Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.
Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.
复制标题
DOI：
10.1001/jamaoncol.2020.7987
复制
发表时间：
2021-04-01
期刊：
影响因子：
28.4
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
--
作者：
Cobain EF;Wu YM;Vats P;Chugh R;Worden F;Smith DC;Schuetze SM;Zalupski MM;Sahai V;Alva A;Schott AF;Caram MEV;Hayes DF;Stoffel EM;Jacobs MF;Kumar-Sinha C;Cao X;Wang R;Lucas D;Ning Y;Rabban E;Bell J;Camelo-Piragua S;Udager AM;Cieslik M;Lonigro RJ;Kunju LP;Robinson DR;Talpaz M;Chinnaiyan AM
晚期实体瘤患者基因组分析的临床效用是什么？在这项对1015例接受整合基因组分析的患者进行的队列研究中，确定了高致病性种系变异率和从测序信息中获得实质性临床获益的患者子集。这些发现支持（1）在所有晚期癌症患者中进行遗传性癌症易感性的定向生殖细胞检测，以及（2）使用整合基因组分析作为未知来源癌症和其他罕见恶性肿瘤患者的标准治疗组成部分。这项队列研究评估了哪些晚期实体瘤患者从下一代测序中获得最大的临床获益。使用下一代测序（NGS）来鉴定临床上可行的基因组靶点已被纳入晚期实体瘤管理的常规临床实践中;然而，该检测的临床实用性仍不确定。确定哪些患者从NGS分析中获得最大程度的临床获益。该队列研究中的患者接受新鲜肿瘤活检和血液样本采集，用于配对肿瘤和正常DNA的基因组分析（全外显子组或靶向外显子组捕获，分析1700个基因）和肿瘤转录组（RNA）测序。体细胞和生殖细胞基因组改变被注释并根据临床作用程度分类。结果返回给治疗肿瘤学家。数据收集时间为2011年5月1日至2018年2月28日，分析时间为2011年5月1日至2020年4月30日。从病历中提取患者的后续治疗和治疗反应，以确定6个月时NGS导向治疗的临床获益率和持续12个月或更长时间的异常反应。在研究期间，对1138例患者的肿瘤尝试了NGS，1015例（89.2%）成功（MET 1000队列）（538例男性[53.0%];平均[SD]年龄，57.7 [13.3]岁）。在817名患者（80.5%）中发现了潜在的临床可操作的基因组改变。其中，132例患者（16.2%）接受了序贯治疗，49例患者（37.1%）获得了临床获益。在26例患者中观察到异常反应（占治疗患者的19.7%）。在160例患者（队列的15.8%）中确定了致病性生殖系变异（PGV），包括49例具有治疗相关性的PGV（队列的4.8%）。对于55例原发性来源不明的癌症患者，NGS确定了28例（50.9%）的原发部位，13例患者的序列导向治疗在7例（53.8%）中产生了临床获益，包括5例异常反应。在不同癌症类型中鉴定出的治疗相关PGV的高比率支持在所有晚期癌症患者中进行定向生殖细胞检测的建议。在原发性来源不明的癌症和其他罕见癌症患者中，治疗相关的体细胞和生殖系发现的频率很高，这支持使用全面的NGS分析作为这些疾病实体的标准治疗组成部分。
What is the clinical utility of genomic profiling for patients with advanced solid tumors? In this cohort study of 1015 patients who underwent integrative genomic profiling, a high rate of pathogenic germline variants and a subset of patients who derive substantial clinical benefit from sequencing information were identified. These findings support (1) directed germline testing for inherited cancer predisposition in all patients with advanced cancer and (2) use of integrative genomic profiling as a component of standard of care for patients with cancer of unknown origin and other rare malignant neoplasms. This cohort study assesses which patients with advanced solid tumors derive the greatest clinical benefit from next-generation sequencing. Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. To determine which patients derived the greatest degree of clinical benefit from NGS profiling. Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. Patients’ subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-14-0603
发表时间：
2014-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Tsimberidou AM;Wen S;Hong DS;Wheler JJ;Falchook GS;Fu S;Piha-Paul S;Naing A;Janku F;Aldape K;Ye Y;Kurzrock R;Berry D
通讯作者：
Berry D
影响因子：
5.7
作者：
Schwaederle, Maria;Daniels, Gregory A.;Kurzrock, Razelle
通讯作者：
Kurzrock, Razelle
影响因子：
158.5
作者：
Soria, J. -C.;Ohe, Y.;Nguyen, Nhung
通讯作者：
Nguyen, Nhung
影响因子：
4.6
作者：
Tsimberidou AM;Hong DS;Ye Y;Cartwright C;Wheler JJ;Falchook GS;Naing A;Fu S;Piha-Paul S;Janku F;Meric-Bernstam F;Hwu P;Kee B;Kies MS;Broaddus R;Mendelsohn J;Hess KR;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
46.9
作者：
Frampton GM;Fichtenholtz A;Otto GA;Wang K;Downing SR;He J;Schnall-Levin M;White J;Sanford EM;An P;Sun J;Juhn F;Brennan K;Iwanik K;Maillet A;Buell J;White E;Zhao M;Balasubramanian S;Terzic S;Richards T;Banning V;Garcia L;Mahoney K;Zwirko Z;Donahue A;Beltran H;Mosquera JM;Rubin MA;Dogan S;Hedvat CV;Berger MF;Pusztai L;Lechner M;Boshoff C;Jarosz M;Vietz C;Parker A;Miller VA;Ross JS;Curran J;Cronin MT;Stephens PJ;Lipson D;Yelensky R
通讯作者：
Yelensky R