Hormone receptor-positive and human epidermal growth factor receptor-2-positive (HR+/HER2+) breast cancer comprise approximately 5-10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched-like subtype in patients with HR+/HER2+ breast cancer.
First, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n=141) and METABRIC (n=104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. We then performed multiplex immunofluorescence to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS).
All four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal-B subtype was the most common, followed by the HER2-enriched and luminal-A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the non-HER2 subtypes better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, rH/E showed a significant prognostic association in the CAMS cohort.
This study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.