Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy

EBioMedicine

Maria Vidal¹  Francesco Schettini¹  Javier Cortés¹  Jesús Soberino¹  Montserrat Muñoz¹  Meritxell Bellet¹  Sònia Pernas²  Fara Brasó-Maristany³  Charles M. Perou³  Mafalda Oliveira³  Eva Ciruelos³  Aleix Prat³  Débora Martínez³  Joaquín Gavilá³  Esther Sanfeliu⁴  Patricia Galván⁴  Olga Martínez-Sáez⁵  Lisa A. Carey⁵  Tomás Pascual⁵  Blanca González-Farré⁵  Cristina Saura⁵  Barbara Adamo⁵  Nuria Chic⁵ 

[1] Department of Medical Oncology, Hospital Clinic of Barcelona, Spain;Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain;SOLTI cooperative group, Barcelona, Spain;co-first authors for equal contribution;Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain;

关键词: Pre-menopause;    Progesterone receptor;    Hormone receptor positive;    Breast cancer;    Chemotherapy;    Oestrogens;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation. Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels. Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy. Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods. Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of “Departament de Salut”, exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s).

【 授权许可】

Unknown