三阴性乳腺癌突变与复发率无关
编者按：由于三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体2（HER2）均为阴性，目前缺乏有效靶向疗法，其全身治疗主要依靠化疗，而且复发率较高。无数科学家正在焚膏继晷夜以继日地探索各种通路基因突变，寻找有效靶点。那么，现有已知基因突变，能否预测三阴性乳腺癌的化疗效果和复发率？
2018年3月27日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表国际乳腺癌研究协作组（IBCSG）、美国达纳法伯癌症研究院、哈佛大学陈曾熙公共卫生学院、哈佛大学医学院、波士顿前沿科学技术研究基金会、欧洲肿瘤研究所、意大利米兰大学、里米尼医院、托斯卡纳肿瘤研究所、托斯卡纳中心医院、普拉托医院、匈牙利国家肿瘤研究院、瑞士临床癌症研究协作组、圣加仑乳腺中心、澳大利亚悉尼大学的二次分析报告，对已知治疗后临床结局的三阴性乳腺癌患者，调查了体细胞突变与预后预测的相关性。
该二次分析从激素受体阴性早期乳腺癌患者术后辅助维持节拍化疗国际多中心随机对照III期研究（IBCSG 22-00）根据当地评定抽样选择三阴性乳腺癌患者135例，按1∶2进行病例组（浸润性乳腺癌局部、区域或远处复发49例）和对照组（无复发86例）匹配，利用Mass ARRAY系统Onco Carta基因组试剂盒1.0版对19个常见癌基因的238个突变位点进行分析，包括PI3K通路、受体酪氨酸激酶、细胞周期代谢组。通过条件逻辑回归，对突变状态与乳腺癌复发的相关性进行评定。
结果发现，37例（27.4%）所选基因至少有一处突变，最常见为：
PIK3CA（18例，13.3%）
BRAF、KIT、PDGFRA（各4例，3.0%）
AKT1（3例，2.2%）
突变与无突变的三阴性乳腺癌患者相比，复发比例高128%（比例比：2.28，95%置信区间：0.88～5.92），但无统计学意义（P=0.09），亦无证据表明这些突变能够预测术后辅助维持节拍化疗的效果。
因此，检测这些癌基因突变与三阴性乳腺癌亚组患者的乳腺癌复发无关。关于这些突变基因之中（例如PIK3CA）能否成为三阴性乳腺癌有效治疗靶点的问题，可能需要正在进行的临床研究和/或更大样本数据集分析进行解答。
Breast Cancer Res Treat. 2018 Mar 27. [Epub ahead of print]
Mutational analysis of triple-negative breast cancers within the International Breast Cancer Study Group (IBCSG) Trial 22-00.
Elisabetta Munzone, Kathryn P. Gray, Caterina Fumagalli, Elena Guerini-Rocco, István Láng, Thomas Ruhstaller, Lorenzo Gianni, Roswitha Kammler, Giuseppe Viale, Angelo Di Leo, Alan S. Coates, Richard D. Gelber, Meredith M. Regan, Aron Goldhirsch, Massimo Barberis, Marco Colleoni.
European Institute of Oncology, Milan, Italy; Dana-Farber Cancer Institute, Boston, USA; Harvard T.H. Chan School of Public Health, Boston, USA; University of Milan, Milan, Italy; National Institute of Oncology, Budapest, Hungary; Breast Center St. Gallen, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; AUSL della Romagna, Rimini, Italy; International Breast Cancer Study Group; Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy; University of Sydney, Sydney, Australia; Harvard Medical School, Boston, USA; Frontier Science & Technology Research Foundation, Boston, USA.
PURPOSE: We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00.
METHODS: A matched case-control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence.
RESULTS: Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88-5.92), though this difference was not statistically significant (p=0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy.
CONCLUSIONS: Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.
KEYWORDS: Triple-negative breast cancer; Somatic mutation; PIK3CA; Mass array system; Prognosis.
DOI: 10.1007/s10549-018-4767-1