Recent studies focusing on the molecular characterization of HER2+ breast cancer are revealing a complex scenario. In this presentation, we will review the main molecular features identified to date in HER2+ disease (both at the tumor cell level as well as the tumor microenvironment), and focus on the associations between these molecular features and prognosis/treatment benefit. At the DNA level, the two most prevalent somatic mutations are TP53 and PIK3CA. Regarding PIK3CA, the proportion of mutated tumors is similar in both HR+ and HR-negative disease (20-25%), with 2/3 of PIK3CA mutations occurring in the tyrosine kinase domain (exon 20). Thus, activation of the PI3K/mTOR signaling pathway is an important characteristic in a substantial proportion of HER2+ tumors. In the clinical setting, a recent combined analyses from 5 neoadjuvant studies (n=967) evaluating PIK3CA mutations and its association with pathological complete response (pCR) following chemotherapy in combination with anti-HER2 therapy (lapatinib, trastuzumab or both), revealed that PIK3CA mutant/HER2+ tumors had significantly lower pCR rates (7.6%) compared with wild-type tumors (24.2%), specially within the HR+ group (5.5% vs. 33.9%). On the other hand, other biomarkers of activation of the PI3K/mTOR pathway, such as low-PTEN by IHC, have not shown to predict response or benefit from anti-HER2-based chemotherapy. Interestingly, in the absence of chemotherapy, a retrospective analysis of samples from TBCRC06 trial, where 64 patients were treated with lapatinib+trastuzumab (and endocrine therapy if HR+), revealed that PIK3CA mutations and PTEN-low are associated with lower pCR rates (0% and 9%) compared with wild-type or PTEN-high tumors (27% and 32%). Overall, these data suggest that activation of PI3K/mTOR pathway might be indicative of resistance to anti-HER2 therapy. Interestingly, recent clinical data suggests that inhibition of PI3K/mTOR pathway in patients with activated PI3K/mTOR pathway might overcome resistance to anti-HER2 therapy. At the RNA level, gene expression analyses within HER2+ disease identify all the main intrinsic subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched [HER2-E] and Basal-like). Among them, the HER2-E subtype is characterized by the high expression of HER2-regulated genes and cell cycle-related genes, together with lower expression of luminal-related genes compared to the Luminal A/B subtypes. Thus, the HER2-E subtype is likely to be the subtype with the highest activation of the EGFR/HER2 pathway. A clinical trial called PAMELA is currently testing this hypothesis and will be presented at SABCS. Finally, at the microenvironment level, immune activation seems to play an important role in HER2+ breast cancer. For example, in several retrospective analyses of samples from clinical trials, including CALGB40601, N9831 and NeoALTTO, immune activation has shown to predict response to anti-HER2-based chemotherapy and survival outcome. These findings open the door to the evaluation of immune therapies, such as immune checkpoint inhibitors, in HER2+ breast cancer. To conclude, there is a need to find predictive models that integrate various biomarkers coming from the DNA, RNA, protein and the microenvironment in order to identify clinically relevant groups of HER2+ breast cancer.

Citation Format: Prat A. Recent insights into the biology of HER2+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES3-1.