Abstract PD9-10: Investigating the clinical utility of tumor mutational burden in predicting rapid progression and death in patients with metastatic breast cancer
Authors: Makhlin Igor , Clark Amy S , Wileyto Paul , Goodman Noah , Ndicu John , DeLuca Shannon , Clark Candace , Stavropoulos S. William , Shih Natalie , Feldman Michael D , Domchek Susan M , Matro Jennifer M , Shah Payal D , Knollman Hayley M , Fox Kevin R , Maxwell Kara N , Chodosh Lewis A , DeMichele Angela 
Published: February 2021

Abstract
Background Up to 30% of breast cancer patients will eventually relapse with metastatic disease. With an increasing array of therapeutic options, there is an ongoing need for predictive biomarkers to help guide treatment strategies including sequencing of therapies in the metastatic setting. We sought to evaluate the prognostic and predictive potential of a panel-specific tumor mutational burden (TMB) in metastatic breast cancer patients.
Methods METAMORPH is a prospective, longitudinal cohort study. Eligible patients (pts) had newly diagnosed or progressive metastatic breast cancer and enrolled prior to starting a new line of therapy (physician’s choice) at the University of Pennsylvania. Pts underwent tissue biopsy of a suspected metastatic site. Tumor samples were analyzed for mutations and copy number alterations (CNA’s) using our institution’s CLIA-certified Center for Personalized Diagnostics (CPD) targeted gene panel, which evolved over the course of the study from 20 genes to 152 genes. TMB-high (TMB-H) was defined as ≥3 mutations and/or copy-number gains (CNG) among 18 genes shared across all panel versions. Pts were followed for time to progression (TTP), progression-free survival (PFS), and overall survival (OS). The frequency of rapid progressors and rapid death (defined as having progressed or died within 3 months of enrollment, respectively) was assessed.
Results Three hundred pts enrolled from 2013-2020, of whom 200 pts had CPD reports generated. Of these, 12 pts were excluded due to either no treatment change on enrollment (n=11) or different primary cancer on biopsy (n=1). Thus 188 pts were included in this analysis. The median age was 55 years (range 28-79). 77% of pts identified as white, 18% as Black or African American, and 3.2% as Asian. Pts had a median of 1 line (range 0-12) of prior systemic therapy in the metastatic setting. 46.8% had no prior therapies for MBC, while 31% had ≥3 prior lines of therapy. 74.4% were HR+, 22.8% TNBC, and 2.7% HR-/HER2+. 6.9% of the cohort were classified as TMB-H. The average mutation/CNG rate was 2.2/sample, and 22.5% had no mutations or CNA’s. The most common mutations were TP53 (35%) and PIK3CA (26%).
While TMB-H patients showed a statistically non-significant trend towards shorter median TTP and PFS compared with TMB-L, they comprised a significantly greater proportion of rapid progressors (54.5% vs 24.1%, p=0.027), with an odds ratio for rapid progression of 3.8 (95% CI 1.08-13.2). In a multivariate logistic regression analysis, TMB-H remained independently associated with rapid progression when adjusted for receptor subtype and next line of therapy. Receptor subtype analysis revealed that ER- (including ER-/PR+) patients with TMB-H had a shorter median TTP compared to ER- TMB-L (147 vs 68 days, p=0.03). TMB-H was also associated with significantly shorter OS compared with TMB-L (587 vs 648 days, p=0.02; HR 2.2 [95% CI 1.11-4.41]). 44.4% of TMB-H pts died within 3 months of enrollment, as compared to 11.0% of TMB-L pts (p=0.005), with an odds ratio for rapid death, adjusted for number of previous lines of therapy and receptor subtype, of 6.7 (95% CI 1.5-31.0).
Conclusion MBC pts who are TMB-H represent a population who are highly resistant to standard therapies, progress rapidly, and have significantly shorter overall survival with more rapid time to death. Our data support further studies investigating the utility of TMB as a predictive biomarker in directing patients away from standard treatment options and towards novel approaches e.g. immunotherapy.
Citation Format: Igor Makhlin, Amy S Clark, Paul Wileyto, Noah Goodman, John Ndicu, Shannon DeLuca, Candace Clark, S. William Stavropoulos, Natalie Shih, Michael D Feldman, Susan M Domchek, Jennifer M Matro, Payal D Shah, Hayley M Knollman, Kevin R Fox, Kara N Maxwell, Lewis A Chodosh, Angela DeMichele. Investigating the clinical utility of tumor mutational burden in predicting rapid progression and death in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-10.