Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Medical Affair, Guardant Health, Dana-Farber Cancer Institute, Boston, USA.
Ann Oncol. 2018 Apr 1;29(4):1037-1048. doi: 10.1093/annonc/mdy034.
To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.
We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples.
Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.
The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.
通过细胞游离基因组学，鉴定接受拉帕替尼治疗的患者中的应答预测标志物，并显示拉帕替尼治疗期间的分子变化。
我们前瞻性地评估了将拉帕替尼与卡培他滨和奥沙利铂联合作为未经治疗的 HER2 过表达晚期胃癌一线新辅助治疗的疗效。通过同时对肿瘤和血液样本进行免疫组织化学和下一代测序（NGS），进行了平行的生物标志物研究。
在 32 名患者中，7 名（21.8%）患者确认完全缓解，其中 2 名患者接受了根治性手术，病理证实完全缓解。观察到 15 名部分缓解（46.8%），总缓解率为 68.6%。16 个肿瘤标本的 NGS 显示，最常见的共同出现的拷贝数改变是 CCNE1 扩增，HER2+肿瘤中存在 40%。CCNE1 扩增与对 HER2 靶向治疗无反应之间存在统计学意义上的趋势（无反应者中有 66.7%存在 CCNE1 扩增，而有反应者中为 22.2%；P=0.08）。通过 NGS 检测到高水平 ERBB2 扩增的患者比低水平 ERBB2 扩增的患者更有可能对治疗有反应（P=0.02）。对 cfDNA 的分析表明，血浆中可检测到的 ERBB2 拷贝数扩增与对治疗的反应相关（100%，反应率），血浆中检测到的基因组改变与拉帕替尼的敏感性和/或耐药性相关。疾病进展时的后续 cfDNA 基因组学显示，存在其他基因组异常的出现，如 MYC、EGFR、FGFR2 和 MET 扩增。
本研究表明，根据 ERBB2 以外的伴随基因组异常，HER2+GC 患者的反应不同，NGS 或 cfDNA 中的高 ERBB2 扩增可作为患者选择的阳性预测因子，并且在靶向药物治疗期间肿瘤基因组改变显著。
