The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform.
The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform.
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复发和转移性头颈癌的分子景观：精确肿瘤学测序平台的见解。
DOI：
10.1001/jamaoncol.2016.1790
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发表时间：
2017-02-01
期刊：
影响因子：
28.4
通讯作者：
Ho AL
中科院分区：
文献类型：
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作者：
Morris LGT;Chandramohan R;West L;Zehir A;Chakravarty D;Pfister DG;Wong RJ;Lee NY;Sherman EJ;Baxi SS;Ganly I;Singh B;Shah JP;Shaha AR;Boyle JO;Patel SG;Roman BR;Barker CA;McBride SM;Chan TA;Dogan S;Hyman DM;Berger MF;Solit DB;Riaz N;Ho AL
复发性和/或转移性头颈癌通常是不可治愈的。对这些患者的精确肿瘤学的实施受到对晚期疾病潜在分子改变的不完全理解的限制。与此同时，许多罕见的头颈癌类型的分子特征尚不清楚。需要解决这些知识上的重大差距，以合理地设计新的疗法。阐明复发性和转移性头颈癌的独特生物学，并回顾晚期疾病患者的精确肿瘤学实施情况。排除后，招募了151名患有晚期，治疗抵抗性头颈部肿瘤的患者，包括鳞状细胞癌（HNSCC），腺样囊性癌（ACC）和其他唾液和皮肤癌，其肿瘤在2014年1月至2015年7月期间在Memorial Sloan Kettering进行了测序。作为临床护理的一部分，下一代肿瘤测序包括410个癌症基因的高深度（中位数600 ×）外显子覆盖和全基因组拷贝数分析。下一代肿瘤和匹配的正常DNA测序。可行性，可操作的分子改变的频率，对决策的影响，以及与复发和转移性疾病相关的改变的鉴定。总体而言，151例患者（95例男性和56例女性;平均[范围]年龄为61.8 [17 - 100]岁）被纳入研究。下一代测序最终指导了151例患者中的21例（14%）（53例HNSCC患者中的13例[25%]）的治疗，通过改进诊断并将患者与特定治疗相匹配，在某些情况下，篮子研究的反应非常明显。135例患者中有28例（21%）的分子改变可能是可行的。复发和转移性肿瘤的基因谱通常不同于原发性肿瘤。与原发性人乳头瘤病毒（HPV）阳性肿瘤相比，许多复发性和转移性HPV阳性肿瘤表现出与HPV阴性肿瘤更相似的分子特征，包括TP53突变（20例肿瘤中的3例[15%]）、全基因组复制（20例肿瘤中的5例[25%]）和3p缺失（20例肿瘤中的11例[55%]）的富集频率。在复发性和转移性HPV阴性HNSCC（30例肿瘤中的13例[43%]）、皮肤SCC（21例肿瘤中的11例[52%]）、基底细胞癌（4例肿瘤中的3例[75%]）和ACC（36例肿瘤中的5例[14%]）中，TERT启动子突变率较高。激活性NOTCH1突变在转移性ACC中富集（36例肿瘤中的8例[22%]）。这些发现揭示了晚期疾病和罕见癌症亚型的分子景观，这两者都是头颈部肿瘤学的主要挑战。为了了解晚期癌症中靶向改变的所有组成部分，有必要对复发性和转移性肿瘤进行测序。这些数据是实施精确头颈肿瘤学的重要第一步。
Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. Next-generation sequencing of tumors and matched normal DNA. Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]). These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.