Samuel Martel

New agents for endocrine resistance in breast cancer

Estrogen receptor positive (ER+) and HER2-negative (HER2-) breast cancer (BC) is the most common BC subtype, defined by expression of the ER and absence of HER2 amplification. Endocrine treatment (ET), aiming at therapeutic blockade of ER signaling, represents the therapeutic mainstay for patients with both early and advanced disease. Despite its wide therapeutic efficacy, ET fails for a proportion of ER+, HER2- BC patients with early disease who develop endocrine resistance, resulting in disease recurrence. Endocrine resistance occurs almost invariably in patients with metastatic disease. Recently, increasing understanding of the molecular mediators of endocrine resistance has been achieved. This review focuses on the molecular mechanisms mediating endocrine resistance, on molecularly targeted agents to overcome or delay it, and potential predictive biomarkers for accurate patient stratification.

Breast cancer treatment-induced cardiotoxicity

ABSTRACT Introduction: Breast cancer is the most frequent cancer affecting women worldwide. In every setting, the majority of women are treated with an evergrowing arsenal of therapeutic agents that have greatly improved their outcomes. However, these therapies can also be associated with significant adverse events. Areas covered: This review aims to thoroughly describe the current state of the evidence regarding the potential cardiotoxicity of agents commonly used in the treatment of breast cancer. These include chemotherapeutic agents, anti-HER2 therapies and CDK4/6 and mTOR inhibitors. Furthermore, issues related to the risk stratification and monitoring tools are explored. Expert opinion: Anthracycline- and trastuzumab-related cardiac toxicities have been extensively studied. Substantial evidence is now available concerning additional anti-HER2 agents such as pertuzumab, T-DM1 and tyrosine kinase inhibitors; overall, the cardiotoxicity profile is reassuring. Cardiac events due to endocrine therapy are mostly ischemic and, in the context of prolonged therapy, need specific attention. Novel agents implicated in the treatment of hormone receptor-positive disease are potentially arrhythmogenic and the exact risk will need to be further refined. As for today, assessment of baseline risk factors prior to treatment initiation and cardiac imaging before and during treatment remains the optimal way to prevent cardiac dysfunction. Cardioprotective therapy in primary prevention is still a matter of debate.

Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis

BACKGROUND Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models. RESULTS Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95). CONCLUSIONS Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used.

Reply to the letter “Body mass index and clinical outcomes in trastuzumab-treated metastatic breast cancer patients: An alternative explanation for the lack of association”

We thank Hermann Dabi and Caroline Diorio for their comments on our study investigating the prognostic value of body mass index (BMI) in metastatic breast cancer patients receiving first-line trastuzumab-based therapy [1]. As properly noted, to be in line with theWorld Health Organization definition and classification of BMI, we should have classified our study population into the following categories: underweight (BMI <18.5), normal weight (BMI 18.5e24.9), overweight (BMI 25e29.9) and obese (BMI 30). According to this definition, our study population was composed as follow: 8 (2.4%) patients were underweight, 168 (51.2%) had normal weight, 109 (33%) were overweight and 44 (13.4%) were obese. The decision to merge the underweight and obese categories with the normal weight and overweight categories, respectively, stems from the fact that patients who belonged to the underweight and obese categories were under-represented in our series. This decision was also supported by the study of Crozier et al. [2] that analyzed the correlation between BMI and clinical outcomes in patients with early-stage HER2-positive breast cancer enrolled in the N9831 adjuvant trial. This study showed a similar worse 5-year disease-free survival in both the overweight and obese patients as compared to women with normal weight. In addition, it should be noted that our study was conducted in an Italian population that is known to have a lower incidence of obesity compared with the USA population [2]. We recognize that our obese population was even smaller than what we expected. As previously reported by Fedele et al. [3] who investigated the prognostic role of BMI variation and of baseline BMI in a consecutive series of patients with early-stage breast cancer treated at a single institution, the obese category represented 31% of the study population while in our study it represented only 13.4% of the included patients. In conclusion, we think that all these reasons (small number of patients in the two extreme BMI categories, similar prognostic impact of overweight and obese categories in patients with earlystage HER2-positive breast cancer as well as the overall low incidence of obesity in the Italian population) justify our choice to combine the overweight and obese categories for the data analysis in our study. Further studies including a larger population of patients are needed to give more conclusive evidence on the