The lack of ESR1 ethnic diversity evidence and its implications for breast cancer personalized treatment

Abstract The ESR1 gene encodes estrogen receptor alpha (ERα), whose central role in breast tumorigenesis has supported the development of endocrine therapies, including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). Despite their proven efficacy, resistance, relapse, and treatment-limiting toxicity remain frequent, underscoring interindividual and interpopulation variability in therapeutic outcomes. Allelic diversity within ESR1 is a key determinant of these differences, as variant frequencies and distributions vary substantially across populations and ethnic groups. Associating ESR1 variants with genomic ancestry can help anticipate variability in drug response, thereby reducing adverse events and facilitating the clinical implementation of pharmacogenetics. Investigating population-specific differences that shape drug efficacy and toxicity not only generates evidence for groups historically underrepresented in genomic studies but also enhances the equity and global applicability of personalized medicine. In conclusion, genetic variation in ESR1 may modulate both the efficacy and safety of breast cancer therapies. Understanding the genetic diversity of populations worldwide is therefore essential for minimizing adverse effects, improving treatment outcomes, and advancing the implementation of pharmacogenetics in clinical practice.