Patel Snehal B, Bookstein Robert, Farahani Navid, Chevarie-Davis Myriam, Pao Andy, Aguiluz Angela, Riley Christian, Hodge Jennelle C, Alkan Serhan, Liu Zhenqui, Deng Nan, Lopategui Jean R
Cedars-Sinai Medical Center, Division of Molecular Pathology and Cytogenetics, Department of Pathology and Laboratory Medicine, 8700 Beverly Blvd., SSB #362, Los Angeles, CA, 90048, USA.
HeloGenika LLC, Dexter, MI, 48130, USA.
Oncol Ther. 2021 Dec;9(2):451-469. doi: 10.1007/s40487-021-00151-7. Epub 2021 Apr 25.
Next-generation sequencing has emerged as a clinical tool for the identification of actionable mutations to triage advanced colorectal cancer patients for targeted therapies. The literature is conflicted as to whether primaries or their metastases should be selected for sequencing. Some authors suggest that either site may be sequenced, whereas others recommend sequencing the primary, the metastasis, or even both tumors. Here, we address this issue head on with a meta-analysis and provide for the first time a set of sensible recommendations to make this determination.
From our own series, we include 43 tumors from 13 patients including 14 primaries, 10 regional lymph node metastases, 17 distant metastases, and two anastomotic recurrences sequenced using the 50 gene Ion AmpliSeq cancer NGS panel v2.
Based on our new cohort and a meta-analysis, we found that ~ 77% of patient-matched primary-metastatic pairs have identical alterations in these 50 cancer-associated genes.
Low tumor cellularity, tumor heterogeneity, clonal evolution, treatment status, sample quality, and/or size of the sequencing panel accounted for a proportion of the differential detection of mutations at primary and metastatic sites. The therapeutic implications of the most frequently discordant alterations (TP53, APC, PIK3CA, and SMAD4) are discussed. Our meta-analysis indicates that a subset of patients who fail initial therapy may benefit from sequencing of additional sites to identify new actionable genomic abnormalities not present in the initial analysis. Evidence-based recommendations are proposed.
新一代测序已成为一种临床工具，用于识别可指导治疗的突变，以便对晚期结直肠癌患者进行靶向治疗的分类。关于应选择原发灶还是转移灶进行测序，文献中存在争议。一些作者建议可以对任何一个部位进行测序，而另一些人则建议对原发灶、转移灶甚至两个肿瘤都进行测序。在此，我们通过荟萃分析直接解决这个问题，并首次提供了一套合理的建议来做出这一决定。
从我们自己的系列研究中，我们纳入了13例患者的43个肿瘤，包括14个原发灶、10个区域淋巴结转移灶、17个远处转移灶以及2个吻合口复发灶，使用50基因Ion AmpliSeq癌症NGS panel v2进行测序。
基于我们的新队列研究和荟萃分析，我们发现约77%的患者匹配的原发灶-转移灶对在这50个癌症相关基因中具有相同的改变。
肿瘤细胞含量低、肿瘤异质性、克隆进化、治疗状态、样本质量和/或测序 panel 的大小是导致原发灶和转移灶突变检测差异的部分原因。讨论了最常见的不一致改变（TP53、APC、PIK3CA和SMAD4）的治疗意义。我们的荟萃分析表明，一部分初始治疗失败的患者可能受益于对其他部位进行测序，以识别初始分析中不存在的新的可指导治疗的基因组异常。提出了基于证据的建议。
