PDF(Pubmed)
Abstract：
Around 75% of breast cancer (BC) patients have tumors expressing the predictive biomarker estrogen receptor α (ER) and are offered endocrine therapy. One-third eventually develop endocrine resistance, a majority with retained ER expression. Mutations in the phosphatidylinositol bisphosphate 3-kinase (PI3K) catalytic subunit encoded by PIK3CA is a proposed resistance mechanism and a pharmacological target in the clinical setting. Here we explore the frequency of PIK3CA mutations in endocrine-resistant BC before and during treatment and correlate to clinical features. Patients with ER-positive (ER +), human epidermal growth factor receptor 2 (HER2)-negative primary BC with an ER + relapse within 5 years of ongoing endocrine therapy were retrospectively assessed. Tissue was collected from primary tumors (n = 58), relapse tumors (n = 54), and tumor-free lymph nodes (germline controls, n = 62). Extracted DNA was analyzed through panel sequencing. Somatic mutations were observed in 50% (31/62) of the patients, of which 29% occurred outside hotspot regions. The presence of PIK3CA mutations was significantly associated with nodal involvement and mutations were more frequent in relapse than primary tumors. Our study shows the different PIK3CA mutations in endocrine-resistant BC and their fluctuations during therapy. These results may aid investigations of response prediction, facilitating research deciphering the mechanisms of endocrine resistance.
摘要：
大约75％的乳腺癌（BC）患者患有表达预测性生物标志物雌激素受体α（ER）的肿瘤，并接受内分泌治疗。三分之一的人最终会产生内分泌抵抗，保留ER表达的多数。由PIK3CA编码的磷脂酰肌醇二磷酸3-激酶（PI3K）催化亚基的突变是临床上提出的抗性机制和药理靶标。在这里，我们探讨了PIK3CA突变在内分泌耐药的BC治疗之前和期间的频率，并与临床特征相关。ER阳性（ER+）患者，对内分泌治疗5年内ER+复发的人表皮生长因子受体2(HER2)阴性原发性BC进行回顾性评估.从原发性肿瘤收集组织（n=58），复发肿瘤（n=54），和无肿瘤淋巴结（种系对照，n=62）。通过组测序分析提取的DNA。在50％（31/62）的患者中观察到体细胞突变，其中29%发生在热点地区之外。PIK3CA突变的存在与淋巴结受累显著相关,并且突变在复发中比原发性肿瘤更频繁。我们的研究显示了内分泌抗性BC中不同的PIK3CA突变及其在治疗期间的波动。这些结果可能有助于研究反应预测，促进研究破译内分泌抵抗的机制。
