ESR1 Mutations are Frequent in Local Recurrence of Endocrine-Treated Breast Cancer and Carry Worse Prognosis

Background: Emerging mutations in the ESR1 gene that encodes for estrogen receptor (ER) have been recently associated with resistance to endocrine therapy in ER positive metastatic breast cancer patients. These mutations promote the active conformation of the receptor, conferring resistance to endocrine therapy, and were associated with shorter progression free survival. ESR1 mutations were found to rarely exist in primary tumors (~1%) but are relatively common in metastatic, endocrine therapy-resistant lesions, with an estimated prevalence of ~10-50%. Nevertheless, not much is known about the incidence of these mutations in local recurrence (breast and adjacent lymph nodes) and its clinical significance. The objective of this study was to determine the prevalence of ESR1 mutations in local recurrence of endocrine-treated breast cancer patients and its clinical outcomes.

Methods: To this end, we collected a cohort of 41 breast cancer patients that had at least one local or loco regional recurrence during or after adjuvant endocrine treatment for primary breast cancer. We analyzed the 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) using droplet digital PCR technology in 57 samples (some of the patients had more than one recurrence).

Results: ESR1 mutations at all allele frequency were identified in 15/41 (36%) patients. Mutations were distributed between D538G (11/41), Y537S+ D538G (3/41) and Y537C (1/41). ESR1 mutations at allele frequency of >1% were detected in 4/41 (~10%) of patients. Fraction of patients developing mutations were comparable based on prior endocrine treatment: 39% (9/23) of patients receiving Tamoxifen only and 33% (6/18) of patients receiving Aromatase Inhibitor (AI) +/- Tamoxifen. Notably, one patient developed ESR mutation while on neoadjuvant endocrine therapy. Disease free survival and distant recurrence free survival were significantly shorter in patients that had ESR mutations (>1%) in their tumor.

Conclusions: This study demonstrates that ESR1 mutations are prevalent in local recurrence of hormone receptor positive breast cancer in a similar or even higher prevalence compared to metastatic disease. Since local recurrences are amenable to curative therapy, the identified unexpected high prevalence of ESR mutations at this stage of the disease may have important consequences for choosing the optimal adjuvant treatment option for these patients.