|
1
|
Thiele B, Stein A, Schultheiß C, Paschold L, Jonas H, Goekkurt E, Rüssel J, Schuch G, Wierecky J, Sinn M, Tintelnot J, Petersen C, Rothkamm K, Vettorazzi E, Binder M. Trifluridine/Tipiracil Based Chemoradiation in locally Advanced Rectal Cancer: The Phase I/II TARC Trial. Clin Colorectal Cancer 2025; 24:11-17. [PMID: 39003182 DOI: 10.1016/j.clcc.2024.06.003] [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: 09/28/2023] [Revised: 06/07/2024] [Accepted: 06/08/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND Optimizing functional outcomes and securing long-term remissions are key goals in managing patients with locally advanced rectal cancer. In this proof-of-concept study, we set out to further optimize neoadjuvant therapy by integrating the radiosensitizer trifluridine/tipiracil and explore the potential of cell free tumor DNA (ctDNA) to monitor residual disease. METHODS About 10 patients were enrolled in the phase I dose finding part which followed a 3 + 3 dose escalation design. Tipiracil/trifluridine was administered concomitantly to radiotherapy. ctDNA monitoring was performed before and after chemoradiation with patient-individualized digital droplet PCRs. RESULTS No dose-limiting toxicities were observed at the maximum tolerated dose level of 2 × 35 mg/m² trifluridine/tipiracil. There were 9 grade 3 adverse events, of which 8 were hematologic with anemia and leukopenia. Chemoradiation yielded a pathological complete response in 1 out of 8 assessable patients, downstaging in nearly all patients, and 1 clinical complete response referred for watchful waiting. Three of 4 assessable patients with residual tumor cells at pathological assessment remained liquid biopsy positive after chemoradiation, but 1 turned negative. CONCLUSION In this exploratory phase I trial, the novel combination of neoadjuvant trifluridine/tipiracil and radiotherapy proved to be feasible, tolerable, and effective. However, the application of liquid biopsy as a potential marker for therapeutic de-escalation in the neoadjuvant setting requires additional research and prospective validation. The trial was registered at ClinicalTrials.gov: NCT04177602.
Collapse
Affiliation(s)
- Benjamin Thiele
- Medical Oncology, University Hospital Basel, Basel, Switzerland; Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
| | - Alexander Stein
- Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Christoph Schultheiß
- Medical Oncology, University Hospital Basel, Basel, Switzerland; Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
| | - Lisa Paschold
- Internal Medicine IV - Oncology/Hematology, University Hospital, Martin-Luther University, Halle, Germany
| | - Hanna Jonas
- Internal Medicine IV - Oncology/Hematology, University Hospital, Martin-Luther University, Halle, Germany
| | - Eray Goekkurt
- Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jörn Rüssel
- Internal Medicine IV - Oncology/Hematology, University Hospital, Martin-Luther University, Halle, Germany
| | - Gunter Schuch
- Hämatologisch- Onkologische Praxis Altona, Hamburg, Germany
| | - Jan Wierecky
- Überörtliche Gemeinschaftspraxis für Innere Medizin Schwerpunkt Hämatologie, Onkologie und Palliativmedizin, Hamburg, Germany
| | - Marianne Sinn
- University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joseph Tintelnot
- University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cordula Petersen
- University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kai Rothkamm
- University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eik Vettorazzi
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mascha Binder
- Medical Oncology, University Hospital Basel, Basel, Switzerland; Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
| |
Collapse
|
|
2
|
Abidoye O, Ahn DH, Borad MJ, Wu C, Bekaii-Saab T, Chakrabarti S, Sonbol MB. Circulating Tumor DNA Testing for Minimal Residual Disease and Its Application in Colorectal Cancer. Cells 2025; 14:161. [PMID: 39936953 DOI: 10.3390/cells14030161] [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: 12/13/2024] [Revised: 01/06/2025] [Accepted: 01/17/2025] [Indexed: 02/13/2025] Open
Abstract
Colorectal cancer (CRC) represents a heterogeneous group of diseases that imposes a considerable global and national health burden. Although most CRC patients are diagnosed at an early stage and undergo potentially curative treatment, a significant proportion experience recurrence. Currently, adjuvant chemotherapy decisions are primarily based on clinicopathological characteristics, which have well-recognized limitations in accurately identifying patients harboring minimal residual disease (MRD), often resulting in unnecessary chemotherapy exposure. Circulating tumor DNA (ctDNA) has emerged as a promising surrogate marker for MRD, offering a more precise approach to identifying patients at risk of recurrence after curative-intent surgery and refining adjuvant chemotherapy decisions. Growing evidence from multiple studies has demonstrated that ctDNA outperforms traditional clinicopathological factors as a marker for MRD. This review synthesizes key studies supporting the role of ctDNA in MRD detection for CRC patients and evaluates clinical trials investigating the application of ctDNA in guiding adjuvant therapy decisions. This emerging strategy holds the potential to transform the adjuvant treatment paradigm in colorectal cancer by optimizing therapeutic precision and minimizing unnecessary treatment.
Collapse
Affiliation(s)
| | - Daniel H Ahn
- Mayo Clinic Cancer Center, Phoenix, AZ 85054, USA
| | | | - Christina Wu
- Mayo Clinic Cancer Center, Phoenix, AZ 85054, USA
| | | | | | | |
Collapse
|
|
3
|
Molinari C, Marisi G, Laliotis G, Spickard E, Rapposelli IG, Petracci E, George GV, Dutta P, Sharma S, Malhotra M, Prochowski Iamurri A, Feliciani G, Liu MC, Ulivi P, Canale M, Saragoni L, Gallo G, Frassineti GL, Muratore M, Romeo A, Jurdi A, Martinelli G, Passardi A. Assessment of circulating tumor DNA in patients with locally advanced rectal cancer treated with neoadjuvant therapy. Sci Rep 2024; 14:29536. [PMID: 39604448 PMCID: PMC11603181 DOI: 10.1038/s41598-024-80855-8] [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: 08/29/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024] Open
Abstract
Post-neoadjuvant therapy (post-NAT) and post-surgical circulating tumor DNA (ctDNA) risk stratification may enhance the management of patients with locally advanced rectal cancer (LARC). In this study, we assessed the prognostic value of ctDNA-based MRD detection in LARC patients using a personalized, tumor-informed ctDNA assay. Plasma samples from LARC patients (N = 30) were analyzed retrospectively using the Signatera™ assay. The neoadjuvant rectal (NAR) score was calculated and compared to ctDNA status to predict recurrence risk and survival outcomes. ctDNA-positive patients post-NAT and post-surgery had worse Disease Free Survival (DFS) (HR: 7.82; p = 0.001, HR: 19.65; p = 0.001) when compared to ctDNA-negative patients. In the post-NAT setting, patients who responded to NAT had superior DFS compared to patients who did not clear their ctDNA or showed no radiological response (HR: 24.7, p = 0.001 and HR: 5.1, p = 0.054, respectively). When ctDNA status is used alongside the NAR score in the post-NAT setting, patients who were ctDNA-positive with an intermediate or high NAR score showed significantly worse DFS (HR: 47.5, p < 0.001) compared to ctDNA-negative patients with either a low or intermediate/high NAR score (HR: 9.8, p = 0.0301). Post-NAT ctDNA status, whether used alone or in combination with the NAR score, may predict NAT response, and improve risk stratification.
Collapse
Affiliation(s)
- Chiara Molinari
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, Meldola (FC), 47014, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, Meldola (FC), 47014, Italy.
| | | | | | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Elisabetta Petracci
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | | | | | | | | | - Andrea Prochowski Iamurri
- Radiology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giacomo Feliciani
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | | | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, Meldola (FC), 47014, Italy
| | - Matteo Canale
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, Meldola (FC), 47014, Italy
| | - Luca Saragoni
- Operative Unit of Pathologic Anatomy, AUSL della Romagna, "S. Maria delle Croci" Hospital, Ravenna, Italy
| | - Graziana Gallo
- Department of Pathology, Bufalini Hospital, Cesena, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Margherita Muratore
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Antonino Romeo
- Radiotherapy Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | | | - Giovanni Martinelli
- Department of Hematology and Sciences Oncology, Institute of Haematology "L. and A. Seràgnoli", S. Orsola University Hospital, Bologna, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| |
Collapse
|
|
4
|
Zhou S, Shen C, Wang Y, Zhao Z, Che G. Values of circulating tumor DNA for non-small cell lung cancer patients receiving neoadjuvant therapy, progress and challenges: a narrative review. J Thorac Dis 2024; 16:4742-4755. [PMID: 39144303 PMCID: PMC11320285 DOI: 10.21037/jtd-24-265] [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] [Received: 02/18/2024] [Accepted: 05/24/2024] [Indexed: 08/16/2024]
Abstract
Background and Objective The value of circulating tumor DNA (ctDNA) in neoadjuvant therapy (NAT) for lung cancer remains controversial. Therefore, we conducted a review to further investigate the role of ctDNA in non-small cell lung cancer (NSCLC) patients undergoing NAT for individualized management. Methods A search of online databases (PubMed, Embase, Web of Science, Science Direct, and Cochrane Library) was conducted to evaluate the value of ctDNA in predicting relapse, risk stratification, and efficacy of NAT in NSCLC. Only articles published in English within the last 25 years, between January 1st, 1998 and November 30th, 2023, were included. Additionally, the application of ctDNA in NSCLC is briefly reviewed. Key Content and Findings ctDNA is a non-invasive and dynamic method that plays an important role in future treatment guidance. Additionally, ctDNA successfully predicted the effect of neoadjuvant immunotherapy before surgery, and positive testing was strongly correlated with a lower major pathological response or complete pathological response rate. Sequential testing of ctDNA may serve as a secondary indicator to guide the adjustment of treatment programs. However, the application of this method has been limited by false negative results, a lack of objective indicators, and high costs. These issues must be addressed by researchers. Conclusions ctDNA has strong potential in NAT, based on positive preliminary studies. However, its widespread use is limited by the high cost of testing. Further research is needed to explore its value in risk stratification and treatment guidance in the future.
Collapse
Affiliation(s)
- Sicheng Zhou
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng Shen
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Wang
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Ziyi Zhao
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Guowei Che
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
5
|
Boldrini L, Chiloiro G, Di Franco S, Romano A, Smiljanic L, Tran EH, Bono F, Charles Davies D, Lopetuso L, De Bonis M, Minucci A, Giacò L, Cusumano D, Placidi L, Giannarelli D, Sala E, Gambacorta MA. MOREOVER: multiomics MR-guided radiotherapy optimization in locally advanced rectal cancer. Radiat Oncol 2024; 19:94. [PMID: 39054479 PMCID: PMC11271028 DOI: 10.1186/s13014-024-02492-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Complete response prediction in locally advanced rectal cancer (LARC) patients is generally focused on the radiomics analysis of staging MRI. Until now, omics information extracted from gut microbiota and circulating tumor DNA (ctDNA) have not been integrated in composite biomarkers-based models, thereby omitting valuable information from the decision-making process. In this study, we aim to integrate radiomics with gut microbiota and ctDNA-based genomics tracking during neoadjuvant chemoradiotherapy (nCRT). METHODS The main hypothesis of the MOREOVER study is that the incorporation of composite biomarkers with radiomics-based models used in the THUNDER-2 trial will improve the pathological complete response (pCR) predictive power of such models, paving the way for more accurate and comprehensive personalized treatment approaches. This is due to the inclusion of actionable omics variables that may disclose previously unknown correlations with radiomics. Aims of this study are: - to generate longitudinal microbiome data linked to disease resistance to nCRT and postulate future therapeutic strategies in terms of both type of treatment and timing, such as fecal microbiota transplant in non-responding patients. - to describe the genomics pattern and ctDNA data evolution throughout the nCRT treatment in order to support the prediction outcome and identify new risk-category stratification agents. - to mine and combine collected data through integrated multi-omics approaches (radiomics, metagenomics, metabolomics, metatranscriptomics, human genomics, ctDNA) in order to increase the performance of the radiomics-based response predictive model for LARC patients undergoing nCRT on MR-Linac. EXPERIMENTAL DESIGN The objective of the MOREOVER project is to enrich the phase II THUNDER-2 trial (NCT04815694) with gut microbiota and ctDNA omics information, by exploring the possibility to enhance predictive performance of the developed model. Longitudinal ctDNA genomics, microbiome and genomics data will be analyzed on 7 timepoints: prior to nCRT, during nCRT on a weekly basis and prior to surgery. Specific modelling will be performed for data harvested, according to the TRIPOD statements. DISCUSSION We expect to find differences in fecal microbiome, ctDNA and radiomics profiles between the two groups of patients (pCR and not pCR). In addition, we expect to find a variability in the stability of the considered omics features over time. The identified profiles will be inserted into dedicated modelling solutions to set up a multiomics decision support system able to achieve personalized treatments.
Collapse
Affiliation(s)
- Luca Boldrini
- Gemelli Advanced Radiotherapy center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Radiomics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Giuditta Chiloiro
- Gemelli Advanced Radiotherapy center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Silvia Di Franco
- Gemelli Advanced Radiotherapy center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
| | - Angela Romano
- Gemelli Advanced Radiotherapy center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Lana Smiljanic
- Gemelli Advanced Radiotherapy center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Elena Huong Tran
- Radiomics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Francesco Bono
- Radiomics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Diepriye Charles Davies
- Radiomics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Loris Lopetuso
- Medicina Interna e Gastroenterologia, CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Maria De Bonis
- Genomics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Angelo Minucci
- Genomics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Luciano Giacò
- Bioinformatics GSTeP core research facility, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | | | - Lorenzo Placidi
- Medical Physics unit, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Diana Giannarelli
- Biostatistics Unit, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Evis Sala
- Gemelli Advanced Radiology center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Istituto di Radiologia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maria Antonietta Gambacorta
- Gemelli Advanced Radiotherapy center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Istituto di Radiologia, Università Cattolica del Sacro Cuore, Rome, Italy
| |
Collapse
|
|
6
|
Friedman G. Surveillance after Total Neoadjuvant Therapy: What to do for Near-Complete Responders. Clin Colon Rectal Surg 2024; 37:229-232. [PMID: 38882942 PMCID: PMC11178382 DOI: 10.1055/s-0043-1770716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
A proportion of patients who undergo total neoadjuvant therapy for rectal cancer will achieve what is classified as a near-complete response. Significant debate exists as to the optimal management strategy for these patients with large heterogeneity in management. This article will examine the therapeutic and surveillance options for these patients as well as the relevant outcomes data.
Collapse
|
|
7
|
Nassar A, Aly NE, Jin Z, Aly EH. ctDNA as a predictor of outcome after curative resection for locally advanced rectal cancer: systematic review and meta-analysis. Colorectal Dis 2024; 26:1346-1358. [PMID: 38802990 DOI: 10.1111/codi.17039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 04/26/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
AIM To assess the efficacy of ctDNA measurement at different time intervals in predicting response and prognosis in patients diagnosed with locally advanced rectal cancer (LARC) who underwent neoadjuvant treatment prior to curative resection. METHOD English language randomized controlled trials and observational studies, published from 1946 to January 2024, comparing outcomes between ctDNA-positive and ctDNA-negative patients with LARC undergoing neoadjuvant treatment prior to curative surgical resection were included in the search. The search included Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews (CDSR). RESULTS Data for 1022 patients were analysed. Patients with positive ctDNA in the preoperative period had more than five times the risk of developing distant metastasis (RR [95% CI] 5.03 [3.31-7.65], p < 0.001), while those with positive ctDNA in the postoperative period had more than six times the risk (RR [95% CI] 6.17 [2.38-15.95], p < 0.001). There was no significant relationship between ctDNA status at baseline, pre-, or postoperative periods and achievement of pCR (RR [95% CI] 1.21 [0.86-1.7], 1.82 [0.94-3.55], 1.48 [0.78-2.82], p = 0.27, 0.08, and 0.23, respectively). However, patients with positive ctDNA in the pre- and postoperative periods had more than 13 and 12 times the risk of overall disease relapse after curative-intent treatment (RR [95% CI] 13.55 [7.12-25.81], 12.14 [3.19-46.14], p < 0.001), respectively. CONCLUSION ctDNA could potentially guide treatment and follow-up in LARC, predicting high-risk patients for disease relapse, allowing individualized surveillance and treatment strategies. Prospective studies are needed for standardization.
Collapse
Affiliation(s)
- Ahmed Nassar
- University of Aberdeen, Aberdeen, Scotland, UK
- Aberdeen Royal Infirmary, Aberdeen, Scotland, UK
| | - Noha E Aly
- Aberdeen Royal Infirmary, Aberdeen, Scotland, UK
| | - Zhaohui Jin
- Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Emad H Aly
- University of Aberdeen, Aberdeen, Scotland, UK
- Aberdeen Royal Infirmary, Aberdeen, Scotland, UK
| |
Collapse
|
|
8
|
O'Sullivan NJ, Temperley HC, Kyle ET, Sweeney KJ, O'Neill M, Gilham C, O'Sullivan J, O'Kane G, Mehigan B, O'Toole S, Larkin J, Gallagher D, McCormick P, Kelly ME. Assessing circulating tumour DNA (ctDNA) as a prognostic biomarker in locally advanced rectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis 2024; 39:82. [PMID: 38809315 PMCID: PMC11136793 DOI: 10.1007/s00384-024-04656-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 05/30/2024]
Abstract
INTRODUCTION Circulating tumour DNA (ctDNA) has emerged as a promising biomarker in various cancer types, including locally advanced rectal cancer (LARC), offering potential insights into disease progression, treatment response and recurrence. This review aims to comprehensively evaluate the utility of ctDNA as a prognostic biomarker in LARC. METHODS PubMed, EMBASE and Web of Science were searched as part of our review. Studies investigating the utility of ctDNA in locally advanced rectal cancer (LARC) were assessed for eligibility. Quality assessment of included studies was performed using the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, ctDNA details and survival data. A meta-analysis was performed on eligible studies to determine pooled recurrence-free survival (RFS). RESULTS Twenty-two studies involving 1676 participants were included in our analysis. Methodological quality categorised by the Newcastle Ottawa Scale was generally satisfactory across included studies. ctDNA detected at various time intervals was generally associated with poor outcomes across included studies. Meta-analysis demonstrated a pooled hazard ratio of 8.87 (95% CI 4.91-16.03) and 15.15 (95% CI 8.21-27.95), indicating an increased risk of recurrence with ctDNA positivity in the post-neoadjuvant and post-operative periods respectively. CONCLUSION Our systematic review provides evidence supporting the prognostic utility of ctDNA in patients with LARC, particularly in identifying patients at higher risk of disease recurrence in the post-neoadjuvant and post-operative periods.
Collapse
Affiliation(s)
- Niall J O'Sullivan
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland.
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
| | - Hugo C Temperley
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
| | - Eimear T Kyle
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Kevin J Sweeney
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Maeve O'Neill
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Charles Gilham
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Department of Radiation Oncology, St. James's Hospital, Dublin 8, Ireland
| | - Jacintha O'Sullivan
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, Trinity College, St. James's Hospital, Dublin, Ireland
| | - Grainne O'Kane
- Department of Medical Oncology, St. James's Hospital, Dublin 8, Ireland
| | - Brian Mehigan
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Sharon O'Toole
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, Trinity College, St. James's Hospital, Dublin, Ireland
| | - John Larkin
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - David Gallagher
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Department of Medical Oncology, St. James's Hospital, Dublin 8, Ireland
- Department of Genetics, St. James's Hospital, Dublin 8, Ireland
| | - Paul McCormick
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Michael E Kelly
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland
- Trinity St. James's Cancer Institute, St. James's Hospital, Dublin 8, Ireland
| |
Collapse
|
|
9
|
Sullo FG, Passardi A, Gallio C, Molinari C, Marisi G, Pozzi E, Solaini L, Bittoni A. Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer. J Clin Med 2024; 13:2562. [PMID: 38731090 PMCID: PMC11084727 DOI: 10.3390/jcm13092562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/12/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, distant tumor recurrence remains a concern, prompting the exploration of total neoadjuvant therapy (TNT) as a comprehensive treatment strategy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Nonoperative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving complete clinical response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.
Collapse
Affiliation(s)
- Francesco Giulio Sullo
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, via P. Maroncelli 40, 47014 Meldola, Italy; (F.G.S.); (C.G.); (A.B.)
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, via P. Maroncelli 40, 47014 Meldola, Italy; (F.G.S.); (C.G.); (A.B.)
| | - Chiara Gallio
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, via P. Maroncelli 40, 47014 Meldola, Italy; (F.G.S.); (C.G.); (A.B.)
| | - Chiara Molinari
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, via P. Maroncelli 40, 47014 Meldola, Italy; (C.M.); (G.M.)
| | - Giorgia Marisi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, via P. Maroncelli 40, 47014 Meldola, Italy; (C.M.); (G.M.)
| | - Eleonora Pozzi
- Department of Medical and Surgical Science, University of Bologna, 47121 Forlì, Italy (L.S.)
| | - Leonardo Solaini
- Department of Medical and Surgical Science, University of Bologna, 47121 Forlì, Italy (L.S.)
| | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, via P. Maroncelli 40, 47014 Meldola, Italy; (F.G.S.); (C.G.); (A.B.)
| |
Collapse
|
|
10
|
Rompen IF, Habib JR, Wolfgang CL, Javed AA. Anatomical and Biological Considerations to Determine Resectability in Pancreatic Cancer. Cancers (Basel) 2024; 16:489. [PMID: 38339242 PMCID: PMC10854859 DOI: 10.3390/cancers16030489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/11/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains associated with poor outcomes with a 5-year survival of 12% across all stages of the disease. These poor outcomes are driven by a delay in diagnosis and an early propensity for systemic dissemination of the disease. Recently, aggressive surgical approaches involving complex vascular resections and reconstructions have become more common, thus allowing more locally advanced tumors to be resected. Unfortunately, however, even after the completion of surgery and systemic therapy, approximately 40% of patients experience early recurrence of disease. To determine resectability, many institutions utilize anatomical staging systems based on the presence and extent of vascular involvement of major abdominal vessels around the pancreas. However, these classification systems are based on anatomical considerations only and do not factor in the burden of systemic disease. By integrating the biological criteria, we possibly could avoid futile resections often associated with significant morbidity. Especially patients with anatomically resectable disease who have a heavy burden of radiologically undetected systemic disease most likely do not derive a survival benefit from resection. On the contrary, we could offer complex resections to those who have locally advanced or oligometastatic disease but have favorable systemic biology and are most likely to benefit from resection. This review summarizes the current literature on defining anatomical and biological resectability in patients with pancreatic cancer.
Collapse
Affiliation(s)
- Ingmar F. Rompen
- Department of Surgery, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Joseph R. Habib
- Department of Surgery, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
| | - Christopher L. Wolfgang
- Department of Surgery, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
| | - Ammar A. Javed
- Department of Surgery, The NYU Grossman School of Medicine and NYU Langone Health, New York, NY 10016, USA
| |
Collapse
|
|
11
|
Yahya J, Baber M, Nabavizadeh N, Goodyear SM, Kardosh A. A Review of Circulating Tumor DNA as a Biomarker Guide for Total Neoadjuvant Therapy in Patients with Locally Advanced Rectal Cancer. J Gastrointest Cancer 2023; 54:1140-1150. [PMID: 36719559 PMCID: PMC10754735 DOI: 10.1007/s12029-022-00906-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2022] [Indexed: 02/01/2023]
Abstract
PURPOSE Non-operative management of patients with locally advanced rectal cancer (LARC) is emerging as a popular approach for patients that have no evidence of disease following neoadjuvant therapy. However, high rates of local recurrence or distant metastases have highlighted the urgent need for robust biomarker strategies to aid clinical management of these patients. METHODS This review summarizes recent advances in the utility of cell-free (cf) and circulating tumor (ct) DNA as potential biomarkers to help guide individualized non-operative management strategies for LARC patients receiving neoadjuvant therapy. RESULTS Liquid biopsies and the detection of cfDNA/ctDNA is an emerging technology with the potential to provide a non-invasive approach to monitor disease response and improve the identification of patients with LARC that would best benefit from non-operative management. CONCLUSIONS Substantial work is still needed before cfDNA/ctDNA monitoring can be widely adopted in the clinical setting. Studies reviewed herein highlight several areas of opportunity for improving the effectiveness and utility of cfDNA/ctDNA for managing patients with LARC.
Collapse
Affiliation(s)
- Jehan Yahya
- Department of Radiation Medicine, Oregon Health & Science University (OHSU), Portland, OR, USA
| | - Miriam Baber
- University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University (OHSU), Portland, OR, USA
- Knight Cancer Institute, OHSU, Portland, OR, USA
| | - Shaun M Goodyear
- Knight Cancer Institute, OHSU, Portland, OR, USA
- Division of Hematology and Oncology, School of Medicine, OHSU, Portland, OR, USA
| | - Adel Kardosh
- Knight Cancer Institute, OHSU, Portland, OR, USA.
- Division of Hematology and Oncology, School of Medicine, OHSU, Portland, OR, USA.
| |
Collapse
|
|
12
|
Honoré N, van Marcke C, Galot R, Helaers R, Ambroise J, van Maanen A, Mendola A, Dahou H, Marbaix E, Van Eeckhout P, Longton E, Magremanne M, Schmitz S, Limaye N, Machiels JP. Tumor-agnostic plasma assay for circulating tumor DNA detects minimal residual disease and predicts outcome in locally advanced squamous cell carcinoma of the head and neck. Ann Oncol 2023; 34:1175-1186. [PMID: 37879442 DOI: 10.1016/j.annonc.2023.09.3102] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing. PATIENTS AND METHODS A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, β = 0.9). RESULTS We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011). CONCLUSIONS Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice.
Collapse
Affiliation(s)
- N Honoré
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - C van Marcke
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - R Galot
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - R Helaers
- Human Molecular Genetics, de Duve Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - J Ambroise
- Center for Applied Molecular Technologies, Institute of Clinical and Experimental Research, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - A van Maanen
- Statistical Support Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - A Mendola
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - H Dahou
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - E Marbaix
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - P Van Eeckhout
- Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - E Longton
- Department of Radiotherapy, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - M Magremanne
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Maxillo-facial Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - S Schmitz
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of ENT and Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - N Limaye
- Department of Genetics of Autoimmune Diseases and Cancer, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - J-P Machiels
- Pôle oncologie, Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium.
| |
Collapse
|
|
13
|
Zhou J, Mo H, Hu D, Zhao X, Zhou H, Pan J. Association of ctDNA detection and recurrence assessment in patients with neoadjuvant treatment. Cancer Med 2023; 12:19794-19806. [PMID: 37746916 PMCID: PMC10587978 DOI: 10.1002/cam4.6544] [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: 05/12/2023] [Revised: 09/02/2023] [Accepted: 09/05/2023] [Indexed: 09/26/2023] Open
Abstract
BACKGROUND The utilization of neoadjuvant therapy is progressively expanding in various clinical settings. However, the absence of a clinically validated biomarker to evaluate the treatment response remains a significant challenge in the field. Circulating tumor DNA (ctDNA) detection, a novel and emerging monitoring approach in the field of oncology, holds promise as a potential prognostic biomarker for patients with cancer. This meta-analysis investigated the clinical significance of ctDNA detection as a predictive tool for cancer recurrence in patients receiving neoadjuvant treatment. METHODS A comprehensive systematic literature search was conducted using public databases to identify relevant studies that investigated the association between ctDNA detection and cancer recurrence in patients receiving neoadjuvant treatment. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CI) were calculated to assess the relationship between cancer recurrence and relevant factors. Cancer recurrence was considered the primary outcome. RESULTS A total of 23 studies encompassing 1590 patients across eight different cancer types were included in the final analysis. Positive ctDNA detection was significantly associated with higher cancer recurrence, especially at post-neoadjuvant treatment and post-surgery time points. The risk values for the different cancer categories and geographic areas also differed significantly. CONCLUSION Our comprehensive meta-analysis revealed a significant positive correlation between ctDNA detection and a higher risk of cancer recurrence in patients receiving neoadjuvant treatment. In addition, the risk of recurrence was influenced by variations in cancer type, timing of detection, and geographic region. These findings highlight the promising clinical applicability of ctDNA as a prognostic marker and monitoring approach for patients with cancer. However, the precise mechanism is unknown and more evidence is needed for further research.
Collapse
Affiliation(s)
- Jiaxin Zhou
- General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
- International School, Jinan University, Guangzhou, China
| | - Haocong Mo
- Department of Physiology, School of Medicine, Jinan University, Guangzhou, China
| | - Dahai Hu
- General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaoxu Zhao
- General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Jinan University, Heyuan, China
| | - Hong Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jinghua Pan
- General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| |
Collapse
|
|
14
|
Xu M, Shi T, Xu R, Chen G, He W. The potential role of minimal/molecular residual disease in colorectal cancer: curative surgery, radiotherapy and beyond. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:203-210. [PMID: 39035199 PMCID: PMC11256684 DOI: 10.1016/j.jncc.2023.05.005] [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: 01/19/2022] [Revised: 04/23/2023] [Accepted: 05/18/2023] [Indexed: 07/23/2024] Open
Abstract
Detection of minimal/molecular residual disease (MRD) based on ctDNA assay develops from hematological malignancies to solid tumors. Generally, there are two mainstream assays in MRD testing technology: tumor-informed and tumor-agnostic. For colorectal cancer (CRC), MRD is used not only to monitor recurrence and predict prognosis, but also to help in clinical decision making and assessment of clinical efficacy in the settings of curative surgery, radiotherapy, chemotherapy and surveillance. Accumulated clinical trials are exploring roles of MRD in early or advanced stages of CRC. Here, we give an overview of how MRD is and will be used in CRC.
Collapse
Affiliation(s)
- Meiyi Xu
- Department of Oncology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Tianhao Shi
- Department of Biology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Ruilian Xu
- Department of Oncology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Gong Chen
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wan He
- Department of Oncology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| |
Collapse
|
|
15
|
Wang XY, Zhang R, Han JH, Chen SQ, Zhao FL, Chen H, Lin J, Fan J, Zhu WW, Lu L, Chen JH. Early Circulating Tumor DNA Dynamics Predict Neoadjuvant Therapy Response and Recurrence in Colorectal Liver Metastases: A Prospective Study. Ann Surg Oncol 2023; 30:5252-5263. [PMID: 37202570 DOI: 10.1245/s10434-023-13604-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/20/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUND For patients with colorectal liver metastases (CRLM) who receive neoadjuvant therapy (NAT), reliable indicators that can early and accurately predict treatment response are lacking. This study was conducted to prospectively investigate the potential of early circulating tumor DNA (ctDNA) dynamics as a precise predictor of NAT response and recurrence in CRLM. METHODS This study prospectively enrolled 34 patients with CRLM who received NAT, with blood samples collected and subjected to deep targeted panel sequencing at two time points: 1 day before the first and the second cycles of NAT. Correlations of ctDNA mean variant allele frequency (mVAF) dynamics and treatment response were assessed. The performance of early ctDNA dynamics in predicting treatment response was assessed and compared with those of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). RESULTS The baseline ctDNA mVAF was significantly associated with pre-NAT tumor diameter (r = 0.65; P < 0.0001). After one cycle of NAT, the ctDNA mVAF declined remarkably (P < 0.0001). The dynamic change in ctDNA mVAF of 50% or more was significantly correlated with better NAT responses. The discriminatory capacity of ctDNA mVAF changes was superior to that of CEA or CA19-9 in predicting radiologic response (area under the curve [AUC], 0.90 vs 0.71 vs 0.61) and pathologic tumor regression grade (AUC, 0.83 vs 0.64 vs 0.67). The early changes in ctDNA mVAF but not CEA or CA19-9 were an independent indicator of recurrence-free survival (RFS) (hazard ratio, 4.0; P = 0.023). CONCLUSIONS For CRLM patients receiving NAT, an early ctDNA change is a superior predictor of treatment response and recurrence compared with conventional tumor markers.
Collapse
Affiliation(s)
- Xiang-Yu Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Rui Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jia-Hao Han
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Shi-Qing Chen
- Department of Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Fei-Long Zhao
- Department of Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Hui Chen
- Department of Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Jing Lin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Fan
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wen-Wei Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jin-Hong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
16
|
Chidharla A, Rapoport E, Agarwal K, Madala S, Linares B, Sun W, Chakrabarti S, Kasi A. Circulating Tumor DNA as a Minimal Residual Disease Assessment and Recurrence Risk in Patients Undergoing Curative-Intent Resection with or without Adjuvant Chemotherapy in Colorectal Cancer: A Systematic Review and Meta-Analysis. Int J Mol Sci 2023; 24:10230. [PMID: 37373376 DOI: 10.3390/ijms241210230] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/07/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for minimal residual disease (MRD) in CRC patients. Recent studies have shown that the ability to detect MRD using ctDNA assay after curative-intent surgery will change how to assess the recurrence risk and patient selection for adjuvant chemotherapy. We performed a meta-analysis of post-operative ctDNA in stage I-IV (oligometastatic) CRC patients after curative-intent resection. We included 23 studies representing 3568 patients with evaluable ctDNA in CRC patient post-curative-intent surgery. Data were extracted from each study to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I-III and oligometastatic stage IV CRC patients. Results showed that the pooled hazard ratio (HR) for recurrence-free survival (RFS) in post-surgical ctDNA-positive versus -negative patients in all stages was 7.27 (95% CI 5.49-9.62), p < 0.00001. Subgroup analysis revealed pooled HRs of 8.14 (95% CI 5.60-11.82) and 4.83 (95% CI 3.64-6.39) for stages I-III and IV CRC, respectively. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA-positive versus -negative patients in all stages was 10.59 (95% CI 5.59-20.06), p < 0.00001. Circulating tumor DNA (ctDNA) analysis has revolutionized non-invasive cancer diagnostics and monitoring, with two primary forms of analysis emerging: tumor-informed techniques and tumor-agnostic or tumor-naive techniques. Tumor-informed methods involve the initial identification of somatic mutations in tumor tissue, followed by the targeted sequencing of plasma DNA using a personalized assay. In contrast, the tumor-agnostic approach performs ctDNA analysis without prior knowledge of the patient's tumor tissue molecular profile. This review highlights the distinctive features and implications of each approach. Tumor-informed techniques enable the precise monitoring of known tumor-specific mutations, leveraging the sensitivity and specificity of ctDNA detection. Conversely, the tumor-agnostic approach allows for a broader genetic and epigenetic analysis, potentially revealing novel alterations and enhancing our understanding of tumor heterogeneity. Both approaches have significant implications for personalized medicine and improved patient outcomes in the field of oncology. The subgroup analysis based on the ctDNA method showed pooled HRs of 8.66 (95% CI 6.38-11.75) and 3.76 (95% CI 2.58-5.48) for tumor-informed and tumor-agnostic, respectively. Our analysis emphasizes that post-operative ctDNA is a strong prognostic marker of RFS. Based on our results, ctDNA can be a significant and independent predictor of RFS. This real-time assessment of treatment benefits using ctDNA can be used as a surrogate endpoint for the development of novel drugs in the adjuvant setting.
Collapse
Affiliation(s)
- Anusha Chidharla
- Department of Medical Oncology, University of Kansas Cancer Center, Kansas City, KS 66205, USA
| | - Eliot Rapoport
- Department of Internal Medicine, Montefiore Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Kriti Agarwal
- Department of Internal Medicine, Hackensack University Medical Center, Hackensack, NJ 07601, USA
| | - Samragnyi Madala
- Department of Medical Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA 55224, USA
| | - Brenda Linares
- Research and Learning Department, Kansas University Medical Center, Kansas City, KS 66211, USA
| | - Weijing Sun
- Department of Medical Oncology, University of Kansas Cancer Center, Kansas City, KS 66205, USA
| | - Sakti Chakrabarti
- Department of Medical Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Anup Kasi
- Department of Medical Oncology, University of Kansas Cancer Center, Kansas City, KS 66205, USA
| |
Collapse
|
|
17
|
Cassese G, Han HS, Yoon YS, Lee JS, Lee B, Cubisino A, Panaro F, Troisi RI. Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives. World J Gastrointest Oncol 2023; 15:911-924. [PMID: 37389109 PMCID: PMC10302990 DOI: 10.4251/wjgo.v15.i6.911] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/17/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.
Collapse
Affiliation(s)
- Gianluca Cassese
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive HPB Surgery and Transplantation Service, Federico II University Hospital, Naples 80131, Italy
| | - Ho-Seong Han
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Jun Suh Lee
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Boram Lee
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Antonio Cubisino
- Department of HPB Surgery and Transplantation, Beaujon Hospital, Clichy 92110, France
| | - Fabrizio Panaro
- Department of Digestive Surgery and Liver Transplantation, CHU Montpellier, Montpellier 34100, France
| | - Roberto Ivan Troisi
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive HPB Surgery and Transplantation Service, Federico II University Hospital, Naples 80131, Italy
| |
Collapse
|
|
18
|
Evaluation of ctDNA in the Prediction of Response to Neoadjuvant Therapy and Prognosis in Locally Advanced Rectal Cancer Patients: A Prospective Study. Pharmaceuticals (Basel) 2023; 16:ph16030427. [PMID: 36986526 PMCID: PMC10057108 DOI: 10.3390/ph16030427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/28/2023] [Accepted: 03/03/2023] [Indexed: 03/18/2023] Open
Abstract
“Watch and wait” is becoming a common treatment option for patients with locally advanced rectal cancer (LARC) submitted to neoadjuvant treatment. However, currently, no clinical modality has an acceptable accuracy for predicting pathological complete response (pCR). The aim of this study was to assess the clinical utility of circulating tumor DNA (ctDNA) in predicting the response and prognosis in these patients. We prospectively enrolled a cohort of three Iberian centers between January 2020 and December 2021 and performed an analysis on the association of ctDNA with the main response outcomes and disease-free survival (DFS). The rate of pCR in the total sample was 15.3%. A total of 24 plasma samples from 18 patients were analyzed by next-generation sequencing. At baseline, mutations were detected in 38.9%, with the most common being TP53 and KRAS. Combination of either positive magnetic resonance imaging (MRI) extramural venous invasion (mrEMVI) and ctDNA increased the risk of poor response (p = 0.021). Also, patients with two mutations vs. those with fewer than two mutations had a worse DFS (p = 0.005). Although these results should be read carefully due to sample size, this study suggests that baseline ctDNA combined with mrEMVI could potentially help to predict the response and baseline ctDNA number of mutations might allow the discrimination of groups with different DFS. Further studies are needed to clarify the role of ctDNA as an independent tool in the selection and management of LARC patients.
Collapse
|
|
19
|
de Abreu AR, Op de Beeck K, Laurent-Puig P, Taly V, Benhaim L. The Position of Circulating Tumor DNA in the Clinical Management of Colorectal Cancer. Cancers (Basel) 2023; 15:1284. [PMID: 36831626 PMCID: PMC9954551 DOI: 10.3390/cancers15041284] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/13/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer type worldwide, with over 1.9 million new cases and 935,000 related deaths in 2020. Within the next decade, the incidence of CRC is estimated to increase by 60% and the mortality by 80%. One of the underlying causes of poor prognosis is late detection, with 60 to 70% of the diagnoses occurring at advanced stages. Circulating cell-free DNA (ccfDNA) is probably the most promising tool for screening, diagnosis, prediction of therapeutic response, and prognosis. More specifically, the analysis of the tumor fraction within the ccfDNA (circulating tumor DNA, ctDNA) has great potential to improve the management of CRC. The present review provides an up-to-date and comprehensive overview of the various aspects related to ctDNA detection in CRC.
Collapse
Affiliation(s)
- Ana Regina de Abreu
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Ken Op de Beeck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium
- Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Pierre Laurent-Puig
- UMR-S1138, CNRS SNC5096, Équipe labélisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Université de Paris, 75006 Paris, France
| | - Valerie Taly
- UMR-S1138, CNRS SNC5096, Équipe labélisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Université de Paris, 75006 Paris, France
| | - Leonor Benhaim
- UMR-S1138, CNRS SNC5096, Équipe labélisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Université de Paris, 75006 Paris, France
- Department of Visceral and Surgical Oncology, Gustave Roussy, Cancer Campus, 114 rue Edouard Vaillant, 94805 Villejuif, France
| |
Collapse
|
|
20
|
van Rees JM, Wullaert L, Grüter AAJ, Derraze Y, Tanis PJ, Verheul HMW, Martens JWM, Wilting SM, Vink G, van Vugt JLA, Beije N, Verhoef C. Circulating tumour DNA as biomarker for rectal cancer: A systematic review and meta-analyses. Front Oncol 2023; 13:1083285. [PMID: 36793616 PMCID: PMC9922989 DOI: 10.3389/fonc.2023.1083285] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/09/2023] [Indexed: 01/31/2023] Open
Abstract
Background Circulating tumour DNA (ctDNA) has been established as a promising (prognostic) biomarker with the potential to personalise treatment in cancer patients. The objective of this systematic review is to provide an overview of the current literature and the future perspectives of ctDNA in non-metastatic rectal cancer. Methods A comprehensive search for studies published prior to the 4th of October 2022 was conducted in Embase, Medline, Cochrane, Google scholar, and Web of Science. Only peer-reviewed original articles and ongoing clinical trials investigating the association between ctDNA and oncological outcomes in non-metastatic rectal cancer patients were included. Meta-analyses were performed to pool hazard ratios (HR) for recurrence-free survival (RFS). Results A total of 291 unique records were screened, of which 261 were original publications and 30 ongoing trials. Nineteen original publications were reviewed and discussed, of which seven provided sufficient data for meta-analyses on the association between the presence of post-treatment ctDNA and RFS. Results of the meta-analyses demonstrated that ctDNA analysis can be used to stratify patients into very high and low risk groups for recurrence, especially when detected after neoadjuvant treatment (HR for RFS: 9.3 [4.6 - 18.8]) and after surgery (HR for RFS: 15.5 [8.2 - 29.3]). Studies investigated different types of assays and used various techniques for the detection and quantification of ctDNA. Conclusions This literature overview and meta-analyses provide evidence for the strong association between ctDNA and recurrent disease. Future research should focus on the feasibility of ctDNA-guided treatment and follow-up strategies in rectal cancer. A blueprint for agreed-upon timing, preprocessing, and assay techniques is needed to empower adaptation of ctDNA into daily practice.
Collapse
Affiliation(s)
- Jan M van Rees
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Lissa Wullaert
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Alexander A J Grüter
- Department of Surgery, Amsterdam University Medical Centres (UMC), Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Yassmina Derraze
- Department of Surgery, Amsterdam University Medical Centres (UMC), Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Pieter J Tanis
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Saskia M Wilting
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Geraldine Vink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands
| | - Jeroen L A van Vugt
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Nick Beije
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| |
Collapse
|
|
21
|
Machado Carvalho JV, Dutoit V, Corrò C, Koessler T. Promises and Challenges of Predictive Blood Biomarkers for Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy. Cells 2023; 12:413. [PMID: 36766755 PMCID: PMC9913546 DOI: 10.3390/cells12030413] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 01/24/2023] [Indexed: 01/27/2023] Open
Abstract
The treatment of locally advanced rectal cancer (LARC) requires a multimodal approach combining neoadjuvant radiotherapy or chemoradiotherapy (CRT) and surgery. Predicting tumor response to CRT can guide clinical decision making and improve patient care while avoiding unnecessary toxicity and morbidity. Circulating biomarkers offer both the advantage to be easily accessed and followed over time. In recent years, biomarkers such as proteins, blood cells, or nucleic acids have been investigated for their predictive value in oncology. We conducted a comprehensive literature review with the aim to summarize the status of circulating biomarkers predicting response to CRT in LARC. Forty-nine publications, of which forty-seven full-text articles, one review and one systematic review, were retrieved. These studies evaluated circulating markers (CEA and CA 19-9), inflammatory biomarkers (CRP, albumin, and lymphocytes), hematologic markers (hemoglobin and thrombocytes), lipids and circulating nucleic acids (cell-free DNA [cfDNA], circulating tumor DNA [ctDNA], and microRNA [miRNA]). Post-CRT CEA levels had the most consistent association with tumor response, while cfDNA integrity index, MGMT promoter methylation, ERCC-1, miRNAs, and miRNA-related SNPs were identified as potential predictive markers. Although circulating biomarkers hold great promise, inconsistent results, low statistical power, and low specificity and sensibility prevent them from reliably predicting tumor response following CRT. Validation and standardization of methods and technologies are further required to confirm results.
Collapse
Affiliation(s)
- Joao Victor Machado Carvalho
- Translational Research Center in Onco-Hematology, Department of Medicine, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland
- Swiss Cancer Center Léman, 1005 Lausanne, Switzerland
- Department of Oncology, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Valérie Dutoit
- Translational Research Center in Onco-Hematology, Department of Medicine, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland
- Swiss Cancer Center Léman, 1005 Lausanne, Switzerland
| | - Claudia Corrò
- Translational Research Center in Onco-Hematology, Department of Medicine, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland
- Swiss Cancer Center Léman, 1005 Lausanne, Switzerland
- Department of Oncology, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Thibaud Koessler
- Translational Research Center in Onco-Hematology, Department of Medicine, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland
- Swiss Cancer Center Léman, 1005 Lausanne, Switzerland
- Department of Oncology, Geneva University Hospital, 1205 Geneva, Switzerland
| |
Collapse
|
|
22
|
Piercey O, Tie J. Circulating tumour DNA in the evolving treatment landscape of locally advanced rectal cancer: where does it fit in? Ther Adv Med Oncol 2023; 15:17588359231160138. [PMID: 36936200 PMCID: PMC10017954 DOI: 10.1177/17588359231160138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 02/03/2023] [Indexed: 03/16/2023] Open
Abstract
The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed.
Collapse
Affiliation(s)
- Oliver Piercey
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | | |
Collapse
|
|
23
|
Xu Y, Zou H, Shao Z, Zhang X, Ren X, He H, Zhang D, Du D, Zou C. Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study. Front Oncol 2023; 13:1119323. [PMID: 36895482 PMCID: PMC9989274 DOI: 10.3389/fonc.2023.1119323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Background This study aims to compare the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) with different radiotherapy doses (45Gy and 50.4Gy) in patients with locally advanced rectal cancer (LARC). Methods Herein, 120 patients with LARC were retrospectively enrolled between January 2016 and June 2021. All patients underwent two courses of induction chemotherapy (XELOX), chemoradiotherapy, and total mesorectum excision (TME). A total of 72 patients received a radiotherapy dose of 50.4 Gy, while 48 patients received a dose of 45 Gy. Surgery was then performed within 5-12 weeks following nCRT. Results There was no statistically significant difference between the baseline characteristics of the two groups. The rate of good pathological response in the 50.4Gy group was 59.72% (43/72), while in the 45Gy group achieved 64.58% (31/48) (P>0.05). The disease control rate (DCR) in the 50.4Gy group was 88.89% (64/72), compared to 89.58% (43/48) in the 45Gy group (P>0.05). The incidence of adverse reactions for radioactive proctitis, myelosuppression, and intestinal obstruction or perforation differed significantly between the two groups (P<0.05). The anal retention rate in the 50.4Gy group was significantly higher in contrast to the 45Gy group (P<0.05). Conclusions Patients receiving a radiotherapy dose of 50.4Gy have a better anal retention rate but also a higher incidence of adverse events such as radioactive proctitis, myelosuppression, and intestinal obstruction or perforation, and a comparable prognosis to patients treated with a radiotherapy dose of 45Gy.
Collapse
Affiliation(s)
- Yuyan Xu
- Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haizhou Zou
- Department of Oncology, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, China
| | - Zhenyong Shao
- Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xuebang Zhang
- Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - XiaoLin Ren
- Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huijuan He
- Department of Radiotherapy, Quzhou People's Hospital, Quzhou, China
| | - Dahai Zhang
- Department of Radiotherapy, Dongyang People's Hospital, Jinhua, China
| | - Dexi Du
- Department of Radiotherapy Oncology, Lishui Central Hospital, Lishui, China
| | - Changlin Zou
- Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
24
|
Pham TT, Lim S, Lin M. Predicting neoadjuvant chemoradiotherapy response with functional imaging and liquid biomarkers in locally advanced rectal cancer. Expert Rev Anticancer Ther 2022; 22:1081-1098. [PMID: 35993178 DOI: 10.1080/14737140.2022.2114457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Non-invasive predictive quantitative biomarkers are required to guide treatment individualization in patients with locally advanced rectal cancer (LARC) in order to maximise therapeutic outcomes and minimise treatment toxicity. Magnetic resonance imaging (MRI), positron emission tomography (PET) and blood biomarkers have the potential to predict chemoradiotherapy (CRT) response in LARC. AREAS COVERED This review examines the value of functional imaging (MRI and PET) and liquid biomarkers (circulating tumor cells (CTCs) and circulating tumor nucleic acid (ctNA)) in the prediction of CRT response in LARC. Selected imaging and liquid biomarker studies are presented and the current status of the most promising imaging (apparent diffusion co-efficient (ADC), Ktrans, SUVmax, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and liquid biomarkers (circulating tumor cells (CTCs), circulating tumor nucleic acid (ctNA)) is discussed. The potential applications of imaging and liquid biomarkers for treatment stratification and a pathway to clinical translation are presented. EXPERT OPINION Functional imaging and liquid biomarkers provide novel ways of predicting CRT response. The clinical and technical validation of the most promising imaging and liquid biopsy biomarkers in multi-centre studies with harmonised acquisition techniques is required. This will enable clinical trials to investigate treatment escalation or de-escalation pathways in rectal cancer.
Collapse
Affiliation(s)
- Trang Thanh Pham
- South West Sydney Clinical School, Faculty of Medicine and Health, University of New South Wales, Liverpool NSW Australia 2170.,Department of Radiation Oncology, Liverpool Cancer Therapy Centre, Liverpool Hospital, Liverpool NSW Australia 2170.,Ingham Institute for Applied Medical Research, Liverpool NSW Australia 2170
| | - Stephanie Lim
- Ingham Institute for Applied Medical Research, Liverpool NSW Australia 2170.,Department of Medical Oncology, Macarthur Cancer Therapy Centre, Campbelltown Hospital, Campbelltown Australia 2560.,School of Medicine, Western Sydney University, Campbelltown, Sydney 2560
| | - Michael Lin
- South West Sydney Clinical School, Faculty of Medicine and Health, University of New South Wales, Liverpool NSW Australia 2170.,School of Medicine, Western Sydney University, Campbelltown, Sydney 2560.,Department of Nuclear Medicine, Liverpool Hospital, Liverpool NSW Australia 2170
| |
Collapse
|
|
25
|
Eibl RH, Schneemann M. Cell-free DNA as a biomarker in cancer. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2022; 3:195-215. [PMID: 39697490 PMCID: PMC11648514 DOI: 10.20517/evcna.2022.20] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/07/2022] [Accepted: 07/26/2022] [Indexed: 12/20/2024]
Abstract
Translational research of liquid biopsy is just at the edge of routine clinical application: an emerging validity of circulating tumor DNA (ctDNA) tests suggests its use for earlier cancer detection and better monitoring of minimal residual disease (MRD) and resistance development, thus offering earlier guidance for therapy choices with the intent to cure cancer. In this review, we focus on ctDNA as an advanced and standardized validated marker in liquid biopsy. We also discuss what will be needed to reach the new milestone of personalized (precision) medicine to be used as a common standard of care. We summarize recent developments of cell-free DNA (cfDNA) and its clinical use as a biomarker in cancer.
Collapse
Affiliation(s)
- Robert H. Eibl
- c/o M. Schneemann, Department of Internal Medicine, Hospitals of Schaffhausen, 8208 Schaffhausen, Switzerland
| | - Markus Schneemann
- Department of Internal Medicine, Hospitals of Schaffhausen, 8208 Schaffhausen, Switzerland
| |
Collapse
|
|
26
|
Mauri G, Vitiello PP, Sogari A, Crisafulli G, Sartore-Bianchi A, Marsoni S, Siena S, Bardelli A. Liquid biopsies to monitor and direct cancer treatment in colorectal cancer. Br J Cancer 2022; 127:394-407. [PMID: 35264786 PMCID: PMC9346106 DOI: 10.1038/s41416-022-01769-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/02/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide. Despite recent improvements in treatment and prevention, most of the current therapeutic options are weighted by side effects impacting patients' quality of life. Better patient selection towards systemic treatments represents an unmet clinical need. The recent multidisciplinary and molecular advancements in the treatment of CRC patients demand the identification of efficient biomarkers allowing to personalise patient care. Currently, core tumour biopsy specimens represent the gold-standard biological tissue to identify such biomarkers. However, technical feasibility, tumour heterogeneity and cancer evolution are major limitations of this single-snapshot approach. Genotyping circulating tumour DNA (ctDNA) has been addressed as potentially overcoming such limitations. Indeed, ctDNA has been retrospectively demonstrated capable of identifying minimal residual disease post-surgery and post-adjuvant treatment, as well as spotting druggable molecular alterations for tailoring treatments in metastatic disease. In this review, we summarise the available evidence on ctDNA applicability in CRC. Then, we review ongoing clinical trials assessing how liquid biopsy can be used interventionally to guide therapeutic choice in localised, locally advanced and metastatic CRC. Finally, we discuss how its widespread could transform CRC patients' management, dissecting its limitations while suggesting improvement strategies.
Collapse
Affiliation(s)
- Gianluca Mauri
- IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Pietro Paolo Vitiello
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy
| | - Alberto Sogari
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy
| | - Giovanni Crisafulli
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
| | | | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
| | - Alberto Bardelli
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy.
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy.
| |
Collapse
|
|
27
|
Finding Waldo: The Evolving Paradigm of Circulating Tumor DNA (ctDNA)—Guided Minimal Residual Disease (MRD) Assessment in Colorectal Cancer (CRC). Cancers (Basel) 2022; 14:cancers14133078. [PMID: 35804850 PMCID: PMC9265001 DOI: 10.3390/cancers14133078] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary After the surgical removal of colorectal cancer (CRC), residual cancer cells undetectable by standard blood tests and imaging studies are responsible for cancer recurrence. Currently, chemotherapy is often administered after surgery to eradicate residual cancer cells, a decision guided by clinical and pathologic criteria, which are imprecise. Circulating tumor DNA (ctDNA) consists of DNA fragments in the bloodstream derived from cancer cells, and the presence of ctDNA likely indicates the presence of residual cancer cells. The current article discusses how ctDNA technology can help guide treatment in patients with CRC after curative surgery. Abstract Circulating tumor DNA (ctDNA), the tumor-derived cell-free DNA fragments in the bloodstream carrying tumor-specific genetic and epigenetic alterations, represents an emerging novel tool for minimal residual disease (MRD) assessment in patients with resected colorectal cancer (CRC). For many decades, precise risk-stratification following curative-intent colorectal surgery has remained an enduring challenge. The current risk stratification strategy relies on clinicopathologic characteristics of the tumors that lacks precision and results in over-and undertreatment in a significant proportion of patients. Consequently, a biomarker that can reliably identify patients harboring MRD would be of critical importance in refining patient selection for adjuvant therapy. Several prospective cohort studies have provided compelling data suggesting that ctDNA could be a robust biomarker for MRD that outperforms all existing clinicopathologic criteria. Numerous clinical trials are currently underway to validate the ctDNA-guided MRD assessment and adjuvant treatment strategies. Once validated, the ctDNA technology will likely transform the adjuvant therapy paradigm of colorectal cancer, supporting ctDNA-guided treatment escalation and de-escalation. The current article presents a comprehensive overview of the published studies supporting the utility of ctDNA for MRD assessment in patients with CRC. We also discuss ongoing ctDNA-guided adjuvant clinical trials that will likely shape future adjuvant therapy strategies for patients with CRC.
Collapse
|
|
28
|
Lee HH, Chen CH, Huang YH, Chiang CH, Huang MY. Biomarkers of Favorable vs. Unfavorable Responses in Locally Advanced Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy. Cells 2022; 11:cells11101611. [PMID: 35626648 PMCID: PMC9139800 DOI: 10.3390/cells11101611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/27/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer is the second leading cause of cancer death globally. The gold standard for locally advanced rectal cancer (LARC) nowadays is preoperative concurrent chemoradiation (CCRT). Approximately three quarters of LARC patients do not achieve pathological complete response and hence suffer from relapse, metastases and inevitable death. The exploration of trustworthy and timely biomarkers for CCRT response is urgently called for. This review focused upon a broad spectrum of biomarkers, including circulating tumor cells, DNA, RNA, oncogenes, tumor suppressor genes, epigenetics, impaired DNA mismatch repair, patient-derived xenografts, in vitro tumor organoids, immunity and microbiomes. Utilizing proper biomarkers can assist in categorizing appropriate patients by the most efficient treatment modality with the best outcome and accompanied by minimal side effects. The purpose of this review is to inspect and analyze accessible data in order to fully realize the promise of precision oncology for rectal cancer patients.
Collapse
Affiliation(s)
- Hsin-Hua Lee
- Ph.D. Program in Environmental and Occupational Medicine, National Health Research Institutes, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chien-Hung Chen
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Radiation Oncology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 801, Taiwan
| | - Yu-Hsiang Huang
- Post-Graduate Year Training, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Cheng-Han Chiang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
| | - Ming-Yii Huang
- Ph.D. Program in Environmental and Occupational Medicine, National Health Research Institutes, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 7158)
| |
Collapse
|
|
29
|
Optimized tools and timing of response reassessment after neoadjuvant chemoradiation in rectal cancer. Int J Colorectal Dis 2022; 37:2321-2333. [PMID: 36243807 PMCID: PMC9569175 DOI: 10.1007/s00384-022-04268-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/08/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Reassessment tools of response to long-course neoadjuvant chemoradiation treatment (nCRT) in patients with locally advanced rectal cancer (LARC) are important in predicting complete response (CR) and thus deciding whether a wait-and-watch strategy can be implemented in these patients. Choosing which routine reassessment tools are optimal and when to use them is still unclear and will be researched in the study. METHODS Altogether, 250 patients with LARC who received nCRT from 2013 to 2021 and were followed up were retrospectively reviewed. Common reassessment tools of response included digital rectal examination (DRE), clinical examination and symptoms, endoscopy, biopsy, magnetic resonance imaging (MRI), and blood biomarkers. RESULTS Overall, 27.20% (68/250) patients had a complete response and 72.80% (182/250) did not. The combination of MRI, endoscopy, and biopsy showed the best performance in terms of accuracy of 74% and area under the curve (AUC, 0.714, 95% CI 0.546-0.882). Reassessing through DRE and presence of symptoms failed to improve the efficacy of response reassessment. After 100 days, biopsy as an assessment tool would obtain a substantial rise in accuracy from 51.28 to 100% (p = 0.003). CONCLUSION The combination of MRI, endoscopy, and biopsy is suitable as the reassessment tool of response for applying a wait-and-watch strategy after long-course nCRT in patients with LARC. The accuracy of biopsy as reassessment tools would be improved if they were used over 100 days after nCRT in patients with rectal cancer.
Collapse
|
|
30
|
Wan JCM, Mughal TI, Razavi P, Dawson SJ, Moss EL, Govindan R, Tan IB, Yap YS, Robinson WA, Morris CD, Besse B, Bardelli A, Tie J, Kopetz S, Rosenfeld N. Liquid biopsies for residual disease and recurrence. MED 2021; 2:1292-1313. [PMID: 35590147 DOI: 10.1016/j.medj.2021.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/27/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023]
Abstract
Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors.
Collapse
Affiliation(s)
| | - Tariq Imdadali Mughal
- Tufts University School of Medicine, Boston, MA 02111, USA; University of Buckingham, Buckingham MK18 1EG, UK
| | - Pedram Razavi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | | | - Esther Louise Moss
- Leicester Cancer Research Centre, College of Life Sciences, University of Leicester, Leicester LE1 7RH, UK; Department of Gynaecological Oncology, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester LE5 4PW, UK
| | | | - Iain Beehuat Tan
- Division of Medical Oncology, National Cancer Centre Singapore, 169610 Singapore, Singapore
| | - Yoon-Sim Yap
- Division of Medical Oncology, National Cancer Centre Singapore, 169610 Singapore, Singapore
| | | | | | - Benjamin Besse
- Department of Cancer Medicine, Institut Gustave Roussy Cancer Center, 94805 Villejuif, France
| | - Alberto Bardelli
- Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo TO, Italy; Department of Oncology, University of Turin, 10060 Candiolo TO, Italy
| | - Jeanne Tie
- Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Scott Kopetz
- MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nitzan Rosenfeld
- Inivata, Cambridge CB22 3FH, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK.
| |
Collapse
|
|
31
|
Mendis S, To YH, Tie J. Biomarkers in Locally Advanced Rectal Cancer: A Review. Clin Colorectal Cancer 2021; 21:36-44. [PMID: 34961731 DOI: 10.1016/j.clcc.2021.11.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 11/03/2022]
Abstract
Locally advanced rectal cancers (LARC) are the subject of a rapidly evolving treatment paradigm. The critical timepoints where management decisions are required during the care of the LARC patient are: prior to the institution of any treatment, post neoadjuvant therapy and post-surgery. This article reviews the clinical, imaging, blood-based, tissue-based, and molecular biomarkers that can assist clinicians at these timepoints in the patient's management, in prognosticating for their LARC patients or in predicting responses to therapy in the multi-modality neoadjuvant treatment era.
Collapse
Affiliation(s)
- Shehara Mendis
- Walter and Eliza Hall Institute, 1G Royal Parade, Parkville VIC 3052, Australia; 2. Western Health, Melbourne, VIC, Australia.
| | - Yat Hang To
- Walter and Eliza Hall Institute, 1G Royal Parade, Parkville VIC 3052, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Jeanne Tie
- Walter and Eliza Hall Institute, 1G Royal Parade, Parkville VIC 3052, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| |
Collapse
|
|
32
|
Honoré N, Galot R, van Marcke C, Limaye N, Machiels JP. Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact. Cancers (Basel) 2021; 13:5364. [PMID: 34771526 PMCID: PMC8582541 DOI: 10.3390/cancers13215364] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients.
Collapse
Affiliation(s)
- Natasha Honoré
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
| | - Rachel Galot
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Cédric van Marcke
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Nisha Limaye
- Genetics of Autoimmune Diseases and Cancer, de Duve Institute, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium;
| | - Jean-Pascal Machiels
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| |
Collapse
|
|
33
|
Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13184547. [PMID: 34572774 PMCID: PMC8471730 DOI: 10.3390/cancers13184547] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Circulating tumor DNA, or ctDNA, are fragments of tumor DNA that can be detected in the blood of patients with colorectal cancer. Measuring ctDNA levels in the blood has shown the potential to provide important information that can be helpful in the clinical care of patients with colorectal cancer. For example, in patients with colon cancer that has been removed by surgery, measuring ctDNA in the blood can predict the likelihood of cancer recurrence, while in those with metastatic colorectal cancer, measuring ctDNA can inform the clinician whether chemotherapy is effective at earlier timepoints than currently available tests. In this review, we discuss the results from ongoing studies describing the utility of ctDNA measurements across all stages of colorectal cancer. We also discuss the various clinical scenarios that ctDNA may have the most immediate impact in colorectal cancer management. Abstract Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.
Collapse
|
|
34
|
Morais M, Pinto DM, Machado JC, Carneiro S. ctDNA on liquid biopsy for predicting response and prognosis in locally advanced rectal cancer: A systematic review. Eur J Surg Oncol 2021; 48:218-227. [PMID: 34511270 DOI: 10.1016/j.ejso.2021.08.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 08/31/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The management of locally advanced rectal cancer (LARC) requires a multidisciplinary approach, with an increasing interest for non-operative strategies. Liquid biopsy for obtaining circulating tumor DNA (ctDNA) can provide information on neoadjuvant chemoradiotherapy (nCRT) pathological response and cancer-specific prognosis, and therefore might be a promising guide for these treatments. METHODS A systematic review of the studies available in literature has been performed to assess the role of ctDNA as a predictive and prognostic biomarker in LARC patients. RESULTS We retrieved 21 publications, of which 17 full-text articles and 4 abstracts. Results have been labelled into two groups: predictive and prognostic. Data about the usefulness of liquid biopsy in this setting is still inconclusive. However, baseline higher levels of longer fragments of cell-free DNA and integrity index, tumor-specific mutations and certain methylated genes could predict non-responders. Also, undetectable baseline ctDNA and decrease of common rectal cancer mutations throughout treatment (dynamic monitoring) were predictive factors of pathological complete response. The continuous detection of ctDNA in different timepoints of treatment (minimal residual disease) was consistently associated with worse prognosis. CONCLUSIONS ctDNA is a promising biomarker that could assist predicting treatment response to nCRT and prognosis in patients with LARC. The ideal methods and timings for the liquid biopsy still have to be defined.
Collapse
Affiliation(s)
- Marina Morais
- Surgery Department, Hospital Pedro Hispano, Matosinhos, Portugal; Surgery Department, Faculty of Medicine, University of Porto, Porto, Portugal.
| | - Diogo Melo Pinto
- Surgery Department, Hospital Pedro Hispano, Matosinhos, Portugal
| | - José Carlos Machado
- I3S - Institute for Research and Innovation in Health and IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Pathology Department, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvestre Carneiro
- Surgery Department, Faculty of Medicine, University of Porto, Porto, Portugal; Surgery Department, Centro Hospitalar de São João, Porto, Portugal
| |
Collapse
|
|
35
|
Biomarkers and cell-based models to predict the outcome of neoadjuvant therapy for rectal cancer patients. Biomark Res 2021; 9:60. [PMID: 34321074 PMCID: PMC8317379 DOI: 10.1186/s40364-021-00313-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022] Open
Abstract
Rectal cancer constitutes approximately one-third of all colorectal cancers and contributes to considerable mortality globally. In contrast to colon cancer, the standard treatment for localized rectal cancer often involves neoadjuvant chemoradiotherapy. Tumour response rates to treatment show substantial inter-patient heterogeneity, indicating a need for treatment stratification. Consequently researchers have attempted to establish new means for predicting tumour response in order to assist in treatment decisions. In this review we have summarized published findings regarding potential biomarkers to predict neoadjuvant treatment response for rectal cancer tumours. In addition, we describe cell-based models that can be utilized both for treatment prediction and for studying the complex mechanisms involved.
Collapse
|