Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy
Nuria Chic,
Francesco Schettini,
Fara Brasó-Maristany,
Esther Sanfeliu,
Barbara Adamo,
Maria Vidal,
Débora Martínez,
Patricia Galván,
Blanca González-Farré,
Javier Cortés,
Joaquín Gavilá,
Cristina Saura,
Mafalda Oliveira,
Sònia Pernas,
Olga Martínez-Sáez,
Jesús Soberino,
Eva Ciruelos,
Lisa A. Carey,
Montserrat Muñoz,
Charles M. Perou,
Tomás Pascual,
Meritxell Bellet,
Aleix Prat
Affiliations
Nuria Chic
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; co-first authors for equal contribution
Francesco Schettini
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; co-first authors for equal contribution
Fara Brasó-Maristany
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Esther Sanfeliu
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain
Barbara Adamo
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Maria Vidal
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Débora Martínez
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Patricia Galván
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Blanca González-Farré
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; Department of Pathology, Hospital Clinic de Barcelona, Barcelona, Spain
Javier Cortés
Vall d´Hebron Institute of Oncology, Barcelona, Spain; Institute of Oncology (IOB)-Quiron, Madrid, Spain
Joaquín Gavilá
SOLTI cooperative group, Barcelona, Spain; Department of Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain
Cristina Saura
SOLTI cooperative group, Barcelona, Spain; Vall d´Hebron Institute of Oncology, Barcelona, Spain
Mafalda Oliveira
SOLTI cooperative group, Barcelona, Spain; Vall d´Hebron Institute of Oncology, Barcelona, Spain
Sònia Pernas
SOLTI cooperative group, Barcelona, Spain; Department of Medical Oncology, Institut Català Oncologia, Barcelona, Spain
Olga Martínez-Sáez
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Jesús Soberino
Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain
Eva Ciruelos
SOLTI cooperative group, Barcelona, Spain; Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
Lisa A. Carey
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
Montserrat Muñoz
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain
Charles M. Perou
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
Tomás Pascual
SOLTI cooperative group, Barcelona, Spain; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
Meritxell Bellet
SOLTI cooperative group, Barcelona, Spain; Vall d´Hebron Institute of Oncology, Barcelona, Spain
Aleix Prat
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA; Department of Medicine, University of Barcelona, Barcelona, Spain; Corresponding author at: Translational Genomic and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Department of Medical Oncology, Hospital Clinic, Carrer de Villarroel, 170, 08036, Barcelona, Spain.
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).