Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer.
Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-18-0412
复制
发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Hyman DM
中科院分区：
文献类型：
--
作者：
Soumerai TE;Donoghue MTA;Bandlamudi C;Srinivasan P;Chang MT;Zamarin D;Cadoo KA;Grisham RN;O'Cearbhaill RE;Tew WP;Konner JA;Hensley ML;Makker V;Sabbatini P;Spriggs DR;Troso-Sandoval TA;Charen AS;Friedman C;Gorsky M;Schweber SJ;Middha S;Murali R;Chiang S;Park KJ;Soslow RA;Ladanyi M;Li BT;Mueller J;Weigelt B;Zehir A;Berger MF;Abu-Rustum NR;Aghajanian C;DeLair DF;Solit DB;Taylor BS;Hyman DM
晚期子宫内膜癌的治疗选择有限，预后不良，这突出表明需要了解治疗脆弱性和/或预后预测因子的遗传驱动因素。我们研究了复发性和转移性疾病的前瞻性分子表征是否可以揭示级别和组织学特异性差异，以促进临床试验的招募。我们将前瞻性临床测序和免疫组化数据与197例肿瘤的详细临床和治疗史相结合，这些肿瘤由189例在Memorial Sloan Kettering接受治疗的患者通过MSK-IMPACT进行分析。患者患有晚期疾病和高级别组织学，一线治疗（PFS 1）的无进展生存期较差。当组织学和分级匹配时，基因组图谱与癌症基因组图谱（TCGA）描述的原发性未治疗疾病的基因组图谱相似。使用多种互补的基因组和突变的签名为基础的方法，我们确定患者微卫星不稳定性（MSI），即使标准的MMR蛋白免疫组化染色失败。肿瘤和匹配的正常DNA测序鉴定了BRCA 2和MLH 1中罕见的致病性种系突变。对DNA拷贝数改变模式的聚类揭示了一个新的子集，其特征在于整个基因组的杂合丢失，与其他聚类相比，结果显著更差（中位PFS 1 9.6个月vs. 17.0和17.4个月，p=0.006）。在68%携带潜在可行突变的患者中，27%的患者参加了匹配的临床试验，其中47%的患者获得了临床获益。晚期子宫内膜癌的前瞻性临床测序可以通过同时检测微卫星状态，生殖系易感综合征和潜在的可操作突变来帮助改善预后和辅助治疗决策。作为临床试验的一部分，所有受试患者中有一小部分接受了研究性基因组匹配治疗。
Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials. We integrated prospective clinical sequencing and immunohistochemical data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering. Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by The Cancer Genome Atlas (TCGA). Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein immunohistochemical staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared to other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months, p=0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials of which 47% of these achieved clinical benefit. Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision-making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically-matched therapy as part of clinical trials.