Background

Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy.

Objective

The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer.

Methods

A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors.

Results

The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%–31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28–26.62, P ≤.001).

Conclusion

ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.

中文翻译：

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激素敏感性晚期乳腺癌患者内分泌治疗类型与雌激素受体1突变发生之间的关联：随机和非随机试验的系统评价和荟萃分析

背景

乳腺癌由于其发病率高，是女性癌症死亡率最高的癌症。乳腺癌最常见的分子类型是管腔亚型，它表达雌激素和孕激素受体，通常通过手术和辅助内分泌治疗 (ET) 进行治疗。由雌激素受体-1 (ESR1) 基因编码的雌激素受体α (ERα) 在大约 70% 的乳腺癌中表达，而 ET 代表了 ERα 阳性癌症的主要治疗方式。然而，对不同 ET 的耐药性经常演变，导致 ER+ 乳腺癌的疾病进展或复发。ERα 配体结合域 (LBD) 中的获得性突变，称为 ESR1 突变；可以由 ET 本身选择导致在 ET 治疗过程中产生耐药性。

客观的

本综述的目的是评估芳香酶抑制剂 (AI)、他莫昔芬 (TAM) 和氟维司群 (FUL) 对激素敏感性晚期乳腺癌 ESR1 突变发展的影响。

方法

使用 PubMed 和 Thomas Reuters Web of Science 数据库对 2007 年 1 月 1 日至 2019 年 3 月 1 日期间发表的定性研究进行了系统评价。搜索词包括 ESR1 突变、雌激素受体、乳腺癌、复发性、转移性疾病、芳香酶抑制剂、氟维司群和他莫昔芬。仅包括关于 ESR1 突变的发展及其对疾病进展结果的英文全文研究。研究的选择是使用预定义的数据字段进行的，同时考虑了研究质量指标。研究人群的纳入标准是：Ghoncheh 等人。(2016) [1] 18岁以上女性患者；尼尔森等人。(2011) [2] 晚期雌激素受体阳性 (ER+) 乳腺癌；莱纳特等人。

结果

本综述纳入了 16 篇文章，包括 4 项多中心双盲 RCT 和 12 个队列，共包括 2632 名患者。ESR1 突变的总体发生率为 24%（95% CI：18%–31%）。我们观察到 D538G 是最常见的 ESR1 突变。几项研究表明，先前的内分泌治疗（AIs、TAM、FUL）可能导致 ESR1 突变和治疗抵抗，从而导致疾病进展或复发。已经暗示了不同的机制来解释潜在的 ET 抗性。这项工作的主要发现之一是接受和未接受 AI 治疗的患者之间 ESR1 突变发生率的显着差异（OR：9.34，95% CI：3.28-26.62，P  ≤.001）。

结论

ESR1 突变在激素敏感性晚期乳腺癌患者中并不少见。与接受不含 AI 的治疗方案的患者相比，接受过含 AI 治疗方案的患者的 ESR1 突变发生率显着更高。这些 ESR1 突变可能导致对 AI 的完全内分泌抗性的发展，而在 TAM 或 FUL 的情况下只能看到部分抗性。