Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK.
Breast Cancer Res Treat. 2010 Apr;120(2):461-7. doi: 10.1007/s10549-010-0747-9. Epub 2010 Jan 28.
Somatic mutations in PIK3CA (encoding a class I phosphoinositide 3 kinase (PI3K) subunit) modulate PI3K signalling to influence tumour behaviour and occur in up to 40% of breast cancers. Inhibitors of PI3K signalling are entering clinical trials, but the impact of PIKC3A mutation on tumour response has yet to be clarified. This study investigated the potential utility of circulating free DNA (cfDNA) as a source for PIK3CA mutation detection in patients with breast cancer. cfDNA extracted (QIAamp Virus spin kit) from blood and matched archival tumour from 46 patients with metastatic breast cancer and 30 patients with localised, operable breast cancer was assessed for hotspot PIK3CA mutations using Amplification Refractory Mutation System (ARMS()) allele-specific PCR and Scorpion probes. PIK3CA mutations were detected in 13/46 (28%) plasma-derived and 10/46 (21%) serum-derived cfDNA samples from metastatic breast cancer patients. In 41 cases with matched tumour and plasma-derived cfDNA data, concordance (same mutation status in plasma and tumour) was 95%. Where a PIK3CA mutation was present in tumour, the 'pick up' in plasma-derived cfDNA was 80%. PIK3CA mutations were present in tumours from 14/30 (47%) localised breast cancers, but no PIK3CA mutations were detected in matched cfDNA. These data demonstrate feasibility and potential utility of cfDNA for PIK3CA mutation detection in patients with metastatic breast cancer. Studies are underway to qualify PIK3CA mutation in cfDNA as a predictive biomarker allowing patient stratification in clinical trials of mechanism-based therapeutics that target PI3K signalling pathways.
PIK3CA 中的体细胞突变（编码 I 类磷酸肌醇 3 激酶（PI3K）亚基）调节 PI3K 信号转导，影响肿瘤行为，在高达 40%的乳腺癌中发生。PI3K 信号通路抑制剂正在进入临床试验，但 PIKC3A 突变对肿瘤反应的影响尚未阐明。本研究探讨了循环游离 DNA（cfDNA）作为乳腺癌患者 PIK3CA 突变检测来源的潜在应用价值。从 46 例转移性乳腺癌和 30 例局部可手术乳腺癌患者的血液中提取（QIAamp 病毒试剂盒）的 cfDNA，使用扩增受阻突变系统（ARMS）等位基因特异性 PCR 和 Scorpion 探针检测热点 PIK3CA 突变。在转移性乳腺癌患者的 13/46（28%）血浆衍生和 10/46（21%）血清衍生 cfDNA 样本中检测到 PIK3CA 突变。在 41 例具有匹配肿瘤和血浆衍生 cfDNA 数据的病例中，一致性（血浆和肿瘤中相同的突变状态）为 95%。在肿瘤中存在 PIK3CA 突变的情况下，在血浆衍生 cfDNA 中“检出”的比例为 80%。在 30 例局部乳腺癌中，14/30（47%）的肿瘤中存在 PIK3CA 突变，但在匹配的 cfDNA 中未检测到 PIK3CA 突变。这些数据表明，cfDNA 用于检测转移性乳腺癌患者的 PIK3CA 突变是可行的，并且具有潜在的应用价值。目前正在进行研究，以将 cfDNA 中的 PIK3CA 突变作为预测生物标志物进行鉴定，从而允许对针对 PI3K 信号通路的机制为基础的治疗药物的临床试验进行患者分层。
