Mutations in the ESR1 gene that evolve under endocrine treatment are associated with resistance to therapy and with worse prognosis of HR positive metastatic breast cancer patients. Here we aimed to study the incidence and clinical implication of these mutations in local recurrence events and newly diagnosed metastases.
A total of 130 archived tumor samples were collected from 103 endocrine-treated breast cancer patients having long-term follow-up. The cohort consisted of 41 patients having at least one loco-regional recurrence sample and 62 patients with metastatic samples, of which 41 samples were from newly diagnosed metastasis and 28 samples from advanced metastatic patients. The 5 ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed.
The prevalence of ESR1 mutations was 5/41 (12%) for newly diagnosed metastasis and 5/28 (18%) for advanced metastases, at allele frequency >1%. In contrast to advanced metastases, most mutations in newly diagnosed metastases (4/5) emerged under Tamoxifen treatment alone. Progression free survival was significantly shorter in metastatic patients with ESR mutations treated with AI. For loco-regional recurrence events, ESR1 mutations were identified in 15/41 (36%) patients with 4/41 (10%) at allele frequency >1%. Again, most mutations (3/4) emerged under Tamoxifen treatment. Disease free survival and distant recurrence free survival were significantly shorter in patients that had ESR1 mutations (>1%) in their loco-regional recurrent tumor.
ESR1 mutations are prevalent in breast cancer local recurrence to a similar extent as newly metastatic hormone receptor positive breast cancer patients. The results may have important implications for choosing the optimal adjuvant treatment for these patients.
Breast Cancer Translational Research Group, Sheba Medical Center.
Israel Cancer Association.
All authors have declared no conflicts of interest.