Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumouri di Milano, Milano, Italy.
Department of Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy.
Eur J Cancer. 2022 Jan;161:90-98. doi: 10.1016/j.ejca.2021.11.018. Epub 2021 Dec 18.
To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer.
In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression.
Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044).
Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.
揭示与 BRAF 突变和微卫星稳定（MSS）转移性结直肠癌患者对 EGFR/BRAF 靶向治疗原发性耐药相关的基因组和免疫组织化学表达谱。
在这项针对接受 EGFR/BRAF±MEK 阻断治疗的患者的多中心病例对照研究中，我们比较了原发性耐药队列（N=20；RECISTv1.1 PD/SD，无进展生存期[PFS]＜16 周）与敏感队列（N=19；RECISTv1.1 PR/CR，PFS≥16 周），通过综合基因组分析、肿瘤突变负担（TMB）、BRAF 突变转录亚型（BM）分类和 PTEN 表达，比较了两组的临床和基因组/表达数据。
左半侧肿瘤（占总数的 28%）在敏感组中比在耐药组中更为丰富（53%比 10%，P=0.010）。PI3KCA/MTOR 通路中的基因组改变、BM1 状态和 PTEN 缺失在耐药和敏感肿瘤患者中的分布相似。CCND1-3 基因的扩增仅在原发性耐药患者中发现（20%比 0%，P=0.106）。耐药组的 TMB 和中间 TMB（TMB-I 6-20 突变/Mb）的发生率高于敏感组（中位 TMB：6[IQR，3-7.29]比 3[IQR，1.26-3.5]；P=0.013；TMB-I/H：60%比 11%；P=0.001）。TMB-I 患者的 PFS 更短（3.3 个月比 5.9 个月；HR=2.19，95%CI，1.07-4.47，P=0.031），总生存期更短（6.3 个月比 10.5 个月；HR=2.22，95%CI，1.02-4.81，P=0.044）。
尽管样本量较小，但 MSS 和 BRAF 突变的 mCRC 患者中相对较高的 TMB 与 EGFR/BRAF 阻断治疗获益有限之间存在关联，值得进一步前瞻性验证。
