Kato Shumei, Okamura Ryosuke, Mareboina Manvita, Lee Suzanna, Goodman Aaron, Patel Sandip P, Fanta Paul T, Schwab Richard B, Vu Peter, Raymond Victoria M, Lanman Richard B, Sicklick Jason K, Lippman Scott M, Kurzrock Razelle
University of California San Diego Moores Cancer Center, La Jolla.
Guardant Health, Redwood City, CA.
JCO Precis Oncol. 2019;3. doi: 10.1200/PO.18.00180. Epub 2019 Jan 22.
To date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.
We assessed amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.
Overall, amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked amplification.
amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring amplification in cfDNA merits additional study.
迄今为止，组织表皮生长因子受体（EGFR）过表达作为抗EGFR治疗生物标志物的证据尚不充分。我们研究了多种癌症患者血液来源的游离肿瘤DNA（cfDNA）中 扩增的基因组格局以及抗EGFR治疗在实现应答中的作用。
我们通过临床级下一代测序（NGS）对血液来源的cfDNA（54至73基因panel）评估了28584例恶性肿瘤患者的 扩增状态。此外，我们整理了加利福尼亚大学圣地亚哥分校1434例接受此NGS检测cfDNA患者的临床特征。
总体而言，在8.5%的患者（28584例中的2423例）的cfDNA中检测到 扩增，最常见于结直肠癌（16.3%[2807例中的458例]）、非小细胞肺癌（9.0%[12197例中的1096例]）和泌尿生殖系统癌症（8.1%[2104例中的170例]）。大多数患者存在基因组改变（96.9%[98例中的95例]），常涉及影响其他酪氨酸激酶的基因（72.4%[98例中的71例]）、丝裂原活化蛋白激酶级联反应（56.1%[98例中的55例]）、细胞周期相关信号（52.0%[98例中的51例]）和磷脂酰肌醇3激酶途径（35.7%[98例中的35例]）。在包括检查点抑制剂（n = 4）在内的各种抗癌治疗后（n = 6），连续cfDNA中出现了 扩增，提示这些扩增在获得性耐药中可能起作用。9例可评估的 扩增患者接受了基于抗EGFR的方案治疗；5例（55.6%）获得部分缓解，包括3例组织NGS未检测到 扩增的患者。
在28584例不同癌症患者中，8.5%的患者cfDNA中检测到 扩增。大多数患者存在共存改变。9例接受EGFR抑制剂治疗的患者中有5例观察到应答。将EGFR抑制剂纳入cfDNA中存在 扩增患者的治疗方案值得进一步研究。
