Loibl Sibylle, Treue Denise, Budczies Jan, Weber Karsten, Stenzinger Albrecht, Schmitt Wolfgang D, Weichert Wilko, Jank Paul, Furlanetto Jenny, Klauschen Frederick, Karn Thomas, Pfarr Nicole, von Minckwitz Gunter, Möbs Markus, Jackisch Christian, Sers Christine, Schneeweiss Andreas, Fasching Peter A, Schem Christian, Hummel Michael, van Mackelenbergh Marion, Nekljudova Valentina, Untch Michael, Denkert Carsten
German Breast Group, Neu-Isenburg, Germany.
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.
Clin Cancer Res. 2019 Jul 1;25(13):3986-3995. doi: 10.1158/1078-0432.CCR-18-3258. Epub 2019 Apr 12.
Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial.
Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (, and ) and 8 genes for copy-number alteration analysis (, and ).
The most common genomic alterations were mutations of (38.4%) and (21.5%), and 8 different amplifications ( 34.9%; 30.6%; 30.1%; 21.9%; 24.1%; 17.7%; 14.9%; 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in -mutated breast cancer [mut: 23.0% vs. wild-type (wt) 38.8%, < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24-0.79), = 0.006]. An increased response to nab-paclitaxel was observed only in wt breast cancer, with univariate significance for the complete cohort ( = 0.009) and the TNBC ( = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction = 0.0074).
High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. mutations could be a major mediator of therapy resistance in breast cancer.
新一代测序（NGS）可用于全面研究乳腺癌中的分子事件。我们在GeparSepto试验中评估了基因组改变与新辅助化疗（NACT）反应的相关性。
对GeparSepto研究中的851份治疗前福尔马林固定石蜡包埋（FFPE）核心活检组织进行测序。该检测 panel 包括16个用于突变检测的基因（……）和8个用于拷贝数改变分析的基因（……）。
最常见的基因组改变是……的突变（38.4%）和……的突变（21.5%），以及8种不同的扩增（……34.9%；……30.6%；……30.1%；……21.9%；……24.1%；……17.7%；……14.9%；……12.6%）。所有其他改变的发生率均低于5%。不同乳腺癌亚型[lum/HER2neg与HER2pos与三阴性乳腺癌（TNBC）]中的遗传异质性与NACT反应的差异显著相关。在……突变的乳腺癌中观察到病理完全缓解率显著降低[突变型：23.0% vs. 野生型（wt）38.8%，P < 0.0001]，特别是在HER2pos亚组中[多变量OR = 0.43（95%CI，0.24 - 0.79），P = 0.006]。仅在wt乳腺癌中观察到对白蛋白结合型紫杉醇的反应增加，在整个队列中具有单变量显著性（P = 0.009），在TNBC中具有单变量显著性（P = 0.013），在HER2pos亚组中具有多变量显著性（交互作用检验P = 0.0074）。
在不同乳腺癌亚型中观察到高度遗传异质性。我们的研究表明，基于FFPE的NGS可用于在临床研究队列中识别治疗抵抗标志物。……突变可能是乳腺癌治疗抵抗的主要介导因素。
