Molecular characterization of the residual disease after neoadjuvant endocrine therapy in ER+/HER2- breast cancer uncovers biomarkers of tumour response

Abstract

Background Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer (BC) allows an in vivo evaluation of treatment sensitivity by the monitoring of tumour response and offers the opportunity of personalized BC therapy. However, the lack of reproducible biomarkers to assess response and long-term prognosis after NET, beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI), is a significant barrier to increase its indications. Methods In this study we searched clinically relevant molecular reporters of NET response and prognosis in a multicentre population of ER+/HER2- BC patients by using: PAM50 gene expression panel, protein evaluation of key proteins involved in tumorigenesis and HER2-Low status evaluation. Results On a cohort of 131 patients our results show that PAM50 categorization (Luminal A vs Luminal B and ROR high vs ROR Low) predicts response to NET, with Luminal A and low ROR score tumours showing better response and prognosis than Luminal B and high ROR score. Moreover, tumours changing from Luminal A to Normal-like after NET presented a significant larger decrease in Ki67 levels at surgery, lower mPEPI score and a lower tumour cellularity size than those with persistent Luminal A status. In addition, we identify that the percentage of p53 positive cells in pre- and post-NET samples are associated with response or prognosis to NET. Conclusion Our findings highlight the change of intrinsic subtype to normal-like after NET as a putative biomarker characterizing a population that benefit highly from NET. If considered conjointly with the pathologic evaluation of response, we could characterize a tumour population benefiting most from endocrine approach and bearing a potential very good prognosis.