Abstract

PurposeTumor mutational burden (TMB) is a surrogate biomarker of neo-antigens and high TMB status is associated with favorable response to immune-checkpoint inhibitors (ICIs). This study aimed to elucidate the association between TMB and the outcome of definitive radiotherapy in patients with cervical cancer.Materials and methodsTMB and treatment outcome were retrospectively analyzed in patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel.ResultsThe study enrolled 98 patients (median follow-up period, 61 months). The median TMB was 9.5 mutations per megabase (range, 3.0–35.5 mutations per megabase). After dichotomization based on this median value, the 5-year overall survival (OS) for TMB-high patients was significantly worse than that of TMB-low patients (61.1% vs. 82.2%). Multivariate analysis identified high TMB status as a significant prognostic factor for worse OS, along with advanced stage, para-aortic lymph node involvement, and absence of concurrent chemotherapy.ConclusionThese data indicate that TMB is a potential prognostic factor for worse survival in patients with cervical cancer treated with definitive radiotherapy, thereby providing a rationale for treatment of TMB-high cervical cancers with a combination of ICIs plus radiotherapy.Secondary abstractThis retrospective study of 98 patients demonstrates for the first time that tumor mutational burden (TMB) is an independent prognostic factor for worse overall survival of patients treated with definitive radiotherapy, providing a rationale for treatment of TMB-high cervical cancers with a combination of immune-checkpoint inhibitors plus radiotherapy.

Highlights

  • Cervical cancer arises in nearly 0.5 million women annually worldwide, and mortality ranks fourth among all cancers [1]

  • We investigated the association of tumor mutational burden (TMB) and treatment outcome in retrospectively collected patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel

  • There was no significant difference between the TMB-high and -low patients in terms of follow-up period, Fig. 1 Overview of the tumor mutational burden (TMB) identified in this study cohort. mut/Mb mutations per megabase age, Federation of Gynecology and Obstetrics (FIGO) stage, tumor diameter, lymph node involvement, and the use of concurrent chemotherapy (Table 1)

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Summary

Introduction

Cervical cancer arises in nearly 0.5 million women annually worldwide, and mortality ranks fourth among all cancers [1]. Radiotherapy is the standard definitive treatment for locally advanced cervical cancer [2]. The treatment outcome has been improved dramatically along with the technological advancement in three-dimensional imageguided adaptive brachytherapy [3]. A subset of patients develops local recurrence or metastasis after definitive radiotherapy, highlighting the need to identify such patients and stratify them to receive treatments with greater intensity. Immune-checkpoint inhibitors (ICIs) are an emerging candidate for use in combination with radiotherapy. A randomized phase 3 PACIFIC study showed

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