New insights into the drivers and dynamics of HER2+/ER+ breast cancer response to targeted treatments

A study led by Fondazione Michelangelo researchers, just published on Nature Communications, examined longitudinal transcriptomic and immune marker changes during neoadjuvant targeted treatment of HER2+/ER+ breast cancers.

Authors used serial tumour biopsies at baseline, Day14, and after completion of all neoadjuvant therapy from patients enrolled in the NA-PHER2 trial to discover predictive biomarkers and study the changes in the tumour and its microenvironment during treatment; The NA-PHER2 trial investigated the efficacy of chemo-free preoperative HER2 and CDK4/6 blockade with or without endocrine therapy in HER2+ER+ breast cancer patients. This subtype shows lower response rates to current standard treatment which include chemotherapy and developing biomarker-guided alternative approaches could improve clinical outcomes while reducing unnecessary toxicities.

High immune infiltration and low ESR1 mRNA expression were major determinants of the probability to achieve complete pathological response. A stratification based on the proliferation marker Ki67 at Day14 and at surgery defined three response groups (Ki67 HighHigh, LowHigh, LowLow), with divergent tumour and stroma expression dynamics. Persistence of high Ki67 is a sign of resistance to treatment. The HighHigh group showed dysfunctional immune infiltration and overexpression of therapeutic targets like PAK4 at baseline, whereas the LowLow group exhibited a Luminal A phenotype by the end of treatment. As authors conclude, these findings «shed light on the mechanisms and dynamics associated with distinct responses of clinical HER2+ER+ tumours to the targeting of the major driver pathways and contribute to the design of de-escalation or escalation strategies fitting the individual therapeutic needs in HER2+ breast cancer. Indeed, patients with high immune infiltration and low ER signalling could be spared chemotherapy and may be candidate to receive the targeted treatments investigated in the NA-PHER2 trial. On the contrary, the HighHigh group of tumours that is quite resistant to the administered drug combination could require treatments targeting PAK4 or with drugs reversing the immune-suppressive microenvironment».