Clinical relevance of circulating tumor DNA in HER2-positive advanced gastric cancer: a collaborative study of a phase Ib trial of dual HER2 and PD-1 targeted therapy (Ni-High).
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引用次数: 0
Abstract
Background: The combination of anti-programmed cell death-1 antibody with human epidermal growth factor receptor 2 (HER2)-targeted therapy and chemotherapy is widely used in the United States and Europe for HER2-positive advanced gastric cancer (AGC). Molecular profiles that predict the efficacy of this dual-target therapy are unclear.
Objectives: To explore the clinical utility of circulating tumor DNA (ctDNA) as a predictive marker of the efficacy of standard chemotherapy plus HER2 and programmed death-ligand 1 dual-targeted therapy in patients with HER2-positive AGC.
Design: Collaborative study of the Ni-High phase Ib clinical trial.
Methods: A total of 21 patients with tissue-confirmed HER2-positive AGC who received chemotherapy with dual-targeted therapy (capecitabine/S-1, oxaliplatin, trastuzumab, and nivolumab) in a phase Ib clinical trial (UMIN000034222) were enrolled. The association of genomic profiles in plasma ctDNA with tissue HER2 amplification status and their correlation with clinical outcomes was investigated.
Results: Among the 21 patients studied, 20 (95.2%) showed somatic alterations in ctDNA. ERBB2 amplifications and single-nucleotide variants (SNVs)/indels were found in 12 (57.1%) and 3 (14.3%) patients, respectively. Significant associations between maximum mutant allele frequency (mMAF) and tumor size and between ctDNA and tissue ERBB2 copy numbers were found. Patients without ERBB2 SNV/indels showed longer median progression-free survival (PFS) and overall survival (OS) than those with these alterations. Patients with focal ERBB2 amplification in ctDNA showed better outcomes than those with aneuploidy (median PFS: 20.8 vs 8.4 months, hazard ratio (HR) = 0.08; median OS: NA vs 14.8 months, HR = 0.077). Lower mMAF at cycle 2 was associated with a better response to chemotherapy with dual-targeted therapy.
Conclusion: ERBB2 genetic status and mMAF changes in ctDNA may, respectively, predict and reflect the efficacy of chemotherapy with dual-targeted therapy in HER2-positive AGC.
背景：抗程序性细胞死亡-1抗体联合人表皮生长因子受体2 （HER2）靶向治疗和化疗在美国和欧洲广泛应用于HER2阳性晚期胃癌（AGC）。预测这种双靶点治疗疗效的分子谱尚不清楚。目的：探讨循环肿瘤DNA （ctDNA）作为HER2阳性AGC患者标准化疗加HER2和程序性死亡-配体1双靶向治疗疗效的预测指标的临床应用价值。设计：协同研究高镍Ib期临床试验。方法：在Ib期临床试验（UMIN000034222）中，共有21例接受双靶向治疗（卡培他滨/S-1、奥沙利铂、曲妥珠单抗和纳武单抗）化疗的组织确诊her2阳性AGC患者入组。研究了血浆ctDNA基因组谱与组织HER2扩增状态的关系及其与临床结果的相关性。结果：在研究的21例患者中，20例（95.2%）出现体细胞ctDNA改变。在12例（57.1%）和3例（14.3%）患者中分别发现ERBB2扩增和单核苷酸变异(snv)/indel。最大突变等位基因频率（mMAF）与肿瘤大小、ctDNA与组织ERBB2拷贝数之间存在显著相关性。无ERBB2 SNV/indels的患者比有这些改变的患者显示出更长的中位无进展生存期（PFS）和总生存期（OS）。ctDNA局灶性ERBB2扩增患者的预后优于非整倍体患者(中位PFS: 20.8 vs 8.4个月，风险比(HR) = 0.08；中位OS: NA vs 14.8个月，HR = 0.077)。周期2时较低的mMAF与双靶向化疗的更好反应相关。结论：ERBB2基因状态和ctDNA中mMAF的变化可分别预测和反映her2阳性AGC双靶向化疗的疗效。试验注册：UMIN000034222。
期刊介绍：
Therapeutic Advances in Medical Oncology is an open access, peer-reviewed journal delivering the highest quality articles, reviews, and scholarly comment on pioneering efforts and innovative studies in the medical treatment of cancer. The journal has a strong clinical and pharmacological focus and is aimed at clinicians and researchers in medical oncology, providing a forum in print and online for publishing the highest quality articles in this area. This journal is a member of the Committee on Publication Ethics (COPE).
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