肿瘤突变负荷与分子匹配治疗的生存。

Tumour mutational burden and survival with molecularly matched therapy.

机构信息

Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany; Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

出版信息

Eur J Cancer. 2023 Sep;190:112925. doi: 10.1016/j.ejca.2023.05.013.

DOI:10.1016/j.ejca.2023.05.013

PMID:37544709

Abstract

BACKGROUND

The impact of tumour mutational burden (TMB) on outcome with molecularly matched therapy is unknown. Higher TMB could predict resistance to molecularly matched therapy through co-occurring driver mutations.

METHODS

One hundred and four patients with advanced cancers underwent molecular profiling in the DKTK-MASTER program. Fifty-five patients received systemic therapy excluding immunotherapy. Patients with molecularly matched (n = 35) or non-molecularly informed therapy (n = 20) were analysed for TMB and survival. Results were validated in an independent cohort of patients receiving molecularly matched (n = 68) or non-molecularly informed therapy (n = 40). Co-occurring driver mutations and TMB were analysed in the exploratory cohort and The Cancer Genome Atlas (TCGA) datasets.

RESULTS

Patients were stratified by the median TMB of 1.67 mutations per Megabase (mut/Mb) of 35 patients receiving molecularly matched therapy into TMB-high or TMB-low groups. Median overall survival (4 months [95% CI, 3.3-7.6] versus 12.8 months [95% CI, 10-not reached], p < 0.001) and progression-free survival (1.8 months [95% CI, 1.1-3.7] versus 7.9 months [95% CI, 2.8-17.0], p = 0.003) were significantly shorter in the TMB-high group compared to the TMB-low group. In the validation cohort, shorter OS and PFS were identified in the TMB-high group (TMB cut-off of 4 mut/Mb) treated with molecularly matched therapy. No differences were observed in patients receiving non-molecularly informed systemic therapy. A significant correlation between co-occurring driver mutations and TMB (n = 104, r = 0.78 [95% CI, 0.68-0.85], p < 0.001) was found in the exploratory cohort as well as the majority (24/33) of TCGA studies.

CONCLUSION

A high TMB was associated with unfavourable outcome in patients receiving molecularly matched therapy, indicating untargeted resistance pathways. Therefore, TMB should be further investigated as a predictive biomarker in precision oncology programs.

摘要

背景

肿瘤突变负荷（TMB）对分子匹配治疗结果的影响尚不清楚。更高的 TMB 可能通过共同发生的驱动突变预测对分子匹配治疗的耐药性。

方法

104 名晚期癌症患者在 DKTK-MASTER 计划中进行了分子谱分析。55 名患者接受了免疫治疗以外的系统治疗。对接受分子匹配（n=35）或非分子信息治疗（n=20）的患者进行 TMB 和生存分析。结果在接受分子匹配（n=68）或非分子信息治疗（n=40）的患者的独立队列中得到验证。在探索性队列和癌症基因组图谱（TCGA）数据集中分析了共同发生的驱动突变和 TMB。

结果

根据 35 名接受分子匹配治疗患者的中位数 TMB（1.67 个突变/Mb），将患者分为 TMB 高或 TMB 低组。中位总生存期（4 个月[95%CI，3.3-7.6]与 12.8 个月[95%CI，10-未达到]，p<0.001）和无进展生存期（1.8 个月[95%CI，1.1-3.7]与 7.9 个月[95%CI，2.8-17.0]，p=0.003）在 TMB 高组明显短于 TMB 低组。在验证队列中，TMB 高组（TMB 截断值为 4 mut/Mb）接受分子匹配治疗的 OS 和 PFS 更短。接受非分子信息系统治疗的患者无差异。在探索性队列以及大多数 TCGA 研究（24/33）中，共同发生的驱动突变与 TMB 之间存在显著相关性（n=104，r=0.78[95%CI，0.68-0.85]，p<0.001）。