Background: With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2-altered GEA. We examined FGFR2 alteration frequency and frequency of co-occurring alterations in GEA.
Subjects, materials, and methods: A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups.
Results: We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2-amplified (amp; 193, 72% of FGFR2-altered), FGFR2-mutated (36, 13%), FGFR2-rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co-occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2-altered GEA. Co-occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild-type samples.
Conclusion: FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2-directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials.
Implications for practice: Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2-altered GEA parallels the heterogeneity findings in HER2-amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.
关键词。成纤维细胞生长因子受体 2 • 胃癌 • 胃食管结合部腺癌 • 异质性 • 受体酪氨酸激酶
摘要
背景。除曲妥珠单抗外，针对胃食管腺癌 (GEA) 中受体酪氨酸激酶 (RTK) 的治疗效果有限。GEA中存在复发性成纤维细胞生长因子受体 2 (FGFR2) 改变；但目前对于 FGFR2 改变型GEA的基因组景观知之甚少。我们检测了 FGFR2 改变的频率及在GEA中共突变的频率。
受试者、材料和方法。通过利用基于杂交捕获法的基因组分析法，共对 6 667 份晚期GEA患者的组织样本进行了检测。在长达 1.1 Mb 的已测序 DNA 上确定了肿瘤突变负荷 (TMB)，在 95 个或 114 个位点上确定了微卫星不稳定性。在对亚组进行对比时，采用了描述性统计。
结果。我们共发现了 269 例 (4.0%) FGFR2 改变型病例，其中包括 FGFR2 扩增型(amp；193 例，占 FGFR2 改变型病例的 72%)、FGFR2 突变型(36 例，占 13%)、FGFR2 重排型(re；23 例，占 8.6%)以及存在多种 FGFR2 改变的病例(17 例，占 6.3%)。纵观各类 FGFR2 改变型GEA，在其他GEA RTK 靶点中也发现了共突变，包括 ERBB2 (10%)、EGFR (8%) 及MET (3%)。此外，还经常观察到 MYC (17%)、KRAS (10%) 及 PIK3CA (5.6%) 的共突变。具有 FGFR2amp和 FGFR2re的病例呈现独特的微卫星稳定性。FGFR2 改变型GRA的中位TMB是 3.6 mut/mb，与 FGFR2 野生型样本的中位TMB (4.3 mut/mb) 无显著性差异。
结论。FGFR2 改变型GEA是一种异质性亚组，20% 的 FGFR2 改变型样本同时存在 RTK 改变。FGFR2 定向治疗的假定共生修饰物也很常见，包括致癌的 MYC、KRAS 及 PIK3CA，这表明可能需要在治疗前进行分子分析，以便于实施合理的联合治疗及优化临床试验的患者选择。
实践意义:在胃食管腺癌 (GEA) 中，在基因组背景下检测到的具有治疗意义的可靶向受体酪氨酸激酶改变仍仅限于 HER2 扩增。对于被选为加入GEA靶向治疗的患者，复合生物标志物和异质性评估对优化治疗至关重要。FGFR2 改变型GEA中所应用的全面基因组分析法与 HER2 扩增型GEA的异质性评估结论相似，从而为在晚期胃食管腺癌中应用基因组分析法提供了依据。
Keywords: Fibroblast growth factor receptor 2; Gastric cancer; Gastroesophageal junction adenocarcinoma; Heterogeneity; Receptor tyrosine kinase.
© AlphaMed Press 2019.