Determinants of response and molecular dynamics in HER2+ER+ breast cancers from the NA-PHER2 trial receiving HER2-targeted and endocrine therapies.

Improved outcomes in HER2+ female breast cancer have resulted from chemotherapy and anti-HER2 therapies. However, HER2+ER+ cancers exhibit lower response rates. The phase 2 NA-PHER2 trial (NCT02530424) investigated chemo-free preoperative HER2 blockade (trastuzumab + pertuzumab) and CDK4/6 inhibition (palbociclib) with or without endocrine therapy (fulvestrant) in HER2+ER+ breast cancer. Clinical endpoints (i.e. Ki67 dynamics and pathological complete response) were previously reported. Here we report on the biomarker analysis, secondary objective of the study. Through RNA sequencing and tumour infiltrating lymphocytes (TIL) assessment in serial biopsies, we identified biomarkers predictive of pCR or Day14 Ki67 response and unveiled treatment-induced molecular changes. High immune infiltration and low ER signalling correlated with pCR, while TP53 mutations associated with high Day14 Ki67. Stratification based on Ki67 at Day14 and at surgery defined three response groups (Ki67 HighHigh, LowHigh, LowLow), with divergent tumour and stroma expression dynamics. The HighHigh group showed dysfunctional immune infiltration and overexpression of therapeutic targets like PAK4 at baseline. The LowLow group exhibited a Luminal A phenotype by the end of treatment. This study expands our understanding of drivers and dynamics of HER2+ER+ tumour response, towards treatment tailoring.