Cabel Luc, Fuerea Alina, Lacroix Ludovic, Baldini Capucine, Martin Patricia, Hollebecque Antoine, Postel-Vinay Sophie, Varga Andrea, Balheda Rastilav, Gazzah Anas, Michot Jean-Marie, Marabelle Aurélien, Rouleau Etienne, Solary Eric, De Baere Thierry, Angevin Eric, Armand Jean-Pierre, Michiels Stefan, Scoazec Jean Yves, Ammari Samy, André Fabrice, Soria Jean-Charles, Massard Christophe, Verlingue Loic
Drug Development Department (DITEP), Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Villejuif, France.
Laboratory of Translational Research and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655 Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France.
Oncotarget. 2018 Jan 12;9(11):9741-9750. doi: 10.18632/oncotarget.24188. eCollection 2018 Feb 9.
A targeted therapy is recommended in case of alteration for breast and gastric carcinomas, but miscellaneous other tumor types are altered at low prevalence. Broadening the administration of HER2 inhibitors across tumor types and genomic alterations could benefit to patients with refractory metastatic tumors. Targeted next-generation-sequencing (tNGS) and comparative genomic hybridization array (CGH) have been performed on fresh tumor biopsies of patients included in the MOSCATO-01 and ongoing MOSCATO-02 trials to administrate HER2 inhibitors in case of pathogenic mutation of amplification. Between December 2011 and January 2017 a molecular analysis was performed for 934 patients (759 CGH and 912 tNGS). A novel alteration has been found in 4.7% ( 44/934), including 1.5% ( 14/912) mutations, and 4% ( 30/759) amplifications. A matched HER2 inhibitor was administrated to 70% (31/44) of patients and consisted in trastuzumab plus chemotherapy for 90% of them (28/31). On the 31 evaluable patients, 1 complete response (CR), 10 partial response (PR) and 2 stable disease (SD) >24 weeks were observed accounting for a clinical benefit rate (CBR) of 42% ( 13/31, 95% CI 25-61%). Besides breast and oesogastric carcinomas, 19 patients affected by 8 different tumor types had a CBR of 25% for mutations ( 2/8, 95% CI 3%-65%, with 2 PR) and 64% for amplifications ( 7/11, 95% CI 31%-89%; with 1 CR, 4 PR, 2 SD). genomic alterations were diffuse across metastatic tumor types and signs of efficacy emerged for HER2 targeted treatments, especially in case of amplifications or a p.S310Y mutation.
对于乳腺癌和胃癌发生改变的情况，推荐进行靶向治疗，但其他多种肿瘤类型的改变发生率较低。扩大HER2抑制剂在不同肿瘤类型和基因组改变中的应用，可能使难治性转移性肿瘤患者受益。对纳入MOSCATO-01试验及正在进行的MOSCATO-02试验的患者新鲜肿瘤活检样本进行了靶向二代测序（tNGS）和比较基因组杂交阵列（CGH）检测，以便在出现扩增的致病突变时应用HER2抑制剂。在2011年12月至2017年1月期间，对934例患者进行了分子分析（759例CGH和912例tNGS）。发现了4.7%（44/934）的新改变，包括1.5%（14/912）的突变和4%（30/759）的扩增。70%（31/44）的患者接受了匹配的HER2抑制剂治疗，其中90%（28/31）接受曲妥珠单抗联合化疗。在31例可评估患者中，观察到1例完全缓解（CR）、10例部分缓解（PR）和2例疾病稳定（SD）>24周，临床获益率（CBR）为42%（13/31，95%CI 25-61%）。除乳腺癌和食管胃癌外，19例受8种不同肿瘤类型影响的患者，其突变的CBR为25%（2/8，95%CI 3%-65%，有2例PR），扩增的CBR为64%（7/11，95%CI 31%-89%；有1例CR，4例PR，2例SD）。基因组改变在转移性肿瘤类型中广泛存在，HER2靶向治疗出现了疗效迹象，尤其是在扩增或p.S310Y突变的情况下。
