Human epidermal growth factor receptor-2 and endocrine resistance in hormone-dependent breast cancer

Abstract

Endocrine therapies are the main treatment strategies for the clinical management of hormone-dependent breast cancer. Despite prolonged time to recurrence in the adjuvant setting and the initial clinical responses in the metastatic setting, many patients eventually encounter tumour relapse due to acquired resistance to these agents. Other patients experience a lack of tumour regression at the beginning of treatment indicating de novo resistance that significantly limits its efficacy in clinic. There is compelling evidence that human epidermal growth factor receptor-2 (HER2) overexpression contributes to resistance to endocrine therapies in oestrogen receptor-positive (ER+) breast cancer. ER+/HER2+ tumours comprise about 10% of all breast cancer cases and about 60% of the whole set of HER2+ tumours. Most patients with primary ER+/HER2+ disease will receive antibody-based HER2-targeted therapy, but this is generally for no more than one year while endocrine treatment is usually for at least 5 years. A number of HER2-kinase inhibitors are also now in clinical use or in clinical trials, and the interaction of these with endocrine treatment may differ from that of antibody treatment. In this review article, we aim to summarise knowledge on molecular mechanisms of breast cancer resistance to endocrine therapies attributable to the impact of HER2 signalling on endocrine sensitivity, to discuss data from clinical trials addressing the role of HER2 in the development of endocrine resistance in the metastatic, neoadjuvant and adjuvant settings and to explore rational new therapeutic strategies.

HER2DX genomic test in HER2-positive/hormone receptor-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab: A correlative analysis from the PerELISA trial

“…Previous preclinical studies have described the inverse relationship between the activation of the estrogenic receptor signalling pathway and the HER2 signalling pathway. 27 Thus, HER2DX pCR score senses this delicate balance between both pathways within HER2-positive/hormone receptor-positive disease.…”

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

“…There is complex bidirectional crosstalk between HER2 and the signaling pathways activated by hormonal receptors for estrogen (ER), progesterone (PgR), and androgens (AR) that can lead to cancer resistance to either antihormonal drugs [ 143 ] or anti-HER2 agents, and thus, co-targeting HER2 and HRs could lead to tumor regression [ 144 ]. Around 50% of HER2 tumors express ER, and most of these patients are treated with anti-HER2 antibodies (usually up to one year), whereas endocrine treatment requires at least 5 years [ 143 ]. It is interesting to note that around 20% of tumors negative for HER2 can become positive during progression, mostly after endocrine treatment [ 145 , 146 ].…”

“…It is interesting to note that around 20% of tumors negative for HER2 can become positive during progression, mostly after endocrine treatment [ 145 , 146 ]. For early-stage HR/HER2 tumors, neratinib could be used for extended adjuvant therapy, while in metastatic ER/HER2 tumors, the current guidelines recommend chemotherapy and anti-HER2 agents, either TKIs (lapatinib, neratinib, tucatinib, or pyrotinib), monoclonal antibodies (trastuzumab, pertuzumab, or margetuximab), or ADC (T-DM1 or T-DXd), regardless of ER status [ 143 ]. Among TKIs, lapatinib is the only one approved in combination with letrozole.…”

“…Among TKIs, lapatinib is the only one approved in combination with letrozole. While different clinical studies have proven the safety of combining endocrine therapy with anti-HER2 agents in advanced or metastatic settings, the relative benefit of endocrine treatment is still uncertain [ 143 ]. However, in these patients, the addition of CDK4/6 inhibitors seems to have clinical benefit in diverse trials [ 123 , 124 ].…”

The role of DYNLT3 in breast cancer proliferation, migration, and invasion via epithelial‐to‐mesenchymal transition

“…2 In addition to surgery and chemoradiotherapy, the recent advances in endocrine and targeted therapies have made them more prominent in individual comprehensive therapy of breast cancer, which benefits the majority of patients with hormone-dependent or HER-2 positive breast cancer. 3,4 Unfortunately, lack of therapeutic targets often lead to a poor prognosis of triple-negative breast cancer (TNBC). 5 In addition, both drug resistance of advanced breast cancer and intolerance to side effects are still the bottlenecks to be solved in the treatment process.…”