APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer.

作者信息

Natesan Divya, Zhang Li, Martell Henry J, Jindal Tanya, Devine Patrick, Stohr Bradley, Espinosa-Mendez Carlos, Grenert James, Van Ziffle Jessica, Joseph Nancy, Umetsu Sarah, Onodera Courtney, Turski Michelle, Chan Emily, Desai Arpita, Aggarwal Rahul, Wong Anthony, Porten Sima, Chou Jonathan, Friedlander Terence, Fong Lawrence, Small Eric J, Sweet-Cordero Alejandro, Koshkin Vadim S

机构信息

Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, CA, United States.

Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, United States.

出版信息

Front Oncol. 2022 Mar 7;12:816706. doi: 10.3389/fonc.2022.816706. eCollection 2022.

DOI:10.3389/fonc.2022.816706

PMID:35321431

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8935010/

Abstract

INTRODUCTION

Tumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study.

METHODS

We retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest.

RESULTS

Among 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.

CONCLUSIONS

In a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment.

摘要