Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma.
Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma.
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DOI：
10.1158/2159-8290.cd-17-0395
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发表时间：
2018-01
期刊：
影响因子：
28.2
通讯作者：
Catenacci DV
中科院分区：
文献类型：
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作者：
Pectasides E;Stachler MD;Derks S;Liu Y;Maron S;Islam M;Alpert L;Kwak H;Kindler H;Polite B;Sharma MR;Allen K;O'Day E;Lomnicki S;Maranto M;Kanteti R;Fitzpatrick C;Weber C;Setia N;Xiao SY;Hart J;Nagy RJ;Kim KM;Choi MG;Min BH;Nason KS;O'Keefe L;Watanabe M;Baba H;Lanman R;Agoston AT;Oh DJ;Dunford A;Thorner AR;Ducar MD;Wollison BM;Coleman HA;Ji Y;Posner MC;Roggin K;Turaga K;Chang P;Hogarth K;Siddiqui U;Gelrud A;Ha G;Freeman SS;Rhoades J;Reed S;Gydush G;Rotem D;Davison J;Imamura Y;Adalsteinsson V;Lee J;Bass AJ;Catenacci DV
胃食管腺癌（GEA）是一种致命性疾病，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。此类疗法失败的一个潜在原因是原发性肿瘤和转移性肿瘤之间的基因组分析结果通常可能不同。为了评估基因组异质性，我们对多个队列中配对的原发性 GEA 和同步转移病灶进行了测序，发现基因组改变存在广泛差异，包括潜在临床相关改变的差异。多区域测序显示原发肿瘤内以及原发肿瘤与播散性疾病之间存在显着差异，癌基因扩增谱通常不一致。此外，cfDNA 测序的初步分析证明了检测原发肿瘤采样中未检测到的基因组扩增的可行性。最后，我们对参加 GEA 靶向治疗 PANGEA 试验的患者的配对原发性、转移性肿瘤和 cfDNA 进行了分析，发现原发性肿瘤和未经治疗的转移性肿瘤之间的基因组生物标志物经常存在差异。原发组织和转移组织分析的不同导致 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 的靶向改变有 87.5% 的一致性，这表明 cfDNA 分析有可能增强治疗选择。
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 tumor. 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. Multi-region sequencing showed significant discrepancy within the primary tumor and between the primary tumor and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, pilot analysis of cfDNA sequencing demonstrated the feasibility of detecting genomic amplifications not detected in primary tumor sampling. Lastly, we profiled paired primary, metastatic tumors and cfDNA from patients enrolled in the PANGEA trial of targeted therapies in GEA, and found that genomic biomarkers were recurrently discrepant between the primary tumor 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.