In recent years, the continuous optimization of anti-tumor therapy has greatly improved the cancer-specific survival rate for patients with breast cancer (BC). The prevention and treatment of breast cancer-related heart diseases have become a new breakthrough in improving the long-term survival for BC patient. The cardiac damages caused by BC treatment are increasingly prominent among BC patients, of which ischemic heart disease (IHD) is the most prominent. Besides, the systemic inflammatory response activated by tumor microenvironment c an induce and exacerbate IHD and increase the risk of myocardial infarction (MI). Conversely, IHD can also exert detrimental effects on tumors. MI not only increases the risk of BC, but also induces specialized immune cell to BC and accelerates the progression of BC. Meanwhile, the treatment of IHD can also promote BC metastasis and transition to more aggressive phenotypes. Although BC and IHD are diseases of two independent systems, their crosstalk increases the difficulty of anti-cancer treatment and IHD management, which reduces the survival for both diseases. Therefore, this review mainly explores the mutual influence and underlying mechanisms between BC and IHD, aiming to provide insights for improving the long-term survival for patients with BC or IHD.

HER2-positive breast cancer (BC) is highly aggressive with a poor prognosis. It is driven by HER2 oncoprotein activation/crosstalk with other receptors like EGFR/(HER1), HER3, and HER4, in addition to IGF-1R, making these receptors ideal therapeutic targets as they are expressed/overexpressed in this subtype. We postulated that targeting HER2 and IGF-1R together is a promising therapy for HER2-positive BC. Thus, we explored the outcome of a novel combination treatment using neratinib, a pan-HER inhibitor, and metformin, an IGF-1R inhibitor, on HER2-positive BC cells.

In this investigation, we used cellular and molecular biology techniques in addition to an angiogenesis model and tissue microarray analysis.

Our data revealed that this combination therapy significantly reduced cell viability compared to individual treatments and exhibited a synergistic effect in HER2-positive BC cells. Moreover, the combination disrupted cell cycle progression and inhibited colony formation, and invasion of HER2-positive BC cells; this is accompanied by the deregulation of HER1-3 and IGF-1R expression patterns, in addition to Caspase-3, BCL2, Fascin, and Vimentin. Moreover, key regulator molecular pathways, including, ERK1/2, AKT, p38 MAPK, and mTOR, were significantly downregulated upon treatment with neratinib and metformin combination. Additionally, our data pointed out that neratinib and metformin combination inhibited angiogenesis, in-ovo, an important biological event in cancer progression. Finally, using a cohort of 55 HER2-positive BC samples, we revealed that HER2 and IGF-1R are co-expressed in most of the cases.

These findings suggest that neratinib and metformin combination can present a promising strategy for targeting multiple pathways in HER2-positive BC.

EGFR and HER2 dual TKIs have been approved for the treatment of advanced breast cancer in patients who are HER2-positive for second and/or third-line treatment. However, there is a lack of attention to the cardiovascular adverse events (AEs) caused by EGFR and HER2 dual TKIs.

We analyzed data spanning between March 2007 and June 2024 using the FAERS database and the reporting odds ratio, proportional reporting ratio, and Bayesian confidence propagation neural network to perform disproportionality analysis.

Compared with non-cardiovascular AEs, cardiovascular AEs were associated with more severe clinical outcomes, such as higher rates of hospitalization, life-threatening events, disability, and death. Our analysis revealed that lapatinib had a higher-than-expected reporting rate for three SMQs, including cardiac failure, embolic and thrombotic events, and cardiomyopathy. No significant cardiovascular signals were observed for neratinib.

Disproportionality analysis results revealed a positive signal for cardiac failure, embolic and thrombotic events, and cardiomyopathy of lapatinib, and no positive signal for neratinib. We should pay attention to high-risk signals in clinical practice and monitor them appropriately.

Studies have shown that some antineoplastic agents may be associated with interstitial lung disease (ILD), but large-scale real-world data are lacking. This study aimed to detect signals of disproportionate reporting for ILD associated with novel antineoplastic agents used in breast cancer treatment.

In this pharmacovigilance study, we collected data from the FDA Adverse Event Reporting System (FAERS; Jan 01, 2004-Dec 31, 2023) and the Japanese Adverse Drug Event Report (JADER; Jan 01, 2004-Mar 31, 2024) databases. Data retrieval involved direct download of structured datasets from the FDA and PMDA portals. Participant selection included reports of FDA-approved novel antineoplastic agents for breast cancer with documented ILD as a preferred term, excluding duplicates, non-breast cancer indications, unapproved drugs, and cases where drugs were classified as concomitant or interacting. Signals of disproportionate reporting were assessed using the reporting odds ratio (ROR), with statistical significance defined as a lower 95% confidence interval >1 and ≥3 ILD cases.

A total of 2913 patients with ILD from FAERS and 1868 from JADER were analysed. We identified 9 agents with reporting signals for ILD in FAERS: ROR and 95% confidence interval (CI) for trastuzumab deruxtecan was 12.17 (95% CI 11.04-13.41), atezolizumab 6.04 (5.02-7.28), everolimus 3.21 (2.95-3.50), abemaciclib 2.87 (2.52-3.27), pertuzumab 2.84 (2.49-3.25), olaparib 2.29 (1.65-3.19), trastuzumab emtansine 2.27 (1.91-2.69), pembrolizumab 2.06 (1.65-2.58), and trastuzumab 1.36 (1.25-1.49). 7 drugs associated with ILD in JADER are also captured in FAERS. Fatal cases presented with a shorter median onset time compared to nonfatal cases (56 vs. 71 days in FAERS, P = 0.015; 59 vs. 76.5 days in JADER, P = 0.046). Analyses indicated stronger reporting associations between novel antineoplastic agents and ILD compared to chemotherapeutics (FAERS: OR 2.47, 2.16-2.81; JADER: OR 1.61, 1.37-1.88; P < 0.0001). ILD reports were more frequent among older patients (FAERS: HR 1.0097, 1.0036-1.0159, P = 0.0020; JADER: HR 1.0183, 1.0094-1.0270, P < 0.0001), while higher weight correlated with fewer reports (FAERS: HR 0.9783, 0.9729-0.9836; P < 0.0001).

Our study detected signals of disproportionate reporting for ILD with some novel antineoplastic agents in breast cancer, fatal cases had a shorter median onset time than nonfatal ones. Novel antineoplastic agents showed stronger signal of disproportionate reporting associations with ILD than chemotherapeutics. Older age and lower weight were associated with more frequent ILD reports. The limitations-including incomplete data, inherent pharmacovigilance biases, and coprescription bias-preclude causal interpretation of the observed associations and may lead to overestimation or underestimation of reporting signals. These findings highlight the need for vigilant ILD monitoring but require validation through prospective studies to clarify true clinical risks.

None.

Breast cancer is one of the leading causes of cancer-related mortality in women worldwide, highlighting the importance of effective therapies. This study evaluates the interaction between camptothecin, a potent anticancer agent, and two key receptors implicated in breast cancer progression: HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor), using molecular docking. The results reveal a stronger binding affinity between camptothecin and HER2 than EGFR, in contrast to neratinib, which demonstrated affinity exclusively for HER2. Camptothecin exhibits significant hydrophobic and pi-alkyl interactions with HER2, whereas its interactions with EGFR are primarily mediated by hydrogen bonds. Molecular dynamics (MD) simulations of the camptothecin-HER2 complex indicate stable binding, with minimal fluctuations observed over 100 nanoseconds, confirming the stability of the ligand-receptor interaction. Pharmacokinetic evaluations, based on Lipinski's rule of five, demonstrate that camptothecin adheres to essential drug-likeness parameters, suggesting favorable bioavailability. Furthermore, the analysis comparing the pharmacological properties of camptothecin with other well-known anticancer compounds, such as neratinib, shows that camptothecin exhibited superior compliance with drug-likeness rules. Despite its low solubility, the binding stability and pharmacokinetic profile suggest its potential as an effective therapeutic agent for breast cancer, particularly when combined with drug delivery systems that enhance solubility. This work underscores the importance of receptor-specific ligand interactions in drug design and highlights the need for further studies into camptothecin's clinical applications, especially in HER2-positive breast cancer treatment.

This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.

To identify adverse event (ADE) signals of three tyrosine kinase inhibitors (TKIs) (Tucatinib, Lapatinib, and Neratinib) used for HER-2 positive breast cancer by utilizing the FAERS database, and to analyze their safety profiles to provide references for clinical risk management.

Data from the FAERS database spanning Q1 2015 to Q3 2024 were retrieved, including reports where Tucatinib, Lapatinib, or Neratinib was identified as the primary suspect drug. Disproportionality analysis (ROR, PRR) and the Comprehensive Standard method were employed to detect potential ADE signals. The distribution of ADEs across different System Organ Classifications (SOCs) was also analyzed.

A total of 7,848 ADE reports were analyzed, identifying 557 significant signals. The primary ADEs were concentrated in gastrointestinal disorders, general conditions, administration site reactions, and skin and subcutaneous tissue disorders. Neratinib exhibited higher gastrointestinal toxicity, Lapatinib was associated with notable skin toxicities, and Tucatinib showed specific adverse reactions linked to combination therapies.

The three TKIs demonstrated distinct ADE signal profiles, with gastrointestinal, systemic, and skin toxicities being the major areas of concern. Future research should validate these findings and develop effective management strategies to enhance treatment safety and improve the quality of life for HER-2 positive breast cancer patients.

Brain metastasis remains an unmet clinical need in advanced cancers with an increasing incidence and poor prognosis. The limited response to various treatments is mainly derived from the presence of the substantive barrier, blood-brain barrier (BBB) and brain-tumour barrier (BTB), which hinders the access of potentially effective therapeutics to the metastatic tumour of the brain. Recently, the understanding of the structural and molecular features of the BBB/BTB has led to the development of efficient strategies to enhance BBB/BTB permeability and deliver drugs across the BBB/BTB to elicit the anti-tumour response against brain metastasis. Meanwhile, novel agents capable of penetrating the BBB have rapidly developed and been evaluated in preclinical studies and clinical trials, with both targeted therapies and immunotherapies demonstrating impressive intracranial activity against brain metastasis. In this review, we summarize the recent advances in the biological properties of the BBB/BTB and the emerging strategies for BBB/BTB permeabilization and drug delivery across the BBB/BTB. We also discuss the emerging targeted therapies and immunotherapies against brain metastasis tested in clinical trials. Additionally, we provide our viewpoints on accelerating clinical translation of novel drugs into clinic for patients of brain metastasis. Although still challenging, we expect this review to benefit the future development of novel therapeutics, specifically from a clinical perspective.

Triple-positive breast cancer (TPBC), a unique subtype of luminal breast cancer, is characterized by concurrent positivity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the crosstalk between the ER and HER2 signaling pathways, the standard of care and drug resistance of this particular subtype are difficult challenges. Recent research and clinical trials have indicated a shift in the treatment paradigm for TPBC from single-target therapies to multi-pathway, multitarget strategies aiming to comprehensively modulate intricate signaling networks, thereby overcoming resistance and enhancing therapeutic outcomes. Among multiple strategies, triple-drug therapy has emerged as a promising treatment modality, demonstrating potential efficacy in patients with TPBC. Moving forward, there is a critical need to perform in-depth analyses of specific mechanisms of cancer pathogenesis and metastasis, decipher the complex interactions between different genes or proteins, and identify concrete molecular targets, thus paving the way for the development of tailored therapeutic strategies to combat TPBC effectively.

Data about the clinical impact of human epidermal growth factor receptor 2 (HER2)-low expression in BRCA1/2-mutated breast cancer (BC) are limited. This study aimed to clarify the clinical relevance of HER2-low in operable BRCA1/2-mutated BC.

A total of 495 HER2-negative operable BC with germline BRCA1/2 pathogenic variants treated at our institute between October 2003 and September 2020 were included. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization-negative, while HER2-zero as IHC 0. Tumor DNA from 25 BRCA1/2-mutated triple-negative BCs (TNBCs) was subjected to whole-exome sequencing.

Among the 186 BRCA1 carriers, 38.8% of TNBC (n = 121) and 52.3% of hormone receptor-positive/HER2-negative BC (n = 65) exhibited HER2-low tumors in the BRCA1 subgroup; among 309 BRCA2 carriers, 44.9% of TNBC (n = 49) and 68.1% of hormone receptor-positive/HER2-negative BC (n = 260) exhibited HER2-low tumors in the BRCA2 subgroup. After a median follow-up of 10.9 years (range, 1.23-19.8 years), among BRCA1-mutated TNBC, HER2-low tumors were significantly associated with better recurrence-free survival (RFS; 10-year RFS: 90.3% v 75.1%; P = .015), distant recurrence-free survival (DRFS; 10-year DRFS: 92.4% v 76.5%; P = .010), and overall survival (OS; 10-year OS: 94.6% v 77.4%; P = .007) than HER2-zero tumors. However, the impact of HER2-low in survival was not observed either in BRCA2-mutated TNBC or in BRCA1- and BRCA2-mutated hormone receptor-positive/HER2-negative BC. Notably, BRCA1-mutated TNBC with HER2-low tumors showed higher homologous recombination deficiency scores than those with HER2-zero tumors.

BRCA1-mutated TNBC patients with HER2-low tumors have a significantly favorable survival, highlighting the possibility of stratifying these patients into two subgroups on the basis of HER2-low status.

Breast cancer remains the most prevalent malignancy among women globally and ranks as the leading cause of cancer-related mortality in this demographic. Approximately 13 %-15 % of all breast cancer cases are classified as HER2-positive, a subtype associated with a particularly unfavorable prognosis. A large number of patients with HER2-positive breast cancer continue to face disease progression after receiving standardized treatment. Given these challenges, a thorough exploration into the mechanisms underlying drug resistance in HER2-targeted therapy is imperative. This review focuses on the factors related to drug resistance in HER2-targeted therapy, including tumor heterogeneity, antibody-binding efficacy, variations in the tumor microenvironment, and abnormalities in signal activation and transmission. Additionally, corresponding strategies to counteract these resistance mechanisms are discussed, to advance therapeutic efficacy and clinical benefits in the management of HER2-positive breast cancer.

Lapatinib, an FDA-approved tyrosine kinase inhibitor, treats HER2+ advanced/metastatic breast cancer. This study comprehensively analyzed its adverse reaction profile using FDA Adverse Event Reporting System (FAERS) to guide clinical use.

Adverse event (AE) reports for lapatinib from the second quarter of 2007 to the second quarter of 2024 in FAERS were analyzed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinkage (MGPS) and Bayesian Confidence Propagation Neural Network (BCPNN) to identify AE signals.

Among 8300 AE reports, females (91.47%) and ages 40-59.9 (33.71%) were predominant. 20 system organ classifications (SOCs) were affected, with gastrointestinal disorders (ROR = 3.46) and skin disorders (ROR = 2.47) most significant. Based on the PT level, a total of 111 PTs were analyzed that met the four algorithms, including typical AEs such as diarrhea (n = 3410), vomiting (n = 856), and rash (n = 856), as well as some rare AEs that were not prompted by the drug inserts, such as neutropenia (n = 252), pericardial effusion (n = 43), lymphedema (n = 20). The majority of lapatinib-associated AEs had onset within 30 days (51%).

Lapatinib has a generally favorable safety profile, but gastrointestinal toxicity and dermatotoxicity require close monitoring to prevent serious AEs.

Lung adenocarcinoma (LUAD) is a common pathological category of lung cancer. Circadian rhythm (CR) disruption has been demonstrated to impact on lung tumorigenesis in mouse models. The aim of this study was to mine genes relevant to CR in LUAD and construct a corresponding risk model.

CRRGs from GSEA-MsigDB were filtered by overlapping DEGs in LUAD and NC specimens, two clusters with survival and clinical discrepancies, and CRRGs. Cox regression analysis (univariate and multivariate) was used to establish a CR-relevant risk model, which was validated in both the training and validation sets. Differences in immune infiltration, immunotherapy, and drug sensitivity between subgroups were explored. Prognostic gene expression was tested in clinical cancer and paracancer tissue samples using RT-qPCR.

A grand total of two prognostic genes (CDK1 and HLA-DMA) related to CR were screened. The AUC values of a CR-relevant risk model in predicting 1/3/5-years survival in LUAD patients were greater than 0.6, indicating that the efficiency of the model was decent. Then, the results of CIBERSORT demonstrated noticeable differences in the tumor microenvironment between CR-relevant high- and low-risk subgroups. In addition, the CR-relevant risk score could be performed to estimate the effectiveness of immunotherapy in LUAD patients. The sensitivity of three common drugs (homoharringtonine, lapatinib, and palbociclib) in LUAD could be evaluated by the CR-relevant risk model. Ultimately, the experimental results confirmed that the expression trends of CDK1 and HLA-DMA in our collected clinical samples were in line with the expression trends in the TCGA-LUAD dataset.

In conclusion, a CR-relevant risk model based on CDK1 and HLA-DMA was constructed by using bioinformatics analysis, which might supply a new insight into the improved prognosis of LUAD.

Antibody drug conjugates (ADCs) are novel drugs that exert specific cytotoxicity against breast cancer. Although ADCs such as trastuzumab emtansine and trastuzumab deruxtecan have significantly improved survival for patients with breast cancer expressing HER2, there is still controversy over options after ADCs. The radiotherapy and ablation should also be used as an effective strategy for oligoprogressions. Herein, we conducted a review of ADCs, and then discussed several strategies to maximize the potential benefit to patients with HER2 expression breast cancer.

Human epidermal growth factor receptor 2 (HER2)-targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer.

In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review.

In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points-clinical benefit rate, duration of response, and reduction in target lesion measurement-tended to favor T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC).

Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.

Breast cancer is a major health challenge for women worldwide, and human epidermal growth factor receptor 2 (HER-2)-positive breast cancers have a relatively high incidence and are highly aggressive. Targeted therapeutic agents, represented by trastuzumab, have been effective in improving the survival rate of HER-2-positive breast cancer patients. However, in clinical applications, this type of targeted drugs exhibits varying degrees of cardiotoxicity, and the mechanism of their cardiotoxicity is currently unclear. In this paper, we classify them into three categories: monoclonal antibodies (mAbs), small-molecule tyrosine kinase inhibitors (TKIs), and antibody-drug conjugate (ADCs). We list the evidence of cardiotoxicity for various drugs based on current clinical trials and summarize their corresponding epidemiological profiles. We also discuss the regulation of cardiotoxicity from three perspectives: clinical biomarkers of cardiotoxicity, permissive cardiotoxicity, and the current status of cardiotoxicity regulation.

Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis. The trifluoromethyl quinazoline compound KZL-201 was designed and synthesized, and its inhibitory effect on the progression of OS cells was investigated. The aim of this study was to investigate the underlying mechanism of action of KZL-201 in OS using a combination of bioinformatics analysis, molecular biology, cytology, and zoology. The in vitro experiments showed that KZL-201 inhibited OS cell proliferation, invasion, and migration; KZL-201 induced apoptosis and arrested the cell cycle at the G2/M phase. The results of molecular docking, the cellular thermal shift assay, and gene silencing experiments showed that KZL-201 had a strong affinity for MMP13. KZL-201 inhibited the progression of 143B cells by regulating the TGF-β1/Smad2/3 pathway. Thus, MMP13 is an important target gene of KZL-201 in inhibiting 143B cell progression. The in vivo experiments showed that KZL-201 inhibited the growth of OS tissues and the expression of MMP13 in OS tissues. In summary, KZL-201 targeted MMP13 and inhibited its expression, consequently suppressing the progression of OS by regulating the TGF-β1/Smad2/3 pathway.

For patients who achieve pathologic complete response (pCR) after neoadjuvant chemotherapy with trastuzumab (T) and pertuzumab (P), the benefit of adding P to T remains uncertain. We compared survival outcomes according to the type of adjuvant anti-HER2 therapy in patients with pCR after chemotherapy with TP.

Patients who achieved pCR in both the breast and axilla after neoadjuvant chemotherapy with TP were included. Recurrence-free survival (RFS) and distant recurrence-free survival (DRFS) were evaluated. Univariate and multivariate Cox proportional hazards analyses were used to assess the impact of different adjuvant therapies on RFS and DRFS.

In total, 386 patients were included, with 69 (17.9%) receiving adjuvant TP and 317 (82.1%) receiving adjuvant T alone. At a median follow-up of 49 months, the 3-year RFS rate was 96.1%. There was no significant difference in the 3-year RFS between groups (94.2% in TP and 95.6% in T), with an adjusted hazard ratio (HR) of 1.15 (95% CI, 0.37-3.55, P = .806). In the clinical node-positive group (n = 294), there was no difference in survival between groups (HR 1.64, 95% CI, 0.58-4.65, P = .35). The multivariate analysis showed no significant predictors of recurrence or distant recurrence, including clinical tumor size, nodal status, ER/PR/HER2 status, and adjuvant radiotherapy receipt. Among 11 patients with brain metastasis after pCR, there was no difference according to the type of adjuvant anti-HER2 therapy.

In patients with pCR who responded to chemotherapy and dual HER2 blockade (TP), the 3-year RFS and brain metastasis-free survival did not differ according to the type of adjuvant anti-HER2 therapy.

In recent years, new anticancer drugs have been investigated and approved for the treatment of breast cancer based on improved survival outcomes. However, these new treatments have specific class-related side effects. Pulmonary toxicity has been identified as an adverse event of special interest with everolimus, and is becoming an increasingly significant clinical challenge with the recent approval of trastuzumab deruxtecan. Overall, the risk of pulmonary toxicity is quite low but in some cases lung damage can be fatal. We conducted an update including the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations, and treatment of lung toxicity induced by new anticancer drugs. A literature search was performed between January and June 2024, considering papers, clinical trials, case reports, case series, meta-analyses, and systematic reviews published from January 2014 to June 2024. We also provide an algorithm for diagnosis and treatment, along with real-life cases managed at the Modena Cancer Center. Data provided here show that pulmonary toxicity is a quite frequent side effect and underline that early recognition and prompt treatment are crucial for the best outcome of patients, whose overall prognosis is being improved by the availability of these new anticancer agents.

Breast cancer (BC) is the leading cause of cancer-related mortality among women. The backbone of first-line treatment in HR+/HER2+ BC is dual anti-HER2 blockade combined with taxane chemotherapy. Although this regimen exhibits high rates of response and disease control in both HR+ and HR- cohorts, some patients could have intrinsic or develop acquired resistance to trastuzumab and/or pertuzumab. Here, we achieved a near-complete response in HR+ HER2-amplified and overexpressing metastatic BC twice through molecular tumor board (MTB) discussions: initially, with trastuzumab deruxtecan (T-DXd) when HER2 IHC was positive, and, then, with neratinib plus fulvestrant plus paclitaxel when IHC was negative. Our case presents GATA3 and NOTCH2 mutations, MCL1 and CKS1B amplifications, as well as ERBB3/KRAS overexpression and ER signaling as potential new mechanisms of resistance to T-DXd. Furthermore, we demonstrated that triplet combination could induce a remarkable response in the T-DXd-refractory setting, which could be explored in future clinical trials in HR+ and HER2-activated (by RNA or protein overexpression, amplification, and mutation) patients. Our case also highlights the importance of the MTBs to dynamically and reactively manage the course of disease and treatment on a per-patient basis.

Biliary tract cancers, which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant biliary tract cancer models that recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in biliary tract cancers to create a resource for modeling precision oncology.

PDXs were derived from biliary tract cancer samples collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole-exome sequencing and RNA sequencing. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as the time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease in tumor volume = partial response, >20% increase in tumor volume = progressive disease, and any non-partial response/progressive disease was considered stable disease.

Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, isocitrate dehydrogenase I, ERRB2, PIK3CA, PTEN, and KRAS. RNA sequencing demonstrated fusions and expression of antibody-drug conjugate targets, including TROP2, HER2, and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically.

In this study, we developed a catalog of biliary tract cancer PDXs that underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of biliary tract cancer PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

Therapeutic decision-making for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer highlights the importance of a comprehensive geriatric assessment (CGA). This assessment considers the functional status, comorbidities, and relevant conditions of the patient, and allows for an estimation of life expectancy, but it does not facilitate individualized treatment plans. There are also other challenges to consider related to the cardiac toxicity of the treatments and the under-representation of older patients in clinical trials. The Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica, SEOM), the Spanish Group for Breast Cancer Research (Grupo Español de Investigación en Cáncer de Mama, GEICAM) and the Spanish Group of Study, Treatment and other Experimental Strategies in Solid Tumours (Grupo Español de Estudio, Tratamiento y otras Estrategias Experimentales en Tumores Sólidos, SOLTI) have gathered an expert committee to evaluate the scientific evidence on the management of older patients with HER2-positive breast cancer and to establish recommendations based on a comprehensive review of the existing literature. These recommendations underscore the importance of individualizing treatment plans based on the patient's physical status and tolerability to maximize efficacy while minimizing toxicity. Emphasis is placed on adapting neoadjuvant and adjuvant therapies according to geriatric assessment and specific patient needs. A careful selection of treatment schedules for advanced stages is needed to improve survival and quality of life, assuming that scientific evidence in this age group is limited.

Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with a generally dismal prognosis and no standard of care established, despite a known association with epidermal growth factor receptor 2 (HER2) and androgen receptor (AR) over-expression.

We report the case of a 64-year-old female with extra- and intracranial metastases of SDC with evidence of AR and HER2 overexpression. After progression on first line chemotherapy, was administered neratinib, a pan-Erb2 receptor tyrosine kinase inhibitor. Even with central nervous system involvement at diagnosis, a durable clinical response was obtained with a PFS of 11 months and no significant toxicities to manage. Best response observed during tratment was partial response.

This case confirms the potential efficacy of neratinib in HER2-positive SDC and underlines the need to define the best therapeutic sequence and potential biomarkers for these rare patients.

Patients with HER2-positive breast cancer have a significant risk of developing brain metastases (BrM), which have detrimental effects on survival outcomes and quality of life. Although there are several systemic treatment options available that may delay the appearance of BrM and secondary progression of previously treated BrM, there are still substantial unmet needs for this patient population and primary prevention remains elusive.

A group of experts created consensus statements, through a modified Delphi process, to bridge the gap between current unmet needs, available evidence, and international guidelines.

The steering committee reviewed all relevant literature and formed research questions to be answered by the subsequent consensus statements. In total, 61 contributors provided feedback on the consensus statements, with 34 statements reaching agreement out of the 55 statements that were voted on altogether. Statements with consensus aimed to define BrM primary and secondary prevention, screening procedures, assessment of symptoms, treatment efficacy, and preventing the occurrence and progression of BrM, while acknowledging the possibilities and limitations in daily clinical practice. Some statements did not reach agreement for a variety of reasons, mostly due to lack of evidence.

The consensus statements outlined in this publication provide a point of reference for daily clinical practice and can act as recommendations for clinical trial procedures and future guidelines.

HER2-positive (+) breast cancer is an aggressive disease with poor prognosis, a narrative that changed drastically with the advent and approval of trastuzumab, the first humanized monoclonal antibody targeting HER2. In addition to another monoclonal antibody, more classes of HER2-targeted agents, including tyrosine kinase inhibitors, and antibody-drug conjugates were developed in the years that followed. While these potent therapies have substantially improved the outcome of patients with HER2+ breast cancer, resistance has prevailed as a clinical challenge ever since the arrival of targeted agents. Efforts to develop new treatment regimens to treat/overcome resistance is futile without a primary understanding of the mechanistic underpinnings of resistance. Resistance could be attributed to mechanisms that are either specific to the tumor epithelial cells or those that emerge through changes in the tumor microenvironment. Reactivation of the HER receptor layer due to incomplete blockade of the HER receptor layer or due to alterations in the HER receptors is one of the major mechanisms. In other instances, resistance may occur due to deregulations in key downstream signaling such as the PI3K/AKT or RAS/MEK/ERK pathways or due to the emergence of compensatory pathways such as ER, other RTKs, or metabolic pathways. Potent new targeted agents and approaches to target key actionable drivers of resistance have already been identified, many of which are in early clinical development or under preclinical evaluation. Ongoing and future translational research will continue to uncover additional therapeutic vulnerabilities, as well as new targeted agents and approaches to treat and/or overcome anti-HER2 treatment resistance.

The advent and success of new drugs for treating HER2-positive metastatic breast cancer has led to a constant improvement in disease and progression-free survival as well as overall survival. Despite these advantages, the overall survival and quality of life of patients with HER2-positive breast cancer brain metastases are significantly worse than the ones of patients with HER2-positive breast cancer metastases outside the brain. For this reason, prevention and treatment of brain metastasis remain a major clinical challenge and the keys to further improving the clinical and survival outcomes of HER2-positive breast cancer patients. This review discusses the etiopathogenesis of brain metastasis, the currently available treatments, and the future perspective on new treatment strategies and diagnostic tools.

Breast cancer is among the deadliest cancers worldwide, highlighting the urgent need for effective treatments. This study employs density functional theory (DFT) and molecular docking analyses to evaluate the anti-cancer efficacy and specificity of drug molecules lapatinib, tucatinib, neratinib, anastrozole, and letrozole. DFT analysis provides comprehensive insights into the structural, electronic, optical, and vibrational properties of these drugs, helping to elucidate their molecular stability and reactivity through global reactivity descriptors. Additionally, molecular docking simulations reveal the binding conformations and interaction profiles of these drugs with key breast cancer targets, underscoring their therapeutic potential. Docking results indicate that lapatinib, tucatinib, and neratinib have high binding affinities for HER2, with lapatinib exhibiting the strongest overall binding, particularly with PDK1 (PDB ID: 1UU7), PAK4 (PDB ID: 2X4Z), GSK3 (PDB ID: 1GNG), and HER2 (PDB ID: 2IOK). The stable hydrogen bonding and other interactions observed with lapatinib support its effectiveness in treating HER2-positive breast cancers, tucatinib's selective HER2 binding reduces off-target effects, while neratinib's irreversible binding provides prolonged inhibition, making it useful for overcoming resistance in HER2-positive cases. In contrast, anastrozole and letrozole show lower binding affinities for HER2 and EGFR due to their simpler structures but are potent aromatase inhibitors, making them effective in treating estrogen receptor-positive (ER-positive) breast cancers. In conclusion, DFT and molecular docking studies affirm the suitability of lapatinib, tucatinib, and neratinib for HER2-positive cancers, while anastrozole and letrozole are effective in ER-positive cancers, emphasizing the role of molecular structure and binding affinity in optimizing cancer treatment strategies.

Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15-30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody-drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches.

Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 7% to 23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3-5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment.

Eligible patients had ECOG performance status 0-2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR8); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety.

Thirty-one patients were included (24/7 with/without prior TKI). ORR8 was 19.4% (95% CI 7.5-37.5); ORR was 32.3% (95% CI: 16.7-51.4); median PFS 5.75 months (95% CI: 2.27-9.23). Two of 7 patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9-9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea).

Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted.

The therapeutic landscape for HER2-positive metastatic breast cancer has exploded in the last two decades following the initial advent of trastuzumab, a monoclonal antibody. While the first line treatment has remained a combination of dual HER2 blockade with taxane chemotherapy, we now have several exciting options in the second line and beyond. The introduction of antibody-drug conjugates, in specific trastuzumab deruxtecan, has resulted in the best progression-free survival among patients with this subtype of breast cancer. Given the excellent outcomes of these drugs, clinical trials are now evaluating the role of ADCs in the front-line setting in previously untreated patients. In addition, there are also clinical trials evaluating the role of other targets in patients with HER2-positive cancers, including PI3KCA mutations, PD-L1 and CDK4/6. Given the predilection for brain metastases in this population, there is enthusiasm to identify the optimal combination of effective treatments. Tucatinib, capecitabine, and trastuzumab combination represent one such promising strategy. With the increasing longevity of these patients, important clinical questions include optimal treatment sequencing, the role of de-escalation of treatment in excellent responders, and the associated financial toxicity. Despite the aggressive nature of this subtype of breast cancer, the outcomes continue to improve for these patients with the evolving treatments.

Trastuzumab-deruxtecan (T-DXd) has demonstrated intracranial efficacy; however, safety and efficacy data remains limited with stereotactic radiosurgery (SRS). A multi-institutional review was performed with HER2+ or HER2-low metastatic breast cancer treated with T-DXd and SRS for active brain metastases. We identified 215 lesions treated over 48 SRS courses in 34 patients. Median follow up from T-DXd initiation was 13.9 months. The cumulative incidence of symptomatic radiation necrosis at 24 months per lesion was 2.1% and per patient 11%. The 12-month LC was 97%. HER2-low was associated with worse distant intracranial control (DIC) (adjusted HR 2.5, 95% CI 1.1-5.6, p = 0.03) and worse systemic progression free survival (PFS) (HR 4.1, 95% CI 1.6-10.7, p = 0.004). Concurrent SRS and T-DXd has excellent local control, without an increased risk of radiation necrosis. HER2-low disease is associated with worse systemic PFS and DIC with T-DXd compared to HER2+.

The development of tumors and their metastasis relies heavily on the process of angiogenesis. When the volume of a tumor expands, the resulting internal hypoxic conditions trigger the body to enhance the production of various angiogenic factors. These include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor-α (TGF-α), all of which work together to stimulate the activation of endothelial cells and catalyze angiogenesis. Antiangiogenic therapy (AAT) aims to normalize tumor blood vessels by inhibiting these angiogenic signals. In this review, we will explore the molecular mechanisms of angiogenesis within the tumor microenvironment, discuss traditional antiangiogenic drugs along with their limitations, examine new antiangiogenic drugs and the advantages of combination therapy, and consider future research directions in the field of antiangiogenic drugs. This comprehensive overview aims to provide insights that may aid in the development of more effective anti-tumor treatments.

Modern cancer therapies greatly improve clinical outcomes for both early and advanced breast cancer patients. However, these advances have raised concerns about potential short- and long-term toxicities, including cardiovascular toxicities. Therefore, understanding the common risk factors and underlying pathophysiological mechanisms contributing to cardiovascular toxicity is essential to ensure best breast cancer outcomes. While cardio-oncology has emerged as a sub-speciality to address these challenges, it is essential that all cardiologists recognize and understand the cardiovascular consequences of cancer therapy. This review aims to provide a comprehensive overview of the potential adverse cardiovascular effects associated with modern breast cancer therapies. A preventive, diagnostic, and therapeutic workflow to minimize the impact of cardiovascular toxicity on patient outcomes is presented. Key aspects of this workflow include regular monitoring of cardiovascular function, early detection and management of cancer therapy-related cardiovascular toxicities, and optimization of cardiovascular risk factor control. By highlighting the gaps in knowledge in some areas, this review aims to emphasize the critical role of cardio-oncology research in ensuring the holistic well-being of patients with breast cancer.

Fam-trastuzumab deruxtecan (T-DXd) has demonstrated substantial antitumor activity and durable responses in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report here the treatment outcomes of T-DXd in a patient with HER2+ breast cancer with brain metastases that repeatedly recurred and progressed after two lines of salvage therapy. In 2016, a 23-year-old G0P0 female with risk factors including menarche at age 9 years, Li-Fraumeni syndrome, and a strong family history of cancer was diagnosed with bilateral, triple-positive breast cancer. She received chemotherapy, HER2-targeted therapies, total mastectomy, and locoregional radiotherapy, but a brain metastasis in the left parieto-occipital lobe was detected in 2020. After receiving capecitabine, lapatinib, gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, multiple new lesions appeared in the brain after 14 months. The patient then received capecitabine, neratinib, GnRH agonist, and letrozole; however, her brain metastases still progressed after 7 months. In 2022, she started T-DXd treatment. Good response to treatment was observed 4 months later, including a continuous decrease in the cancer antigen 15-3 level, a reduction in the size of the major brain tumor, and the absence of new lesions. Now aged 30, the patient is continuing to receive T-DXd treatment to prevent recurrence. We conclude that T-DXd was effective for the treatment of brain metastases in this young patient with triple-positive metastatic breast cancer who had multiple risk factors and had received several anti-HER2 therapies prior to T-DXd.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of breast cancer associated with a poor prognosis when sub-optimally treated. Recent advances include new and effective targeted therapies that have significantly improved outcomes for patients. Despite these advances, there are significant gaps across Canada, underscoring the need for evidence-based consensus guidance to inform treatment decisions. Addressing these gaps is crucial to ensuring that effective therapies are integrated into clinical practice, so as to improve the lives of patients affected by this aggressive form of breast cancer. The Research Excellence, Active Leadership (REAL) Canadian Breast Cancer Alliance is a standing nucleus committee of clinical-academic oncologists across Canada and Breast Cancer Canada, a patient organization. The mandate of this group is to provide evidence-based guidance on best practices in the management of patients with breast cancer. These consensus recommendations were developed using a modified Delphi process with up to three rounds of anonymous voting. Consensus was defined a priori as ≥75% of voters agreeing with the recommendation as written. There are 9 recommendations in the early setting; 7 recommendations in the metastatic setting; and 10 recommendations for patients with brain metastases.