Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer

Abstract

Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer [1]. It is the most common female cancer and the second most common cause of cancer death in women [2]. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC) [3].HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors [4]. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition [5].In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127]. In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way [8–10]. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1.This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.

Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer

“…One patient received trastuzumab for 1 year as part of adjuvant therapy and had no sign of disease at follow-up 6 years later, one was alive with stable bone metastases after receiving trastuzumab as maintenance treatment for 4 years, and one was enrolled on a clinical trial with an anti-PD1 antibody after experiencing progression of disease after 1 year of trastuzumab treatment. Alterations leading to activation of the PI3K/AKT/mTOR pathway may cause ERBB2 inhibitor resistance in breast cancer (38), and AKT1 amplifications, RPTOR amplification/mutations or truncating PTEN mutations were detected in 4 of 10 ERBB2 amplified tumors (Figure 1 and Supplementary Figure 7A). Our findings warrant further studies to investigate the effect of such alterations on response to ERBB2 inhibition in SDCs harboring ERBB2 gene amplification.…”

ERBB2 -Mutated Metastatic Non–Small Cell Lung Cancer: Response and Resistance to Targeted Therapies

“…Resistance to ERBB2 targeted therapies has also been observed in other ERBB2 driven cancers. In the case of breast cancer, putative resistance mechanisms include PIK3CA mutation, Src activation, insulin-like growth factor-I receptor signaling, and c-Met overexpression [20]. Activation of PI3K pathway has also been found to contribute to trastuzumab resistance in breast cancer [21, 22].…”

Expression of T-Lymphocyte Markers in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

“…Several mechanisms of resistance to targeted therapies have been suggested including escape from ADCC; alteration in HER2 (known as p95-HER2); expression of other growth factor signal receptors such as epidermal growth factor receptor, HER3, and insulin-like growth factor-1 receptor; cross-talk between ER and HER2 signaling; and upregulation of PI3K-AKT-mTOR pathway [6726]. The discordance in the expression rates of T-lymphocyte markers between primary and metastatic tissues have not been fully understood, but our study demonstrated that half of the samples showed discordant findings.…”