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Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma
Cancer Discovery ( IF 29.7 ) Pub Date : 2018-01-01 , DOI: 10.1158/2159-8290.cd-17-0395
Eirini Pectasides 1, 2 , Matthew D. Stachler 1, 3 , Sarah Derks 1, 4 , Yang Liu 1, 5 , Steven Maron 6 , Mirazul Islam 1, 5 , Lindsay Alpert 7 , Heewon Kwak 7 , Hedy Kindler 6 , Blase Polite 6 , Manish R. Sharma 6 , Kenisha Allen 6 , Emily O'Day 6 , Samantha Lomnicki 6 , Melissa Maranto 6 , Rajani Kanteti 6 , Carrie Fitzpatrick 7 , Christopher Weber 7 , Namrata Setia 7 , Shu-Yuan Xiao 7 , John Hart 7 , Rebecca J. Nagy 8 , Kyoung-Mee Kim 9 , Min-Gew Choi 10 , Byung-Hoon Min 11 , Katie S. Nason 12 , Lea O'Keefe 12 , Masayuki Watanabe 13 , Hideo Baba 14 , Rick Lanman 8 , Agoston T. Agoston 3 , David J. Oh 15 , Andrew Dunford 5 , Aaron R. Thorner 16 , Matthew D. Ducar 16 , Bruce M. Wollison 16 , Haley A. Coleman 16 , Yuan Ji 17 , Mitchell C. Posner 18 , Kevin Roggin 18 , Kiran Turaga 18 , Paul Chang 19 , Kyle Hogarth 20 , Uzma Siddiqui 21 , Andres Gelrud 21 , Gavin Ha 5 , Samuel S. Freeman 5 , Justin Rhoades 5 , Sarah Reed 5 , Greg Gydush 5 , Denisse Rotem 5 , Jon Davison 12 , Yu Imamura 13, 14 , Viktor Adalsteinsson 5 , Jeeyun Lee 22 , Adam J. Bass 1, 5 , Daniel V. Catenacci 6
Affiliation  

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.

Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37–48. ©2017 AACR.

See related commentary by Sundar and Tan, p. 14.

See related article by Janjigian et al., p. 49.

This article is highlighted in the In This Issue feature, p. 1



中文翻译:

基因组异质性成为胃食管腺癌精密医学的障碍。

胃食管腺癌(GEA)是一种致命疾病,即使在基因组生物标志物的指导下,靶向治疗的疗效也有限。此类疗法失败的潜在原因是,原发性和转移性肿瘤之间的基因组分析结果通常可能有所不同。为了评估基因组异质性,我们在多个队列中对配对的原发性GEA和同步转移灶进行了测序,发现了基因组变化的广泛差异,包括可能与临床相关的变化之间的差异。多区域测序显示原发肿瘤(PT)内以及PT和播散性疾病之间存在显着差异,致癌基因扩增图谱通常不一致。此外,对无细胞DNA(cfDNA)测序的初步分析表明,检测PT采样中未检测到的基因组扩增的可行性。最后,我们从GEA靶向治疗的个性化GEA(PANGEA)试验中招募的患者中,对成对的原发肿瘤,转移性肿瘤和cfDNA进行了分析,发现PT和未经治疗的转移灶之间经常存在基因组生物标志物差异。原发性和转移性组织分布不同导致32%(9/28)的患者重新分配治疗。在不一致的原发性和转移性病变中,我们发现转移组织和cfDNA的靶向变化一致率为87.5%,这表明cfDNA谱分析可能会增强治疗选择。和cfDNA来自参与GEA靶向疗法的GEA个性化抗体试验的患者(PANGEA),发现PT和未经治疗的转移灶之间经常存在基因组生物标志物差异。原发性和转移性组织分布不同导致32%(9/28)的患者重新分配治疗。在不一致的原发性和转移性病变中,我们发现转移组织和cfDNA的靶向变化一致率为87.5%,这表明cfDNA谱分析可能会增强治疗选择。和cfDNA来自参与GEA靶向疗法的GEA个性化抗体试验的患者(PANGEA),发现PT和未经治疗的转移灶之间经常存在基因组生物标志物差异。原发性和转移性组织分布不同导致32%(9/28)的患者重新分配治疗。在不一致的原发性和转移性病变中,我们发现转移组织和cfDNA的靶向变化一致率为87.5%,这表明cfDNA谱分析可能会增强治疗选择。

启示:我们在GEA的可靶向基因组改变中证明了频繁的基线异质性,表明当前用于生物标志物检测的组织采样方法不能有效地指导这种疾病的精确医学,并且应系统评价转移性病变和/或cfDNA的常规概况。巨蟹座Discov; 8(1);37-48。©2017 AACR。

请参见Sundar和Tan的相关评论,第1页。14

参见Janjigian等人的相关文章,第1页。49

本文在本期功能中突出显示。1个

更新日期:2018-01-08
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