Department of Medical Oncology, Institut Curie, Paris, France.
Department of Pathology-Genetics-Immunology, Institut Curie, Paris, France.
J Pathol Clin Res. 2024 May;10(3):e12372. doi: 10.1002/2056-4538.12372.
Everolimus is widely used in patients with advanced ER-positive, HER2-negative breast cancer. We looked at alterations in the PIK3CA/AKT/mTOR pathway in a multicenter cohort as potential biomarkers of efficacy. Patients with advanced ER-positive, HER2-negative breast cancer treated with everolimus and endocrine therapy between 2012 and 2014 in two cancer centers were included. Targeted sequencing examined mutations in PIK3CA, ESR1, and AKT1 genes. An immunochemical analysis was conducted to evaluate expression of PTEN, INPP4B, STK11, p4EBP1, and pS6. We analyzed 71 patients (44 primary tumors; 27 metastatic tissues). Median age was 63 years [58-69]. All patients had heavily pretreated advanced disease. A mutation in the PIK3CA pathway was observed in 32 samples (PIK3CA exons 10 and 21 and AKT1 exon 4 in 15.5%, 24.0%, and 5.6% of samples), and in ESR1 in 5 samples (7.0%), respectively. Most samples showed cytoplasmic expression of the PIK3CA pathway proteins. Progression-free survival was longer in patients with a pS6 or p4EBP1 histoscore ≥ median value (6.6 versus 3.7 months, p = 0.037), and in patients with a PTEN histoscore ≤ median value (7.1 versus 5.3 months, p = 0.02). Overall survival was longer in patients with pS6 ≥ 3rd quartile (27.6 versus 19.3 months, p = 0.038) and in patients with any mutation in the PIK3CA/AKT/mTOR pathway (27.6 versus 19.3 months, p = 0.011). The prognosis of patients treated with everolimus for advanced ER-positive, HER2-negative breast cancer appears primarily driven by molecular features associated with the activation of the PIK3CA/AKT/mTOR pathway.
依维莫司广泛用于治疗晚期雌激素受体阳性、HER2 阴性乳腺癌患者。我们在两个癌症中心的多中心队列中观察了 PIK3CA/AKT/mTOR 通路的改变，以作为潜在的疗效生物标志物。纳入了 2012 年至 2014 年间在两个癌症中心接受依维莫司和内分泌治疗的晚期雌激素受体阳性、HER2 阴性乳腺癌患者。对 PIK3CA、ESR1 和 AKT1 基因的突变进行了靶向测序检测。进行了免疫化学分析以评估 PTEN、INPP4B、STK11、p4EBP1 和 pS6 的表达。我们分析了 71 例患者（44 例原发性肿瘤；27 例转移性组织）。中位年龄为 63 岁[58-69]。所有患者均患有晚期疾病且经大量预处理。在 32 例样本中观察到 PIK3CA 通路突变（PIK3CA 外显子 10 和 21 及 AKT1 外显子 4 分别为 15.5%、24.0%和 5.6%），在 5 例样本中观察到 ESR1 突变（7.0%）。大多数样本显示 PIK3CA 通路蛋白的细胞质表达。pS6 或 p4EBP1 组织评分≥中位数的患者无进展生存期更长（6.6 个月与 3.7 个月，p=0.037），PTEN 组织评分≤中位数的患者无进展生存期更长（7.1 个月与 5.3 个月，p=0.02）。pS6≥第 3 四分位数的患者总生存期更长（27.6 个月与 19.3 个月，p=0.038），PIK3CA/AKT/mTOR 通路存在任何突变的患者总生存期更长（27.6 个月与 19.3 个月，p=0.011）。接受依维莫司治疗的晚期雌激素受体阳性、HER2 阴性乳腺癌患者的预后似乎主要由与 PIK3CA/AKT/mTOR 通路激活相关的分子特征驱动。
