Twenty years of anti-HER2 therapy-associated cardiotoxicity

Over the past 20...years, the prognosis of HER2-positive breast cancer has been transformed by the development of anti-HER2 targeted therapies. In early clinical trials of trastuzumab (ie, the first anti-HER2 agent to be developed) cardiotoxicity became a major concern. In the first published phase 3 trial of trastuzumab, 27% of patients receiving anthracyclines and trastuzumab experienced cardiac events and 16% suffered from severe congestive heart failure. In subsequent trials conducted in advanced and early settings, the incidence of cardiac events was reduced through changes in chemotherapy regimens, more strict patient selection and close cardiac assessment. However, cardiotoxicity remains a significant problem in clinical practice that is likely to increase as new agents are approved and exposure times increase through improved patients' survival. Though numerous trials have led to improved understanding of many aspects of anti-HER2 therapy-related cardiotoxicity, its underlying physiopathology mechanisms are not well understood. The purpose of this article is to provide an in-depth review on anti-HER2 therapy-related cardiotoxicity, including data on both trastuzumab and the recently developed anti-HER2 targeted agents

Adjuvant trastuzumab: a 10-year overview of its benefit

Introduction: Anti-HER2 targeted therapy is one of the key advances in the treatment of breast cancer that have occurred in the last 20\ua0years. In the adjuvant setting, the use of trastuzumab has led to prolonged and sustained survival benefit with very little toxicity as also confirmed by the 10-year follow-up results from the pivotal trials. Despite the survival improvement, several key issues are not entirely resolved in this field. These issues have led to multiple research efforts in de-escalating or escalating the standard treatment with chemotherapy and 1\ua0year of adjuvant trastuzumab. Areas covered: In this paper, we present an in depth overview on the state of the art on these key issues of refining decision-making in adjuvant anti-HER2 therapy. Expert commentary: Despite many important research efforts in the field, chemotherapy plus trastuzumab for a total duration of 1\ua0year remains the standard of care. However, recent data showed that besides standard anthracycline- and taxane-based cytotoxic therapy, alternative chemotherapy regimens can now be proposed to patients with small tumors without nodal involvement and to women at high-risk of developing cardiotoxicity. Of note, besides HER2 itself, biomarkers predicting patients who may truly benefit from anti-HER2 agents are still lacking

Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects

Introduction: HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in \u2018dual HER2-blockade\u2019 regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness. Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the \u2018triple-positive\u2019 (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments