Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
J Natl Cancer Inst. 2013 Jul 3;105(13):960-7. doi: 10.1093/jnci/djt121. Epub 2013 Jun 5.
Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset.
The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (P(interaction): DDFS P = .14; OS P = .24).
In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.
某些乳腺癌的体细胞改变可以定义预后和对治疗的反应。本研究使用随机、辅助、三期临床试验数据集，调查了已知癌症体细胞突变的频率、预后影响和预测影响。
FinHER 试验是一项涉及 1010 名女性的三期、随机辅助乳腺癌试验。人表皮生长因子受体 2（HER2）阳性乳腺癌患者进一步随机分为接受 9 周曲妥珠单抗治疗或不接受曲妥珠单抗治疗。705 例肿瘤中有 705 例有足够的 DNA，使用质谱法对 20 个基因中的 70 个体细胞热点突变进行基因分型。采用 Kaplan-Meier 和 Cox 回归分析探讨无远处疾病生存（DDFS）、总生存（OS）和与曲妥珠单抗的相互作用。所有统计检验均为双侧。
中位随访时间为 62 个月。在 705 例肿瘤中，687 例成功进行了基因分型。PIK3CA 突变（外显子 1、2、4、9、13、18 和 20）存在于 25.3%（174/705），TP53 突变存在于 10.2%（70/705）。发现了少数其他突变：三个 ERBB2 和单个 KRAS、ALK、STK11/LKB1 和 AKT2。PIK3CA 突变与雌激素受体阳性（P <.001）和 luminal-A 表型（P =.04）相关，但与预后无统计学显著相关性（DFS：风险比[HR] = 0.88，95%置信区间[CI] = 0.58 至 1.34，P =.56；OS：HR = 0.603，95% CI =.32 至 1.13，P =.11），尽管 DDFS 观察到统计学上显著的非比例预后效应（P =.002）。PIK3CA 突变与曲妥珠单抗获益无统计学显著相关性（P（交互）：DFS P =.14；OS P =.24）。
在该数据集，靶向基因分型显示仅两种突变的频率大于 10%，其他突变很少见。PIK3CA 突变与更好的结局相关，但该效应在 3 年后消失。与曲妥珠单抗获益无统计学显著相关性。
