ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+HER2-BC)

Author summaryBreast cancer is the most frequently diagnosed cancer and represents the leading cause of cancer-related death in women. Hormone receptor positive tumors account for 70-80% of all breast cancers. They are characterized by estrogen dependent growth, and are routinely treated by endocrine therapy, aiming at blocking estrogen receptor (e.g., tamoxifen) or inhibiting the production of estrogen (aromatase inhibitors and LHRH analogues). Unfortunately, a significant proportion of patients develops endocrine resistance, ultimately leading to tumor recurrence. In this study, we analyzed a cohort of 74 hormone receptor positive breast cancer patients by performing a deep molecular characterization of treatment-naive primary tumor samples and their matched metastatic localizations, to highlight putative mechanisms of endocrine resistance. Along with expected acquired molecular alterations, including mutation in ESR1 gene, that encodes for estrogen receptor, we found that an increase of the number of copies of the ESR1 gene (amplification) and mutations in MAP3K are significantly enriched in relapsing tumors, thus expanding the spectrum of known endocrine therapy resistance mechanisms. Interestingly, we found that patients with MAP3K mutations were associated with a worse prognosis. BackgroundPrevious studies have provided a comprehensive picture of genomic alterations in primary and metastatic Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer (HR+ HER2- BC). However, the evolution of the genomic landscape of HR+ HER2- BC during adjuvant endocrine therapies (ETs) remains poorly investigated. Methods and findingsWe performed a genomic characterization of surgically resected HR+ HER2- BC patients relapsing during or at the completion of adjuvant ET. Using a customized panel, we comprehensively evaluated gene mutations and copy number variation (CNV) in paired primary and metastatic specimens. After retrieval and quality/quantity check of tumor specimens from an original cohort of 204 cases, 74 matched tumor samples were successfully evaluated for DNA mutations and CNV analysis. Along with previously reported genomic alterations, including PIK3CA, TP53, CDH1, GATA3 and ESR1 mutations/deletions, we found that ESR1 gene amplification (confirmed by FISH) and MAP3K mutations were enriched in metastatic lesions as compared to matched primary tumors. These alterations were exclusively found in patients treated with adjuvant aromatase inhibitors or LHRH analogs plus tamoxifen, but not in patients treated with tamoxifen alone. Patients with tumors bearing MAP3K mutations in metastatic lesions had significantly worse distant relapse-free survival (hazard ratio [HR] 3.4, 95% CI 1.52-7.70, p value 0.003) and worse overall survival (HR 5.2, 95% CI 2.10-12.8, p-value < 0.001) independently of other clinically relevant patient- and tumor-related variables. ConclusionsESR1 amplification and activating MAP3K mutations are potential drivers of acquired resistance to adjuvant ETs employing estrogen deprivation in HR+ HER2- BC. MAP3K mutations are associated with worse prognosis in patients with metastatic disease.

Automated summary

Breast cancer is the most common cancer in women and is often treated with endocrine therapy. However, many patients develop resistance to this therapy, leading to tumor recurrence. In this study, researchers analyzed the molecular characteristics of hormone receptor positive breast cancer patients and identified potential mechanisms of endocrine resistance, including amplification of the ESR1 gene and mutations in MAP3K. Patients with MAP3K mutations had a worse prognosis.