HER2-E Biomarker Associated With Poor Aromatase Inhibitor Response and Worse Outcomes in ER-Positive/HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 enriched (HER2-E) and erythroblastic oncogene B (ERBB2) biomarkers were identified as having an association with resistance to aromatase inhibitors and increased risk of recurrence in patients with ER-positive (ER+)/HER2-positive (HER2+) breast cancer.

“Most studies investigating mechanisms of resistance to endocrine therapy have been performed in ER+/HER2-[negative] disease and are not well understood in HER2+ [breast cancer],” explained Milana A Bergamino, MD, The Institute of Cancer Research, London, UK, and colleagues, adding, “As such, identifying robust molecular features and defining novel subgroups based on tumour biology is essential to identify the most adequate treatment strategies for this particular [breast cancer] subgroup.”

The study included all available baseline ER+/HER2+ tumors from the POETIC trial (n = 342), which randomized patients with hormone-sensitive early breast cancer to either 2 weeks of peri-surgical aromatase inhibitors, or no aromatase inhibitors. The tumors were gene expression profiled and assessed for changes in Ki67 expression, and residual Ki67 at 2 weeks of treatment. Study authors also determined time-to-recurrence (TTR), adjusting for standard clinicopathological variables.

After a median follow-up of 62.9 months, the TTR of patients with HER2-E subtype breast cancers (44.7%) was significantly poorer compared to patients with luminal (53.5%) breast cancers (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.14 to 5.69; P = .02). The study also found HER2-E subtype breast cancers exhibited poorer Ki67 response and higher residual level of Ki672 at 2 weeks (P < .0001) than non-HER2-E breast cancers. High ERBB2 expression, homologous recombination deficiency, and TP53 mutational score were associated with immune-related signatures with high Ki672wk and poor response to aromatase inhibitors. The study identified 5 new molecular subgroups associated with resistance to aromatase inhibitors and found to be independent predictors of TTR.

Dr Bergamino et al, concluded, “Our results show HER2-E as a standardised biomarker associated with poor response to [aromatase inhibitors] and worse outcome in ER+/HER2+,” adding, “Altogether, the combination of these biomarkers would lead to a better tailoring of treatment strategies, including escalation and de-escalation approaches, to improve resistance to treatment in early [breast cancer].”

Source:

Bergamino MA, López-Knowles E, Morani G, et al. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. EBioMedicine. 2022;83:104205. doi:10.1016/j.ebiom.2022.104205