized carbon 13 (13C) MRI with dynamic contrast material-enhanced (DCE) MRI in the detection of early treatment response in breast cancer. Materials and Methods In this institutional review board-approved prospective study, a woman with triple-negative breast cancer (age, 49 years) underwent 13C MRI after injection of hyperpolarized [1-carbon 13 {13C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The 13C-labeled lactate-to-pyruvate ratio derived from hyperpolarized 13C MRI and the pharmacokinetic parameters transfer constant (K trans) and washout parameter (k ep) derived from DCE MRI were compared before and after treatment. Results Exchange of the 13C label between injected hyperpolarized [1-13C]-pyruvate and the endogenous lactate pool was observed, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the 13C-labeled lactate-to-pyruvate ratio resulted in correct identification of the patient as a responder to therapy, which was subsequently confirmed via a complete pathologic response. However, DCE MRI showed an increase in mean K trans (132%) and mean k ep (31%), which could be incorrectly interpreted as a poor response to treatment. Conclusion Hyperpolarized 13C MRI enabled successful identification of breast cancer response after one cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI.Published under a CC BY 4.0 license.
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Affiliation(s)
- Ramona Woitek
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Mary A. McLean
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Andrew B. Gill
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - James T. Grist
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Elena Provenzano
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Andrew J. Patterson
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Stephan Ursprung
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Turid Torheim
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Fulvio Zaccagna
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Matthew Locke
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Marie-Christine Laurent
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Sarah Hilborne
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Amy Frary
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Lucian Beer
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Leonardo Rundo
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Ilse Patterson
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Rhys Slough
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Justine Kane
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Heather Biggs
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Emma Harrison
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Titus Lanz
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Bristi Basu
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Richard Baird
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Evis Sala
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Martin J. Graves
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Fiona J. Gilbert
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Jean E. Abraham
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Carlos Caldas
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Kevin M. Brindle
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
| | - Ferdia A. Gallagher
- From the Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.)
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Zhang C, Xiong J, Lan Y, Wu J, Wang C, Huang Z, Lin J, Xie J. Novel cucurmosin-based immunotoxin targeting programmed cell death 1-ligand 1 with high potency against human tumor in vitro and in vivo. Cancer Sci 2020; 111:3184-3194. [PMID: 32589330 PMCID: PMC7469839 DOI: 10.1111/cas.14549] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/14/2020] [Accepted: 06/23/2020] [Indexed: 12/30/2022] Open
Abstract
Immunotoxins are Ab‐cytotoxin chimeric molecules with mighty cytotoxicity. Programmed cell death 1‐ligand 1 (PD‐L1), is a transmembrane protein expressed mainly in inflammatory tumor tissues and plays a pivotal role in immune escape and tumor progression. Although PD‐L1 immune checkpoint therapy has been successful in some cases, many patients have not benefited enough due to primary/secondary resistance. In order to optimize the therapeutic efficacy of anti‐PD‐L1 mAb, we used durvalumab as the payload and CUS245C, a type I ribosome‐inactivating protein isolated from Cucurbita moschata, as the toxin moiety, to construct PD‐L1‐specific immunotoxin (named D‐CUS245C) through the engineered cysteine residue. In vitro, D‐CUS245C selectively killed PD‐L1+ tumor cells. In vivo studies also showed that D‐CUS245C had obvious antitumor effect on PD‐L1+ human xenograft tumors in nude mice. In conclusion, in the combination of the toxin with mAb, this study developed a new immunotoxin targeting PD‐L1, emphasizing a novel and promising treatment strategy and providing a valuable way to optimize cancer immunotherapy.
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Affiliation(s)
- Caiyun Zhang
- Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China
| | - Jiani Xiong
- Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China.,Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Yinxiang Lan
- Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China
| | - Jingyu Wu
- Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China
| | - Chengyan Wang
- Institute of Laboratory Animal Center, Fujian Medical University, Fuzhou, China
| | - Zhihong Huang
- Public Technology Service Center, Fujian Meidcal University, Fuzhou, China
| | - Jizhen Lin
- The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Jieming Xie
- Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China
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30
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Quiaoit K, DiCenzo D, Fatima K, Bhardwaj D, Sannachi L, Gangeh M, Sadeghi-Naini A, Dasgupta A, Kolios MC, Trudeau M, Gandhi S, Eisen A, Wright F, Look-Hong N, Sahgal A, Stanisz G, Brezden C, Dinniwell R, Tran WT, Yang W, Curpen B, Czarnota GJ. Quantitative ultrasound radiomics for therapy response monitoring in patients with locally advanced breast cancer: Multi-institutional study results. PLoS One 2020; 15:e0236182. [PMID: 32716959 PMCID: PMC7384762 DOI: 10.1371/journal.pone.0236182] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neoadjuvant chemotherapy (NAC) is the standard of care for patients with locally advanced breast cancer (LABC). The study was conducted to investigate the utility of quantitative ultrasound (QUS) carried out during NAC to predict the final tumour response in a multi-institutional setting. METHODS Fifty-nine patients with LABC were enrolled from three institutions in North America (Sunnybrook Health Sciences Centre (Toronto, Canada), MD Anderson Cancer Centre (Texas, USA), and Princess Margaret Cancer Centre (Toronto, Canada)). QUS data were collected before starting NAC and subsequently at weeks 1 and 4 during chemotherapy. Spectral tumour parametric maps were generated, and textural features determined using grey-level co-occurrence matrices. Patients were divided into two groups based on their pathological outcomes following surgery: responders and non-responders. Machine learning algorithms using Fisher's linear discriminant (FLD), K-nearest neighbour (K-NN), and support vector machine (SVM-RBF) were used to generate response classification models. RESULTS Thirty-six patients were classified as responders and twenty-three as non-responders. Among all the models, SVM-RBF had the highest accuracy of 81% at both weeks 1 and week 4 with area under curve (AUC) values of 0.87 each. The inclusion of week 1 and 4 features led to an improvement of the classifier models, with the accuracy and AUC from baseline features only being 76% and 0.68, respectively. CONCLUSION QUS data obtained during NAC reflect the ongoing treatment-related changes during chemotherapy and can lead to better classifier performances in predicting the ultimate pathologic response to treatment compared to baseline features alone.
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Affiliation(s)
- Karina Quiaoit
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Daniel DiCenzo
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Kashuf Fatima
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Divya Bhardwaj
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Lakshmanan Sannachi
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Mehrdad Gangeh
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Ali Sadeghi-Naini
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Department of Electrical Engineering and Computer Sciences, Lassonde School of Engineering, York University, Toronto, Canada
| | - Archya Dasgupta
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | | | - Maureen Trudeau
- Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Sonal Gandhi
- Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Andrea Eisen
- Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Frances Wright
- Surgical Oncology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Nicole Look-Hong
- Surgical Oncology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Arjun Sahgal
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Greg Stanisz
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Christine Brezden
- Department of Medical Oncology, Saint Michael's Hospital, University of Toronto, Toronto, Canada
| | - Robert Dinniwell
- Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Canada
- Department of Radiation Oncology, London Health Sciences Centre, London, Canada
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - William T. Tran
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Evaluative Clinical Sciences, Sunnybrook Research Institute, Toronto, Canada
| | - Wei Yang
- Department of Diagnostic Radiology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Belinda Curpen
- Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Medical Imaging, University of Toronto, Toronto, Canada
| | - Gregory J. Czarnota
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Canada
- Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Department of Electrical Engineering and Computer Sciences, Lassonde School of Engineering, York University, Toronto, Canada
- Department of Physics, Ryerson University, Toronto, Canada
- * E-mail:
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31
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Gallagher FA, Woitek R, McLean MA, Gill AB, Manzano Garcia R, Provenzano E, Riemer F, Kaggie J, Chhabra A, Ursprung S, Grist JT, Daniels CJ, Zaccagna F, Laurent MC, Locke M, Hilborne S, Frary A, Torheim T, Boursnell C, Schiller A, Patterson I, Slough R, Carmo B, Kane J, Biggs H, Harrison E, Deen SS, Patterson A, Lanz T, Kingsbury Z, Ross M, Basu B, Baird R, Lomas DJ, Sala E, Wason J, Rueda OM, Chin SF, Wilkinson IB, Graves MJ, Abraham JE, Gilbert FJ, Caldas C, Brindle KM. Imaging breast cancer using hyperpolarized carbon-13 MRI. Proc Natl Acad Sci U S A 2020; 117:2092-2098. [PMID: 31964840 PMCID: PMC6995024 DOI: 10.1073/pnas.1913841117] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.
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Affiliation(s)
- Ferdia A Gallagher
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Ramona Woitek
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom;
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Mary A McLean
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Andrew B Gill
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Raquel Manzano Garcia
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Elena Provenzano
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
- Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Frank Riemer
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Joshua Kaggie
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Anita Chhabra
- Pharmacy Department, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom
| | - Stephan Ursprung
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - James T Grist
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Charlie J Daniels
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Fulvio Zaccagna
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | | | - Matthew Locke
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Sarah Hilborne
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Amy Frary
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Turid Torheim
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Chris Boursnell
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Amy Schiller
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Ilse Patterson
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Rhys Slough
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Bruno Carmo
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Justine Kane
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Heather Biggs
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emma Harrison
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Surrin S Deen
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Andrew Patterson
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Titus Lanz
- RAPID Biomedical GmbH, 97222 Rimpar, Germany
| | - Zoya Kingsbury
- Medical Genomics Research, Illumina, Great Abington, Cambridge CB21 6DF, United Kingdom
| | - Mark Ross
- Medical Genomics Research, Illumina, Great Abington, Cambridge CB21 6DF, United Kingdom
| | - Bristi Basu
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Richard Baird
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - David J Lomas
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Evis Sala
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - James Wason
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Institute of Health and Society, Newcastle University, Newcastle-upon-Tyne NE2 4AX, United Kingdom
| | - Oscar M Rueda
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Suet-Feung Chin
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Ian B Wilkinson
- Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Martin J Graves
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jean E Abraham
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
- Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Fiona J Gilbert
- Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
- Department of Radiology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Carlos Caldas
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cambridge Breast Cancer Research Unit, Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom
- Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Kevin M Brindle
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Department of Biochemistry, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
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32
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Hong T, Ding J, Li W. miR-7 Reverses Breast Cancer Resistance To Chemotherapy By Targeting MRP1 And BCL2. Onco Targets Ther 2019; 12:11097-11105. [PMID: 31908478 PMCID: PMC6924589 DOI: 10.2147/ott.s213780] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 10/07/2019] [Indexed: 01/01/2023] Open
Abstract
Background MicroRNAs (miRNAs) are a class of non‐coding RNAs that have been linked with breast cancer chemoresistance, which is a major clinical problem causing disease relapse and poor prognosis. miR-7 exerts several tumor suppressive activities. Purpose This study was designed to clarify whether and how miR-7 regulates breast cancer chemoresistance. Methods miR-7 level in breast cancer was determined by qRT-PCR analysis. Cell viability was assessed by MTS assay to quantify the IC50 value of paclitaxel and carboplatin. The targets of miR-7 were confirmed by luciferase reporter assay. Results Higher miR-7 expression predicts better pathological complete response (pCR) of breast cancer patients receiving paclitaxel/carboplatin chemotherapy. In vitro, miR-7 sensitizes breast cancer cell lines (MCF-7 and MDA-MB-231) to paclitaxel and carboplatin, alone and in combination. In addition, we reveal that both the multidrug resistance-associated protein 1 (MRP1) and anti-apoptotic B cell lymphoma 2 (BCL2) are targets of miR-7 in breast cancer cells. Furthermore, miR-7-induced sensitization of breast cancer to paclitaxel/carboplatin is markedly reversed by restoration of MRP1 and BCL2. Conclusion These findings show that miR-7 reverses breast cancer chemoresistance through suppressing MRP1 and BCL2, and also suggest that miR-7 may possess a predictive value and represent a therapeutic target in breast cancer chemotherapy.
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Affiliation(s)
- Tianzi Hong
- Department of Thyroid and Breast Surgery, Jinjiang Hospital of Quanzhou Medical College, Jinjiang 362200, People's Republic of China
| | - Jian Ding
- Department of Breast Surgery, Zhongshan Hospital of Xiamen University, Xiamen 361004, People's Republic of China
| | - Wenlian Li
- Department of Breast Surgery, Zhongshan Hospital of Xiamen University, Xiamen 361004, People's Republic of China
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Omarini C, Palumbo P, Pecchi A, Draisci S, Balduzzi S, Nasso C, Barbolini M, Isca C, Bocconi A, Moscetti L, Galetti S, Tazzioli G, Torricelli P, Cascinu S, Piacentini F. Predictive Role Of Body Composition Parameters In Operable Breast Cancer Patients Treated With Neoadjuvant Chemotherapy. Cancer Manag Res 2019; 11:9563-9569. [PMID: 32009814 PMCID: PMC6859164 DOI: 10.2147/cmar.s216034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/04/2019] [Indexed: 01/16/2023] Open
Abstract
Background Fat tissue is strongly involved in BC tumorigenesis inducing insulin resistance, chronic inflammation and hormonal changes. Computed tomography (CT) imaging instead of body mass index (BMI) gives a reliable measure of skeletal muscle mass and body fat distribution. The impact of body composition parameters (BCPs) on chemosensitivity is still debated. We examined the associations between BCPs and tumor response to neoadjuvant chemotherapy (NC) in patients treated for operable breast cancer (BC). Methods A retrospective review of BC patients treated with NC in Modena Cancer Center between 2005 and 2017 was performed. BCPs, such as subcutaneous fat area (SFA), visceral fat area (VFA), lumbar skeletal muscle index (LSMI) and liver-to-spleen (L/S) ratio were calculated by Advance workstation (General Electric), software ADW server 3.2 or 4.7. BMI and BCPs were correlated with pathological complete response (pCR) and survival outcomes. Results 407 patients were included in the study: 55% with BMI < 25 and 45% with BMI ≥ 25. 137 of them had pre-treatment CT scan imagines. Overweight was significantly associated with postmenopausal status and older age. Hormonal receptor positive BC was more frequent in overweight patients (p<0.05). Postmenopausal women had higher VFA, fatty liver disease and obesity compared to premenopausal patients. No association between BMI classes and tumor response was detected. High VFA and liver steatosis were negative predictive factors for pCR (pCR rate: 36% normal VFA vs 20% high VFA, p= 0.048; no steatosis 32% vs steatosis 13%, p=0.056). Neither BMI classes nor BCPs significantly influenced overall survival and relapse-free survival. Conclusion Visceral adiposity as well as steatosis were closely involved in chemosensitivity in BC patients treated with NC. Their measures from clinically acquired CT scans provide significant predictive information that outperform BMI value. More research is required to evaluate the relationship among adiposity site and survival outcomes.
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Affiliation(s)
- Claudia Omarini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Patrizia Palumbo
- Division of Clinical Nutrition and Metabolism, Department of Specialist Medicines, University Hospital of Modena, Modena, Italy
| | - Annarita Pecchi
- Department of Radiology, University Hospital of Modena, Modena, Italy
| | - Stefano Draisci
- Department of Radiology, University Hospital of Modena, Modena, Italy
| | - Sara Balduzzi
- Statistics Unit, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Cecilia Nasso
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Monica Barbolini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Chrystel Isca
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Alessandro Bocconi
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Luca Moscetti
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Silvia Galetti
- Division of Clinical Nutrition and Metabolism, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Giovanni Tazzioli
- Department of General Surgery and Surgical Specialities, University Hospital of Modena, Modena, Italy
| | - Pietro Torricelli
- Department of Radiology, University Hospital of Modena, Modena, Italy
| | - Stefano Cascinu
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Federico Piacentini
- Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
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Abdel-Fatah TMA, Ali R, Sadiq M, Moseley PM, Mesquita KA, Ball G, Green AR, Rakha EA, Chan SYT, Madhusudan S. ERCC1 Is a Predictor of Anthracycline Resistance and Taxane Sensitivity in Early Stage or Locally Advanced Breast Cancers. Cancers (Basel) 2019; 11:cancers11081149. [PMID: 31405143 PMCID: PMC6721618 DOI: 10.3390/cancers11081149] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/30/2019] [Accepted: 08/08/2019] [Indexed: 01/12/2023] Open
Abstract
Genomic instability could be a beneficial predictor for anthracycline or taxane chemotherapy. We interrogated 188 DNA repair genes in the METABRIC cohort (n = 1980) to identify genes that influence overall survival (OS). We then evaluated the clinicopathological significance of ERCC1 in early stage breast cancer (BC) (mRNA expression (n = 4640) and protein level, n = 1650 (test set), and n = 252 (validation)) and in locally advanced BC (LABC) (mRNA expression, test set (n = 2340) and validation (TOP clinical trial cohort, n = 120); and protein level (n = 120)). In the multivariate model, ERCC1 was independently associated with OS in the METABRIC cohort. In ER+ tumours, low ERCC1 transcript or protein level was associated with increased distant relapse risk (DRR). In ER−tumours, low ERCC1 transcript or protein level was linked to decreased DRR, especially in patients who received anthracycline chemotherapy. In LABC patients who received neoadjuvant anthracycline, low ERCC1 transcript was associated with higher pCR (pathological complete response) and decreased DRR. However, in patients with ER−tumours who received additional neoadjuvant taxane, high ERCC1 transcript was associated with a higher pCR and decreased DRR. High ERCC1 transcript was also linked to decreased DRR in ER+ LABC that received additional neoadjuvant taxane. ERCC1 based stratification is an attractive strategy for breast cancers.
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Affiliation(s)
| | - Reem Ali
- Translational Oncology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK
| | - Maaz Sadiq
- Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK
| | - Paul M Moseley
- Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK
| | - Katia A Mesquita
- Translational Oncology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK
| | - Graham Ball
- School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK
| | - Andrew R Green
- Academic Pathology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK
| | - Emad A Rakha
- Academic Pathology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK
| | - Stephen Y T Chan
- Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
| | - Srinivasan Madhusudan
- Department of Oncology, Nottingham University Hospitals, Nottingham NG5 1PB, UK.
- Translational Oncology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
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Firouzabadi D, Rezvani A, Dehghanian A, Mahmoudi L. Association of ki67 and tumor marker p53 in locally advanced breast cancer patients and evaluation of response to neoadjuvant chemotherapy: a survey in South Iran. Cancer Manag Res 2019; 11:6489-6497. [PMID: 31372050 PMCID: PMC6628949 DOI: 10.2147/cmar.s203831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 05/16/2019] [Indexed: 01/09/2023] Open
Abstract
Purpose Heterogeneity of breast cancer, the most common cancer in women, complicates approach to its treatment. Neoadjuvant chemotherapy (NAC) in the treatment of locally advanced breast cancer (LABC) with the endpoint of achieving pathologic complete response (pCR) is not always successful. The purpose of this study was to evaluate the clinicopathologic characteristics, biomarker status and response of LABCs to NAC. Patients and methods Core biopsies and post-surgical specimens of LABC patients were evaluated after receiving NAC. Their lymph node involvement, tumor staging, grading, size, tumoral and stromal lymphocytic infiltration (TLI, SLI), hormonal status, ki67, p53 and HER2 expression were evaluated. Response to NAC was assessed using pCR, Miller-Payne grading and residual cancer burden. Results In a total of 71 patients, pCR rate was 5.6%. Strong association was observed between ki67 positivity and p53 expression (P-value˂0.001). Also ki67, TLI and SLI showed association with triple negative tumor subtype (P-value 0.011, 0.002 and 0.014). Good response to NAC was associated with p53 expression. Nodal metastatic residue was also associated with primary tumor’s nuclear grade. Conclusion Strong correlation of ki67 and p53 can suggest probable interchangeability of both markers in the prognosis of LABC. In this study p53 even showed superiority to ki67 having association with good response. Strong association of ki67, TLI and SLI with triple negative tumor subtype can be parallel to an overall better response rate of this subtype. We can also propose the effectiveness of defining nuclear grade as a prognostic factor towards residual lymph node involvement post NAC.
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Affiliation(s)
- Dena Firouzabadi
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Rezvani
- Hematology and Oncology Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Hematology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirreza Dehghanian
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Trauma Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Laleh Mahmoudi
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Resende U, Cabello C, Ramalho SOB, Zeferino LC. Prognostic assessment of breast carcinoma submitted to neoadjuvant chemotherapy with pathological non-complete response. BMC Cancer 2019; 19:601. [PMID: 31208353 PMCID: PMC6580604 DOI: 10.1186/s12885-019-5812-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 06/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background Breast cancer with pathological non-complete response (non-pCR) after neoadjuvant chemotherapy (NAC) has a worse prognosis. Despite Neo-Bioscore has been validated as an independent prognostic model for breast cancer submitted to NAC, non-pCR carcinoma was not assessed in this setting. Methods This is a retrospective trial that included women with localized breast cancer who underwent NAC and had non-pCR carcinoma in surgical specimen between 01/01/2013 to 12/31/2015 with a three-year follow-up. Survival analysis was performed by Kaplan-Meier estimator and hazard ratio (HR) set by log-rank test for the primary and secondary endpoints, respectively Disease-Free Survival (DFS) and Overall Survival (OS). According to Neo-Bioscore, the proposed prognostic model named Clustered Neo-Bioscore was classified into low (0–3), low-intermediate (4–5), high-intermediate (6) and high (7) risk. The prognostic accuracy for recurrence risk was assessed by time-dependent receiver operating characteristic (time-ROC) methodology. Multivariate Cox regression assessed the menopausal status, histological grade, Ki-67, estrogen receptor, HER2, tumor subtype, pathological and clinical stages. Confidence interval at 95% (CI95%) and statistical significance at set 2-sided p-value less than 0.05 were adopted. Results Among the 310 women enrolled, 267 patients (86.2%) had non-pCR carcinoma presenting size T3/T4 (63.3%), node-positive axilla (74.9%), stage III (62.9%), Ki-67 ≥ 20% (71.9%) and non-luminal A (78.3%). Non-pCR carcinoma presented worse DFS-3y (HR = 3.88, CI95% = 1.18–11.95) but not OS-3y (HR = 2.73, CI95% = 0.66–11.40). Clustered Neo-Bioscore discerned the recurrence risk for non-pCR carcinoma: low (DFS-3y = 0.86; baseline), low-intermediate (DFS-3y = 0.70; HR = 2.61), high-intermediate (DFS-3y = 0.13, HR = 14.05), and high (DFS-3y = not achieved; HR = 22.19). The prognostic accuracy was similar between Clustered Neo-Bioscore and Neo-Bioscore (0.76 vs 0.78, p > 0.05). Triple-negative subtype (HR = 3.6, CI95% = 1.19–10.92) and pathological stages II (HR = 5.35, CI95% = 1.19–24.01) and III (HR = 6.56, CI95% = 1.29–33.32) were prognoses for low-intermediate risk, whereas pathological stage III (HR = 13.0, CI95% = 1.60–106.10) was prognosis for low risk. Conclusions Clustered Neo-Bioscore represents a novel prognostic model of non-pCR carcinoma undergoing NAC with a more simplified and appropriate score pattern in the assessment of prognostic factors. Electronic supplementary material The online version of this article (10.1186/s12885-019-5812-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Uanderson Resende
- Division of Gynecological and Mammary Oncology, Woman's Hospital Dr José Aristodemo Pinotti (CAISM) of State University of Campinas (UNICAMP), Rua Alexander Fleming 101, Campinas, São Paulo, 13083-083, Brazil.
| | - César Cabello
- Division of Gynecological and Mammary Oncology, Woman's Hospital Dr José Aristodemo Pinotti (CAISM) of State University of Campinas (UNICAMP), Rua Alexander Fleming 101, Campinas, São Paulo, 13083-083, Brazil
| | - Susana Oliveira Botelho Ramalho
- Division of Gynecological and Mammary Oncology, Woman's Hospital Dr José Aristodemo Pinotti (CAISM) of State University of Campinas (UNICAMP), Rua Alexander Fleming 101, Campinas, São Paulo, 13083-083, Brazil
| | - Luiz Carlos Zeferino
- Division of Gynecological and Mammary Oncology, Woman's Hospital Dr José Aristodemo Pinotti (CAISM) of State University of Campinas (UNICAMP), Rua Alexander Fleming 101, Campinas, São Paulo, 13083-083, Brazil
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Selli C, Sims AH. Neoadjuvant Therapy for Breast Cancer as a Model for Translational Research. Breast Cancer (Auckl) 2019; 13:1178223419829072. [PMID: 30814840 PMCID: PMC6381436 DOI: 10.1177/1178223419829072] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 01/21/2023] Open
Abstract
Neoadjuvant therapy, where patients receive systemic therapy before surgical removal of the tumour, can downstage tumours allowing breast-conserving surgery, rather than mastectomy. In addition to its impact on surgery, the neoadjuvant setting offers a valuable opportunity to monitor individual tumour response. The effectiveness of standard and/or potential new therapies can be tested in the neoadjuvant pre-surgical setting. It can potentially help to identify markers differentiating patients that will potentially benefit from continuing with the same or a different adjuvant treatment enabling personalised treatment. Characterising the molecular response to treatment over time can more accurately identify the significant differences between baseline samples that would not be identified without post-treatment samples. In this review, we discuss the potential and challenges of using the neoadjuvant setting in translational breast cancer research, considering the implications for improving our understanding of response to treatment, predicting therapy benefit, modelling breast cancer dormancy, and the development of drug resistance.
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Affiliation(s)
- Cigdem Selli
- Applied Bioinformatics of Cancer, University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics & Molecular Medicine, Edinburgh, UK
- Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey
| | - Andrew H Sims
- Applied Bioinformatics of Cancer, University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics & Molecular Medicine, Edinburgh, UK
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Pathologic Complete Response (pCR) and Survival of Women with Inflammatory Breast Cancer (IBC): An Analysis Based on Biologic Subtypes and Demographic Characteristics. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16010124. [PMID: 30621221 PMCID: PMC6339010 DOI: 10.3390/ijerph16010124] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 12/03/2018] [Accepted: 12/28/2018] [Indexed: 12/25/2022]
Abstract
In this US-based study of the National Cancer Database (NCDB), we examined 8550 patients diagnosed with non-metastatic, invasive inflammatory breast cancer (IBC) who received surgery from 2004–2013. Patients were grouped into four biologic subtypes (HR+/HER2−, HR+/HER2+, HR−/HER2+, HR−/HER2−). On average, women were 56 years of age at diagnosis and were followed for a median of 3.7 years. The majority were white (80%), had private health insurance (50%), and presented with poorly differentiated tumors (57%). Approximately 46% of the cancers were >5 cm. Most patients underwent mastectomy (94%) and received radiotherapy (71%). Differences by biologic subtypes were observed for grade, lymph node invasion, race, and tumor size (p < 0.0001). Patients experiencing pathologic complete response (pCR, 12%) vs. non-pCR had superior 5-year overall survival (OS) (77% vs. 54%) (p < 0.0001). Survival was poor for triple-negative (TN) tumors (37%) vs. other biologic subtypes (60%) (p < 0.0001). On multivariable analysis, TN-IBC, positive margins, and not receiving either chemotherapy, hormonal therapy or radiotherapy were independently associated with poor 5-year survival (p < 0.0001). In this analysis of IBC, categorized by biologic subtypes, we observed significant differential tumor, patient and treatment characteristics, and OS.
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The synthetic antihyperlipidemic drug potassium piperate selectively kills breast cancer cells through inhibiting G1-S-phase transition and inducing apoptosis. Oncotarget 2018; 8:47250-47268. [PMID: 28467790 PMCID: PMC5564562 DOI: 10.18632/oncotarget.16872] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/14/2017] [Indexed: 01/09/2023] Open
Abstract
Piper longum L. is a well-known traditional antihyperlipidemic medicine in China, containing medicinal constituents of piperine, pipernonaline and piperlonguminine in its fruit. However, the antitumor properties of these constituents have not yet been studied. We found that potassium piperate (GBK), a derivative of piperine, inhibited proliferation of cancer cells. GBK selectively inhibited the G1-S-phase transition in breast cancer cells and the G1 arrest was correlated with induction of p27 expression, which is an inhibitor for cyclin-dependent kinases, and inhibition of cyclin A, cyclin E and cyclin B expression. Moreover, GBK treatment led to a downregulation of the mini-chromosome maintenance protein expression and induction of mitochondrial-dependent cell apoptosis in breast cancer cells. Our results also suggested that GBK might also inhibit cancer cell proliferation through epigenetic signaling pathways. A synergistic effect in inhibition of cancer cell proliferation was found when GBK was combined with chemotherapy medicines etoposide phosphate or cisplatin at middle or low doses in vitro. These results show that GBK is a novel potential anti-breast cancer drug that inhibits cell proliferation and promotes cell apoptosis.
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Galvez M, Castaneda CA, Sanchez J, Castillo M, Rebaza LP, Calderon G, Cruz MDL, Cotrina JM, Abugattas J, Dunstan J, Guerra H, Mejia O, Gomez HL. Clinicopathological predictors of long-term benefit in breast cancer treated with neoadjuvant chemotherapy. World J Clin Oncol 2018; 9:33-41. [PMID: 29651385 PMCID: PMC5893995 DOI: 10.5306/wjco.v9.i2.33] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/19/2017] [Accepted: 02/05/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the survival impact of clinicopathological factors, including pathological complete response (pCR) and tumor-infiltrating lymphocytes (sTIL) levels according to subtypes, in breast cancer (BC) patients who received neo-adjuvant chemotherapy (NAC).
METHODS We evaluated 435 BC patients who presented and received NAC at the Instituto Nacional de Enfermedades Neoplasicas from 2003 to 2014. sTIL was analyzed as the proportion of tumor stroma occupied by lymphocytes, and was prospectively evaluated on hematoxylin and eosin-stained sections of the preNAC core biopsy. pCR was considered in the absence of infiltrating cancer cells in primary tumor and axillary lymph nodes. Analysis of statistical association between clinical pathological features, sTIL, pCR and survival were carried out using SPSSvs19.
RESULTS Median age was 49 years (range 24-84 years) and the most frequent clinical stage was IIIB (58.3%). Luminal A, Luminal B, HER2-enriched and (triple-negative) TN phenotype was found in 24.6%, 37.9%, 17.7% and 19.8%, respectively. pCR was observed in 11% and median percentage of sTIL was 40% (2%-95%) in the whole population. pCR was associated to Ct1-2 (P = 0.045) and to high sTIL (P = 0.029) in the whole population. There was a slight trend towards significance for sTIL (P = 0.054) in Luminal A. sTIL was associated with grade III (P < 0.001), no-Luminal A subtype (P < 0.001), RE-negative (P < 0.001), PgR-negative (P < 0.001), HER2-positive (P = 0.002) and pCR (P = 0.029) in the whole population. Longer disease-free survival was associated with grade I-II (P = 0.006), cN0 (P < 0.001), clinical stage II (P = 0.004), ER-positive (P < 0.001), PgR-positive (P < 0.001), luminal A (P < 0.001) and pCR (P = 0.002). Longer disease-free survival was associated with grade I-II in Luminal A (P < 0.001), N0-1 in Luminal A (P = 0.045) and TNBC (P = 0.01), clinical stage II in Luminal A (P = 0.003) and TNBC (P = 0.038), and pCR in TNBC (P < 0.001). Longer overall survival was associated with grade I-II (P < 0.001), ER-positive (P < 0.001), PgR-positive (P < 0.001), Luminal A (P < 0.001), cN0 (P = 0.002) and pCR (P = 0.002) in the whole population. Overall survival was associated with clinical stage II (P = 0.017) in Luminal A, older age (P = 0.042) in Luminal B, and pCR in TNBC (P = 0.005).
CONCLUSION Predictive and prognostic values of clinicopathological features, like pCR and sTIL, differ depending on the evaluated molecular subtype
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Affiliation(s)
- Marco Galvez
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Carlos A Castaneda
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
- Faculty of Medicine, Universidad Peruana San Juan Bautista, Lima 15067, Peru
| | - Joselyn Sanchez
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Miluska Castillo
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Lia Pamela Rebaza
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Gabriela Calderon
- Department of Breast Cancer Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Miguel De La Cruz
- Department of Breast Cancer Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jose Manuel Cotrina
- Department of Breast Cancer Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Julio Abugattas
- Department of Breast Cancer Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jorge Dunstan
- Department of Breast Cancer Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Henry Guerra
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Omar Mejia
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Henry L Gomez
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
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Cabrera-Galeana P, Muñoz-Montaño W, Lara-Medina F, Alvarado-Miranda A, Pérez-Sánchez V, Villarreal-Garza C, Quintero RM, Porras-Reyes F, Bargallo-Rocha E, Del Carmen I, Mohar A, Arrieta O. Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy. Oncologist 2018; 23:670-678. [PMID: 29490940 DOI: 10.1634/theoncologist.2017-0396] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 01/09/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant-chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease-free survival (DFS) and overall survival (OS) in patients without pCR. SUBJECTS, MATERIALS, AND METHODS Four hundred thirty-five patients with stage IIA-IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. RESULTS Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8-6.37) and 7.03 (95% CI 2.6-18.7), respectively. CONCLUSION Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. IMPLICATIONS FOR PRACTICE This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse prognoses that cannot be treated using a single algorithm, pose a challenge to clinicians. This study identified a subgroup of these patients with a poor prognosis, those with luminal B-like tumors without a Ki67 decrease after NAC, thus justifying the introduction of new therapeutic strategies for patients who already present a favorable prognosis (luminal B-like with Ki67 decrease).
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Affiliation(s)
- Paula Cabrera-Galeana
- Department of Breast Medical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Wendy Muñoz-Montaño
- Department of Breast Medical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Fernando Lara-Medina
- Department of Breast Medical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Alberto Alvarado-Miranda
- Department of Breast Medical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Victor Pérez-Sánchez
- Department of Breast Pathology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Cynthia Villarreal-Garza
- Department of Breast Medical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - R Marisol Quintero
- Department of Medical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Fany Porras-Reyes
- Department of Breast Pathology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Enrique Bargallo-Rocha
- Department of Breast Surgical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Ignacio Del Carmen
- Department of Breast Surgical Oncology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Alejandro Mohar
- Unit of Breast Epidemiology, National Institute of Cancer (INCan), Mexico City, Mexico
| | - Oscar Arrieta
- Unit of Thoracic Oncology and Personalized Medicine Laboratory, National Institute of Cancer (INCan), Mexico City, Mexico
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Jin Y, Hu W, Liu T, Rana U, Aguilera-Barrantes I, Kong A, Kumar SN, Wang B, Gao P, Wang X, Duan Y, Shi A, Song D, Yang M, Li S, Han B, Zhao G, Fan Z, Miao QR. Nogo-B receptor increases the resistance of estrogen receptor positive breast cancer to paclitaxel. Cancer Lett 2018; 419:233-244. [PMID: 29373839 DOI: 10.1016/j.canlet.2018.01.054] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 12/20/2017] [Accepted: 01/19/2018] [Indexed: 12/28/2022]
Abstract
Intrinsic or acquired chemoresistance is a hurdle in oncology. Only 7%-16% of estrogen receptor α (ERα) positive breast cancer cases achieve a pathological complete response (pCR) after neo-adjuvant chemotherapy. Nogo-B receptor (NgBR) is a cell surface receptor that binds farnesylated Ras and promotes Ras translocation to the plasma membrane. Here, we demonstrate NgBR as a potential therapeutic target for ERα positive breast cancer patients to attenuate paclitaxel resistance. NgBR knockdown enhanced paclitaxel-induced cell apoptosis by modulating expression of p53 and survivin in ERα positive breast cancer cells via NgBR-mediated PI3K/Akt and MAPK/ERK signaling pathways. NgBR knockdown attenuated either 17β-estradiol or epidermal growth factor stimulated phosphorylation of ERα at Serine 118 residue. The ChIP-PCR assay further demonstrated that NgBR knockdown decreased ERα binding to the estrogen response element (ERE) of the ERα target gene and increased the binding of p53 to the promoter region of survivin to attenuate survivin transcription. In summary, our data suggest that NgBR expression is essential to promoting ERα positive breast cancer cell resistance to paclitaxel. Findings from this study implicate a novel therapeutic target for treating ERα positive breast cancer in neo-adjuvant/adjuvant chemotherapy.
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Affiliation(s)
- Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China; Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Wenquan Hu
- Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Tong Liu
- Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun, Jilin, 130033, China
| | - Ujala Rana
- Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Irene Aguilera-Barrantes
- Department of Pathology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Amanda Kong
- Department of Surgery, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Suresh N Kumar
- Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Bei Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Pin Gao
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China; Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Xiang Wang
- Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA
| | - Yajun Duan
- Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China
| | - Aiping Shi
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Dong Song
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Ming Yang
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Sijie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Bing Han
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Gang Zhao
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Zhimin Fan
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Qing Robert Miao
- Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA; Divisions of Pediatric Pathology, Department of Pathology, Children's Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA.
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Tumor Infiltrating Lymphocytes in Breast Cancer Patients with Progressive Disease during Neoadjuvant Chemotherapy. Pathol Oncol Res 2017; 25:1341-1347. [PMID: 29222623 DOI: 10.1007/s12253-017-0368-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 11/29/2017] [Indexed: 10/18/2022]
Abstract
A minority of breast cancer (BC) patients progress during neoadjuvant chemotherapy (NCT). The aim of this study was to assess the value of Tumor infiltrating lymphocytes (TILs) in such a high-risk population where valid biomarkers are eagerly needed. A retrospective review identified BC patients who either progressed during NCT or achieved a pathologic complete response (pCR). An experienced BC pathologist semi-quantified stromal TILs in pre-treatment core biopsies using hematoxylin and eosin stained slides. The primary outcome was to compare the levels of TILs between the 2 groups as a continuous and categorical variable using the t-test and X2 test as appropriate. The secondary outcome was to compare survival outcomes between patients with high versus low TILs level using the log-rank test. Fifty patients were successfully identified and assessed for TILs: 21 progressed during NCT and 29 had a pCR. Patients with progressive disease were older with more advanced disease (p = 0.03, p = 0.0001 respectively). A significantly lower mean level of TILs was found in patients with progressive disease compared to patients with pCR: 14.3% (Standard Deviation (SD): 16.9) versus 32.8% (SD: 31), p = 0.01). The level of TILs was neither associated with baseline characteristics nor with survival outcomes. BC patients progressing during NCT have low TILs levels compared to patients with pCR. Prospective studies are needed to establish the utility of TILs as early biomarkers of tumor response, particularly in patients with disease progression who need novel treatment approaches.
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Peppe A, Wilson R, Pope R, Downey K, Rusby J. The use of ultrasound in the clinical re-staging of the axilla after neoadjuvant chemotherapy (NACT). Breast 2017; 35:104-108. [DOI: 10.1016/j.breast.2017.05.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 05/23/2017] [Accepted: 05/25/2017] [Indexed: 10/19/2022] Open
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Sorace AG, Harvey S, Syed A, Yankeelov TE. Imaging Considerations and Interprofessional Opportunities in the Care of Breast Cancer Patients in the Neoadjuvant Setting. Semin Oncol Nurs 2017; 33:425-439. [PMID: 28927763 DOI: 10.1016/j.soncn.2017.08.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To discuss standard-of-care and emerging imaging techniques employed for screening and detection, diagnosis and staging, monitoring response to therapy, and guiding cancer treatments. DATA SOURCES Published journal articles indexed in the National Library of Medicine database and relevant websites. CONCLUSION Imaging plays a fundamental role in the care of cancer patients and specifically, breast cancer patients in the neoadjuvant setting, providing an excellent opportunity for interprofessional collaboration between oncologists, researchers, radiologists, and oncology nurses. Quantitative imaging strategies to assess cellular, molecular, and vascular characteristics within the tumor is needed to better evaluate initial diagnosis and treatment response. IMPLICATIONS FOR NURSING PRACTICE Nurses caring for patients in all settings must continue to seek education on emerging imaging techniques. Oncology nurses provide education about the test, ensure the patient has appropriate pre-testing instructions, and manage patient expectations about timing of results availability.
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Chan HM, van der Velden BHM, Loo CE, Gilhuijs KGA. Eigentumors for prediction of treatment failure in patients with early-stage breast cancer using dynamic contrast-enhanced MRI: a feasibility study. ACTA ACUST UNITED AC 2017; 62:6467-6485. [DOI: 10.1088/1361-6560/aa7dc5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Castrellon AB, Pidhorecky I, Valero V, Raez LE. The Role of Carboplatin in the Neoadjuvant Chemotherapy Treatment of Triple Negative Breast Cancer. Oncol Rev 2017; 11:324. [PMID: 28382189 PMCID: PMC5365000 DOI: 10.4081/oncol.2017.324] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 02/24/2017] [Accepted: 02/27/2017] [Indexed: 12/24/2022] Open
Abstract
Triple negative breast (TNBC) cancer constitutes a heterogeneous group of disease with histologic and molecular differences. Complete pathologic response to neoadjuvant chemotherapy (NACT) in TNBC is associated with improved outcomes. Efforts have been made in identifying drug combinations that will increase the response rate to preoperative chemotherapy. In this review we present recent studies that have incorporated carboplatin (Cb) in the NACT of TNBC. We discuss the homologous recombination deficiency score and the somatic or germline mutation for BRCA as potential biomarkers for future selection of patients that could benefit from the addition of Cb to NACT.
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Affiliation(s)
| | - Ihor Pidhorecky
- Surgical Oncology Services & Pancreaticobiliary Center, Memorial Cancer Institute, Memorial Healthcare System, Hollywood, FL
| | - Vicente Valero
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Luis Estuardo Raez
- Hematology/Oncology and Medical Director of Memorial Cancer Institute, Memorial Healthcare System, Hollywood, FL, USA
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Kieber-Emmons T, Makhoul I, Pennisi A, Siegel ER, Emanuel PD, Monzavi-Karbassi B, Steplewski Z, Beck JT, Hutchins LF. Managing Expectations in the Transition to Proof of Concept Studies. Rev Recent Clin Trials 2017; 12:111-123. [PMID: 28325150 PMCID: PMC9252264 DOI: 10.2174/1574887112666170321121250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/17/2017] [Accepted: 03/16/2017] [Indexed: 06/06/2023]
Abstract
BACKGROUND As we move away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborating on the toxicity assessment, with no expectation of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics show limited toxicities and draw attention to the need to demonstrate efficacy in the early evaluation of new agents. METHODS Literature searches indicate that molecular oncology mechanistic-based agents are being linked with molecular disease status and clinical benefit. Biomarkers and other endpoints are being employed to accomplish this. Perspectives for a meaningful context of integrating biomarkers and clinical trial design are reviewed. RESULTS The design and conduct of clinical trials have not been fully adjusted to the new era of personalized oncology, and so we are in transition. A part of this transition is the management of expectations and trial designs that need to be considered relative to preclinical experience in the development of therapeutics. For example, pathological complete response is now considered a surrogate marker for favorable prognosis in breast cancer patients who are treated in the neoadjuvant setting. This surrogate marker is tied to novel agents' mechanistic characteristics with no preclinical counterpart. CONCLUSION The old paradigm considers patients equal with similar chances to respond to treatments, but the new paradigm considers patient's heterogeneity, a major fact that informs the design of clinical trials. By linking every treatment to a mechanism of action and to the presence of a specific biomarker, new trials are going to have more subjects who are likely to respond to the treatment.
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Affiliation(s)
- Thomas Kieber-Emmons
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
| | - Issam Makhoul
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
| | - Angela Pennisi
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
| | - Eric R. Siegel
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
| | - Peter D. Emanuel
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
| | - Behjatolah Monzavi-Karbassi
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
| | | | | | - Laura F. Hutchins
- Winthrop P. Rockefeller Cancer Institute of the University of Arkansas for Medical Sciences, Little Rock AR, USA
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