Duke University Medical Center, Durham, NC, United States of America; Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD, United States of America.
Duke University Medical Center, Durham, NC, United States of America.
Gynecol Oncol. 2019 Jul;154(1):199-206. doi: 10.1016/j.ygyno.2019.04.010. Epub 2019 Apr 13.
Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies.
DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies.
A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively p < 0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, p < 0.0001 in uterine and 3.5% vs 0.3% respectively, p = 0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48 months.
While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.
内分泌治疗通常被认为是激素反应性妇科恶性肿瘤的一种治疗方法。在乳腺癌中，雌激素受体（mutESR1）的激活突变导致对内分泌治疗，特别是芳香酶抑制剂（AIs）的治疗耐药。本研究旨在评估妇科恶性肿瘤中 ESR1 基因组改变的频率和临床相关性。
通过杂交捕获下一代测序，对来自 9645 例妇科恶性肿瘤（卵巢、输卵管、子宫、宫颈、阴道、外阴和胎盘）的 FFPE 肿瘤组织中的 DNA 进行了所有类型的基因组改变（碱基替换（突变）、插入、缺失、重排和扩增）的分析。对内分泌治疗反应的实验室基础转录测定对部分改变进行了特征分析。
在 285 例（3.0%）病例中发现了 295 个 ESR1 基因组改变。在 86 例（0.9%）病例中存在 mutESR1，在子宫癌中比其他癌症更常见（分别为 2.0%和<1%，p<0.001）。mutESR1 在具有子宫内膜样组织学的癌中更为丰富，而在浆液性组织学中则较少见（分别为 4.4%和 0.2%，在子宫癌中 p<0.0001；分别为 3.5%和 0.3%，在卵巢癌中 p=0.0004）。在四名患者中有三名进行了连续采样，mutESR1 在 AI 治疗的选择性压力下出现。尽管在转录测定中，雌激素受体（ER）拮抗剂的效力降低，但在接受选择性 ER 靶向治疗后仍观察到临床获益，一例持续>48 个月。
虽然妇科恶性肿瘤中 ESR1 突变的发生率较低，但仍有重要的临床意义，有助于指导这些癌症的治疗方法。
