Prevalence of Estrogen Receptor Alpha (ESR1) Somatic Mutations in Breast Cancer

Area of Science:

• Oncology
• Genomics
• Endocrinology

Background:

• Estrogen receptor-positive breast cancer often develops resistance to endocrine therapy.
• Genomic alterations, particularly in Estrogen Receptor Alpha (ESR1), are implicated in acquired resistance.
• A recent hypothesis suggested pre-existing ESR1 mutations might cause intrinsic resistance, warranting primary screening.

Purpose of the Study:

• To determine the incidence of de novo ESR1 mutations in hormone-positive, treatment-naïve primary breast tumors.
• To evaluate if ESR1 mutations are a significant intrinsic resistance mechanism in early-stage breast cancer.

Main Methods:

• Analysis of 12 publicly available international datasets via cBioPortal.
• Retrospective study of genomic data from hormone-positive, treatment-naïve primary breast tumors.
• Comparison of mutation prevalence between treatment-naïve primary, metastatic, and previously treated primary tumors.

Main Results:

• The prevalence of de novo ESR1 mutations in treatment-naïve primary tumors was very low (0.16%, 6/3682).
• In contrast, ESR1 mutations were significantly more common in metastatic (14.3%) and previously treated primary tumors (12.0%).
• Statistical analysis confirmed a significant difference in prevalence (P < .001).

Conclusions:

• Pathogenic ESR1 mutations are a frequent cause of acquired endocrine therapy resistance.
• ESR1 mutations are not a common mechanism of intrinsic resistance in treatment-naïve primary breast cancer.
• Universal genetic testing for ESR1 mutations in all primary breast cancer patients is likely not warranted.