Precision medicine continues to improve for breast cancer, and new discoveries are likely to influence treatment decisions for early-stage and metastatic HER2-positive breast cancer.

At the “HER2+ Breast Cancer” education session, held on December 6 at the 2016 San Antonio Breast Cancer Symposium (SABCS) in Texas, the latest advances of the understanding of HER2-positive breast cancer, including its underlying biology, the nuances of managing early-stage disease, and long-term treatment considerations for metastatic disease, were discussed.1

HER2-positive Pathophysiology

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During the last 15 years, researchers have identified 4 major molecular subtypes of breast cancer: luminal A, luminal B, HER2-enriched, and basal-like. A study by The Cancer Genome Atlas (TCGA) Project confirmed that the 4 intrinsic subtypes encompass most of the heterogeneity found in breast cancer.2 Aleix Prat, MD, PhD, of the August Pi i Sunyer Biomedical Research Institute and Vall d´Hebron Institute of Oncology in Barcelona, Spain presented “Recent Insights into the Biology of HER2+ Breast Cancer” at the education session, which included a discussion of the intrinsic subtypes.

The luminal A and B subtypes express proliferation or cell cycle-associated genes and genes involved in hormone-regulated pathways, with luminal B expressing these genes to a higher extent than luminal A subtypes, but lower levels of the progesterone receptor and FOXA1. HER2-enriched breast cancers highly express their namesake, HER2, and genes associated with it. In contrast, basal-like subtypes express high levels of proliferation-associated genes, as well as keratin-related genes.

About 45% of HER2-positive breast cancers are classified as HER2-enriched, with 27%, 18%, and 11% classified as luminal B, luminal A, and basal-like, respectively. 

But the current treatment paradigm bases therapy selection on pathologic surrogates that categorize breast cancer as hormone receptor-positive, HER2-positive, or triple-negative. HER2-directed therapy (such as trastuzumab), for example, is associated with improved outcomes among patients with HER2-positive disease.

“The clinical significance of intrinsic subtypes within HER2+ breast cancer is currently under investigation,” Dr Prat told Cancer Therapy Advisor. “The limited evidence so far suggests that HER2+ tumors of the HER2-enriched subtype benefit the most from anti-HER2 therapies, though further evidence is needed.” HER2-enriched disease is associated with improved pathologic complete response (pCR) and event-free survival compared with non-HER2-enriched disease.

A study conducted by Dr Prat and colleagues demonstrated differences in pCR after treatment with HER2-directed therapy with or without chemotherapy based on intrinsic subtype.3 According to Dr Prat, “the probability of a HER2+ tumor to disappear at surgery following treatment with dual HER2 blockade is 40% compared to 10% if the tumor is non-HER2-enriched.”

An important aspect of this finding is the potential to identify a subgroup of patients for whom treatment de-escalation by treating without chemotherapy may be appropriate. “Further studies are needed to demonstrate this hypothesis, since we are aware that we are overtreating many patients with HER2+ disease,” he noted.

Researchers are continuing to fine-tune the clinical use of intrinsic subtype, particularly to optimize treatment selection. Dr Prat told Cancer Therapy Advisor that “the big challenge in the upcoming years is to demonstrate that the identification of a particular biological feature, or a combination of features, can help us make better treatment decisions. To accomplish this, integrative analysis of multidimensional genomic and clinical data will likely be needed.”