Low Positivity for Hormone Receptors in Early Breast Cancer: Therapy-Response and Prognosis -A Systematic Analysis of a Total of 9027 Patients

Background: Breast cancer (BC) with a low hormone receptor (HR) expression (1-9%), although qualifying for endocrine therapy, very often have a molecular phenotype similar to triple-negative BC. In this study we evaluated the clinical behavior of low HR-expressing tumors in a multiparametric cohort of 9027 patients. Methods: We analyzed neoadjuvant clinical trial cohorts (n=4366) and a cancer registry cohort (n=5138). We compared patients with negative [oestrogen (ER) and progesterone receptor (PR) <1%], low positive (ER and/or PR 1-9%), and strong positive (ER or PR 10-100%) HR expression. Endpoints were pathological complete response (pCR), disease-free survival (DFS), time to relapse (TTR), distant-disease free survival (DDFS), time to metastasis (TTM) and overall survival (OS). Findings: 145 (3∙4%) patients in the neoadjuvant cohort had low HR-positive, 2455 (57∙7%) strong HR-positive and 1658 (38∙9%) HR-negative tumours. Patients with low HR-positive tumours had a similar pCR rate (37∙9%) as HR-negative tumours (40∙2%). Patients with low HR-positive tumours had a significantly higher pCR rate (16∙3%; OR 0∙41, 95%-CI:0∙28-0∙60), but worse DFS (hazard ratio 0∙47, 95%-CI: 0∙34-0∙64) and DDFS (hazard ratio 0∙49, 95%-CI: 0∙35-0∙70) than patients with strong HR-positive tumours. In the cancer registry cohort, 91 (1∙9%) patients had low HR-positive, 4074 (85∙4%) strong HR-positive, and 604 (12∙6%) HR-negative tumours. OS, TTR, and TTM did not significantly differ between patients with low HR-positive and HR-negative tumours. TTR-differences between patients with low HR-positive and strong HR-positive BC were only significant in univariate analyses. Interpretation: Low HR-positive tumours have a similar clinical behavior as HR-negative tumours with high pCR rates and poor survival, and are significantly different from strong HR-positive tumours. Current cutpoints for HR-positivity should be reconsidered and patients with low HR-positive tumours should be regarded as candidates for therapy strategies and clinical trials targeting HR-negative BC. Funding Statement: German Cancer Aid (projects Transluminal-B #111536 and Integrate-TN #70113450). Declaration of Interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, grants from Molecular Partner, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work. CD reports grant support from the European Commission (Responsify and Oncobiome project) as well as from the German Cancer Aid (Deutsche Krebshilfe, TransLuminal-B and Integrate-TN project) during the conduct of the study; ownership interest in Sividon Diagnostics outside the submitted work; and honoraria from Pfizer, Merck, Sharp & Dohme, Amgen, Myriad, Teva, Celgene, Roche, and AstraZeneca outside the submitted work. CH reports personal fees from Novartis, personal fees from Celgene, personal fees from Lilly, personal fees from Astra Zeneca, personal fees from Amgen, outside the submitted work. CJ reports personal fees from Roche , personal fees from Celegen, personal fees from Amgen, outside the submitted work. FM reports personal fees from Roche, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Tesaro, personal fees from Novartis, personal fees from Amgen, personal fees from PharmaMar, personal fees from GenomicHealth, personal fees from CureVac, personal fees from EISAI, personal fees from Clovis, personal fees from Celgene, outside the submitted work. HT reports personal fees and non-financial support from Roche, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Novartis, personal fees and nonfinancial support from AstraZeneca, outside the submitted work. JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees from Abbvie, personal fees from Pfizer, personal fees from Roche, personal fees from MSD, personal fees from Astra Zeneca, grants and personal fees from Celgene, outside the submitted work. KEW reports personal fees and other from Myriad, outside the submitted work. MK reports grants from Deutsche Krebshilfe (German Cancer Aid), grants from DFG/BMBF, grants from Senator Roesner Foundation, grants from Dr. Pommer-Jung Foundation, personal fees from Springer Press, personal fees from Biermann Press, personal fees from Celgene, personal fees from Astra Zeneca, personal fees from Myriad Genetics, personal fees from TEVA, personal fees from Bavarian KVB, personal fees from DKMS Life, personal fees from BLAK, other from Therawis Diagnostics GmbH, other from Busenfreundin GmbH, outside the submitted work. MU reports personal fees and non-financial support from Abbvie, personal fees and non-financial support from Amgen GmbH , personal fees and non-financial support from Astra Zeneca, personal fees from BMS, personal fees and non-financial support from Celgene GmbH , personal fees and nonfinancial support from Daiji Sankyo , personal fees and non-financial support from Eisai GmbH , personal fees from Lilly Deutschland, personal fees and non-financial support from Lilly Int., personal fees and non-financial support from MSD Merck, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Myriad Genetics , personal fees and nonfinancial support from Odonate, personal fees and non-financial support from Pfizer GmbH, personal fees from PUMA Biotechnology, personal fees and non-financial support from Roche Pharma AG, personal fees and non-financial support from Sanofi Aventis Deutschland GmbH, personal fees and non-financial support from TEVA Pharmaceuticals Ind Ltd, personal fees and non-financial support from Novartis , personal fees from Pierre Fabre, outside the submitted work. MVM reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from Genomic Health, non-financial support from Novartis, non-financial support from Lilly, outside the submitted work. PAF reports grants from Novartis, grants from Biontech, personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Celgene, personal fees from DaiichiSankyo, personal fees from TEVA, personal fees from Astra Zeneca, personal fees from Merck Sharp & Dohme, personal fees from Myelo Therapeutics, personal fees from Macrogenics, personal fees from Eisai, personal fees from Puma, grants from Cepheid, personal fees from Lilly, during the conduct of the study . SL reports grants and other from Abbvie, grants and other from Amgen, grants and other from AstraZeneca, grants and other from Celgene, grants and other from Novartis, grants and other from Pfizer, grants and other from Roche, other from Seattle Genetics, other from Prime/ Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from Eirgenix, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending. WDS reports personal fees from AstraZeneca, outside the submitted work. WW reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, Astellas and grants from Roche, MSD, BMS, Bruker outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: Written informed consent for participation, data collection and data use for translational studies was obtained from all patients and the respective ethics committees approved all trials.