Journal
BREAST
Volume 34, Issue -, Pages S19-S26Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.breast.2017.06.022
Keywords
HER2-positive breast cancer; HER2-targeted therapy resistance; Oncogenic addiction; PI3K/PTEN; Estrogen receptor; Tumor microenvironment
Categories
Funding
- NIH: SPORE [P50 CA058183, CA186784]
- Cancer Center Grant [P30 CA125123]
- Breast Cancer Research Foundation
- Cancer Prevention & Research Institute of Texas [CPRIT RP 140102]
- Conquer Cancer Foundation - Gianni Bonadonna Breast Cancer Research Fellowship
- Pas a Pas
- Instituto de Salud Carlos III [PI16/00904]
- Susan Komen Foundation [CCR13261208]
- NIH/NCI Cancer Center [P30 CA008748]
- NATIONAL CANCER INSTITUTE [P50CA186784, P30CA008748, P50CA058183, P30CA125123] Funding Source: NIH RePORTER
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Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15-20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only a single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy. (C) 2017 Published by Elsevier Ltd.
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