Cancer Center, Massachusetts General Hospital, Bldg 149, 13th Street, Charlestown, MA, 02129, USA.
Division of Oncology, San Francisco Medical Center, San Francisco, CA, USA.
Breast Cancer Res Treat. 2021 Jul;188(1):43-52. doi: 10.1007/s10549-021-06270-z. Epub 2021 Jun 8.
Therapeutic efficacy of hormonal therapies to target estrogen receptor (ER)-positive breast cancer is limited by the acquisition of ligand-independent ESR1 mutations, which confer treatment resistance to aromatase inhibitors (AIs). Monitoring for the emergence of such mutations may enable individualized therapy. We thus assessed CTC- and ctDNA-based detection of ESR1 mutations with the aim of evaluating non-invasive approaches for the determination of endocrine resistance.
In a prospective cohort of 55 women with hormone receptor-positive metastatic breast cancer, we isolated circulating tumor cells (CTCs) and developed a high-sensitivity method for the detection of ESR1 mutations in these CTCs. In patients with sufficient plasma for the simultaneous extraction of circulating tumor DNA (ctDNA), we performed a parallel analysis of ESR1 mutations using multiplex droplet digital PCR (ddPCR) and examined the agreement between these two platforms. Finally, we isolated single CTCs from a subset of these patients and reviewed RNA expression to explore alternate methods of evaluating endocrine responsiveness.
High-sensitivity ESR1 sequencing from CTCs revealed mono- and oligoclonal mutations in 22% of patients. These were concordant with plasma DNA sequencing in 95% of cases. Emergence of ESR1 mutations was correlated both with time to metastatic relapse and duration of AI therapy following such recurrence. The Presence of an ESR1 mutation, compared to ESR1 wild type, was associated with markedly shorter Progression-Free Survival on AI-based therapies (p = 0.0006), but unaltered to other non-AI-based therapies (p = 0.73). Compared with ESR1 mutant cases, AI-resistant CTCs with wild-type ESR1 showed an elevated ER-coactivator RNA signature, consistent with their predicted response to second-line hormonal therapies.
Blood-based serial monitoring may guide the selection of precision therapeutics for women with AI-resistant ER-positive breast cancer.
针对雌激素受体 (ER) 阳性乳腺癌的激素治疗的疗效受到配体非依赖性 ESR1 突变的限制，这些突变赋予了芳香酶抑制剂 (AIs) 的治疗耐药性。监测此类突变的出现可能使个体化治疗成为可能。因此，我们评估了基于 CTC 和 ctDNA 的 ESR1 突变检测，旨在评估用于确定内分泌抵抗的非侵入性方法。
在 55 名患有激素受体阳性转移性乳腺癌的前瞻性队列中，我们分离了循环肿瘤细胞 (CTC)，并开发了一种用于检测这些 CTC 中 ESR1 突变的高灵敏度方法。在有足够血浆同时提取循环肿瘤 DNA (ctDNA) 的患者中，我们使用多重液滴数字 PCR (ddPCR) 平行分析 ESR1 突变，并检查这两种平台之间的一致性。最后，我们从这些患者中的一部分中分离出单个 CTC，并检查 RNA 表达以探索评估内分泌反应性的替代方法。
从 CTC 中进行高灵敏度 ESR1 测序显示，22%的患者存在单克隆和寡克隆突变。这些与 95%的病例中血浆 DNA 测序一致。ESR1 突变的出现与转移性复发的时间以及复发后 AIs 治疗的持续时间均相关。与 ESR1 野生型相比，存在 ESR1 突变与基于 AI 的治疗的无进展生存期明显缩短相关 (p = 0.0006)，但与其他非 AI 治疗无关 (p = 0.73)。与 ESR1 突变病例相比，具有野生型 ESR1 的 AI 耐药性 CTC 表现出升高的 ER 共激活子 RNA 特征，与其预测对二线激素治疗的反应一致。
基于血液的连续监测可能指导选择针对 AI 耐药性 ER 阳性乳腺癌的精准治疗药物。
