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

This is the authors' abstract. We don't add key points for this paper.

• We have identified that the change of intrinsic PAM50 subtype to normal-like after NET is a potential biomarker of response to NET that identifies a patient population that benefits highly from endocrine therapy. • Our histological analysis of multiple proteins related to apoptosis and senescence has revealed that the percentage of positive cells for p53 in diagnostic pre-treatment samples and its change after NET associate with poor response to NET. • In addition, we have proved that these molecular biomarkers are associated to the tumour cellularity size (TCS), the novel biomarker of response to NET that we described in our previous study (López-Velazco et al., Breast Cancer Research 2024). Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive /HER2-negative breast cancer (ER+/HER2- BC) allows real-time evaluation of treatment sensitivity by monitoring tumour response and offers the opportunity of personalised therapy. However, the lack of reproducible biomarkers to assess response and long-term prognosis after NET is a significant barrier to increase its indications. In this study we searched for clinically relevant molecular reporters of response to NET in a multicentre population of ER+/HER2- BC patients ( n = 87) by using: PAM50 gene expression panel and immunohistochemical evaluation of key proteins involved in tumorigenesis. Our PAM50 analyses show that tumours changing from luminal A to normal-like subtype after NET presented better radiological and pathological tumour responses, a significant larger decrease in Ki67 at surgery, lower preoperative endocrine prognostic index score (PEPI) and lower tumour cellularity size (TCS) than those with persistent luminal A status. Patients with the highest response to NET showed the largest decrease in PAM50-derived risk of recurrence (ROR) following NET. In addition, the percentage of p53 positive cells was associated with decreased response to NET. Our findings highlight the change of intrinsic subtype from luminal A to normal-like after NET as a putative biomarker characterising the patient population that obtains the highest benefit from NET. Our study also suggests that changes in PAM50-derived ROR score and p53 evaluation could also help to identify those patients. Thus, this study uncovers potential biomarkers of response to NET and prognosis, which should be validated in independent cohorts, helping to the implementation of NET in the clinical practice.