Meric-Bernstam Funda, Raghav Kanwal Pratap Singh, Sweeney Christopher J, Swanton Charles, Spigel David R, Bose Ron, Burris Howard A, Friedman Claire F, Espenschied Carin R, Grindheim Jessica M, Malato Julia, Schulze Katja, Price Richard, Kurzrock Razelle
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2025 Jul 15;31(14):2935-2944. doi: 10.1158/1078-0432.CCR-24-2763.
A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown.
Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA dynamics and association with response.
Forty-one (98%) of 42 patients had genomic alterations detected in ctDNA at C1D1, and 29 (69%) had ERBB2 amplification in ctDNA. There was a strong correlation between the ERBB2 copy number on next-generation sequencing in tissue and C1D1 ERBB2 ctDNA copy number. Thirty-seven percent achieved a molecular response by C3D1 on P + T, which was associated with prolonged progression-free survival and overall survival. CDKN2A and KRAS mutations were associated with shorter overall survival, and a trend was seen with PIK3CA mutations. Several emerging co-alterations were identified in ctDNA at progression, including in the MAPK and PI3K pathways and other tyrosine receptor kinases.
ctDNA can detect ERBB2 amplification in many, but not all, patients with ERBB2 amplification detected in tumor samples. ctDNA molecular response was associated with better survival, and ctDNA co-alterations may offer insights into mechanisms of intrinsic and acquired resistance.
两种HER2靶向抗体帕妥珠单抗和曲妥珠单抗（P+T）联合使用对HER2阳性结直肠癌具有抗肿瘤活性。尽管液体活检在临床肿瘤学中的应用越来越广泛，但肿瘤与循环肿瘤DNA（ctDNA）中ERBB2状态之间的关联以及用于早期反应和耐药性监测的ctDNA情况尚不清楚。
在MyPathway试验中，85例ERBB2扩增和/或过表达的结直肠癌患者接受了P+T治疗；42例在第1周期第1天（C1D1）进行了ctDNA检测，38例进行了ctDNA的纵向血浆检测。我们分析了ctDNA与组织ERBB2的一致性、基因组共改变、ctDNA动态变化及其与反应的关联。
42例患者中有41例（98%）在C1D1的ctDNA中检测到基因组改变，29例（69%）在ctDNA中有ERBB2扩增。组织中下一代测序的ERBB2拷贝数与C1D1时ERBB2的ctDNA拷贝数之间存在强相关性。37%的患者在C3D1时对P+T达到分子反应，这与无进展生存期和总生存期的延长相关。CDKN2A和KRAS突变与较短的总生存期相关，PIK3CA突变也有此趋势。在疾病进展时的ctDNA中发现了几种新出现的共改变，包括丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI3K）途径以及其他酪氨酸受体激酶中的共改变。
ctDNA可在许多（但并非全部）肿瘤样本中检测到ERBB2扩增的患者中检测到ERBB2扩增。ctDNA分子反应与更好的生存相关，ctDNA共改变可能有助于深入了解内在和获得性耐药机制。
