Estrogen receptor (ESR1) mutation in bone metastases from breast cancer

Abstract

Activating mutations of estrogen receptor α gene (ESR1) in breast cancer can cause endocrine resistance of metastatic tumor cells. The skeleton belongs to the metastatic sides frequently affected by breast cancer. The prevalence of ESR1 mutation in bone metastasis and the corresponding phenotype are not known. In this study bone metastases from breast cancer (n=231) were analyzed for ESR1 mutation. In 27 patients (12%) (median age 73 years, range: 55-82 years) activating mutations of ESR1 were detected. The most frequent mutation was p.D538G (53%), no mutations in exon 4 (K303) or 7 (S463) were found. Lobular breast cancer was present in 52% of mutated cases (n=14) and in 49% of all samples (n=231), respectively. Mutated cancers constantly displayed strong estrogen receptor expression. Progesterone receptor was positive in 78% of the mutated cases (n=21). From 194 estrogen receptor-positive samples, 14% had ESR1 mutated. Except for one mutated case, no concurrent HER2 overexpression was noted. Metastatic breast cancer with activating mutations of ESR1 had a higher Ki67 labeling index than primary luminal cancers (median 30%, ranging from 5 to 60% with 85% of cases revealing ≥20% Ki67-positive cells). From those patients from whom information on endocrine therapy was available (n=7), two had received tamoxifen only, 4 tamoxifen followed by aromatase inhibitors and one patient had been treated with aromatase inhibitors only. We conclude that ESR1 mutation is associated with estrogen receptor expression and high proliferative activity and affects about 14% of estrogen receptor-positive bone metastases from breast cancer.

De Novo ESR1 Hotspot Mutation in a Patient With Endometrial Cancer Treated With an Aromatase Inhibitor

“…The activating ESR1 hotspot exon 8 mutation (c.1609-1610TA>AG; p.Y537S) identified was previously reported in patients with breast cancer treated with the same hormone therapy. 5 - 8 These data highlight the putative secondary resistance characteristic of the ESR1 mutation detected in our case report.…”

“…4 In breast cancer, ESR1 mutations were clearly identified as a mechanism of resistance to aromatase inhibitors. 5 - 8 ESR1 mutations were reported in 2% of endometrial cancers, 9 yet their potential occurrence following hormonal therapy is unknown. In this study, we report a de novo ESR1 hotspot mutation in a patient with endometrial carcinoma treated with an aromatase inhibitor.…”

Network Pharmacology-based Research of the Therapeutic Effects of Epimedium Brevicornu Maxim on Diminished Ovarian Reserve

“…And the Network Analyzer was used to select some critical factors in this process such as ESR1, AR, NOTCH1 and VEGFA. Among them, ESR1 is an estrogen receptor which could promote the proliferation and differentiation of breast cells by binding to estrogen [24]. AR is one kind of the androgen receptors which existed in the tissues of prostate, testes, ovary and fat [25].…”

Bone Tumors: Types and Treatments

“…But in patients with hormone receptor-positive breast cancer, both the disease and its therapeutic treatment with antiestrogenic agents negatively impact the bone and result in decrease in bone mineral density. Therefore anti-hormonal therapy is considered only in cases where cancer cells express the ERα [58]. However, unlike nonsteroidal aromatase inhibitors, a steroidal aromatase inhibitor, e.g., exemestane (probably due to its steroid structure), has been reported to exert beneficial effects on the bone through its primary metabolite 17-hydroexemestane [51,57].…”