PTEN公司
医学
结直肠癌
内科学
肿瘤科
封锁
队列
微卫星不稳定性
癌症研究
癌症
免疫组织化学
PI3K/AKT/mTOR通路
微卫星
生物
基因
受体
等位基因
遗传学
细胞凋亡
作者
Giovanni Randon,Rossana Intini,Chiara Cremolini,Elena Elez,Michael J. Overman,Jeeyun Lee,Francesco Pantano,Francesca Bergamo,Filippo Pagani,Maria Antista,Valentina Angerilli,J. Ros,Daniele Lavacchi,Alessandra Boccaccino,Giovanni Fucà,Silvia Brich,Laura Cattaneo,Matteo Fassan,Filippo Pietrantonio,Sara Lonardi
标识
DOI:10.1016/j.ejca.2021.11.018
摘要
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.
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