Preexisting Somatic Mutations of Estrogen Receptor Alpha ( ESR1 ) in Early-Stage Primary Breast Cancer

• Published in: JNCI cancer spectrum Vol. 5; no. 2
• Main Authors: Dahlgren, Malin, George, Anthony M, Brueffer, Christian, Gladchuk, Sergii, Chen, Yilun, Vallon-Christersson, Johan, Hegardt, Cecilia, Häkkinen, Jari, Rydén, Lisa, Malmberg, Martin, Larsson, Christer, Gruvberger-Saal, Sofia K, Ehinger, Anna, Loman, Niklas, Borg, Åke, Saal, Lao H
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2021
• Subjects: Antineoplastic Agents, Hormonal - therapeutic use; Bioinformatics (Computational Biology); Bioinformatics and Systems Biology; Bioinformatik (beräkningsbiologi); Bioinformatik och systembiologi; Biologi; Biological Sciences; Breast cancer; Breast Neoplasms - chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer and Oncology; Cancer och onkologi; Clinical Medicine; Computer and Information Science; Confidence Intervals; Data- och informationsvetenskap (Datateknik); Disease-Free Survival; dPCR; Drug Resistance, Neoplasm - genetics; Endocrine therapy; ESR1; Estrogen Receptor alpha - genetics; Estrogen Receptor Antagonists - therapeutic use; Female; Fulvestrant - therapeutic use; Humans; Kaplan-Meier Estimate; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Middle Aged; Mutation; Natural Sciences; Naturvetenskap; Neoplasm Staging; RNA-seq; Sequence Analysis, RNA; Therapy resistance
• ISSN: 2515-5091; 2515-5091
• DOI: 10.1093/jncics/pkab028

More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test < .001 and = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.