Abstract P2-02-18: Higher mutation burden and mutant allele fraction of circulating tumor DNA corresponds to worse progression free survival in metastatic breast cancer patients
Authors: Keenan T , Juric D , Niemierko A , Spring L , Park H , Malvarosa G , Beeler M , Moy B , Ellisen L , Isakoff S , Bardia A 
Published: February 2018

Introduction: Genomic profiling of circulating tumor DNA (ctDNA) allows non-invasive monitoring of tumor genetic changes and molecular heterogeneity. In addition to actionable mutations, mutational landscape derived from ctDNA could provide a better representation of overall tumor burden and tumor heterogeneity, as well as potentially impact clinical outcomes. To evaluate this hypothesis, this study assessed the association of mutation burden and average mutant allele fraction (MAF) with tumor subtype, therapeutic response, and survival in patients with metastatic breast cancer.

Methods: Whole blood samples from patients with metastatic breast cancer were collected during clinic visits before start of a new therapy. Plasma-derived cell-free DNA underwent complete next-generation sequencing of 73 cancer-related genes with the Guardant360 test. Mutation burden was defined as the number of genes with mutations, and average MAF was calculated as the sum of the highest MAF for each mutated gene divided by the number of genes with mutations. Time to progression was measured from the date of new treatment initiation after circulating tumor DNA collection to the date of progression. Multivariate cox proportional hazard models assessed the association of mutation burden and average MAF with progression free survival (PFS), adjusted for age, receptor subtype (hormone receptor positive, HR+; human epidermal growth factor 2 positive, HER2+; triple negative breast cancer, TNBC), treatment subtype (chemotherapy vs. targeted therapy), and number of prior metastatic breast cancer therapies. A p value of 0.05 was considered statistically significant.

Results: The study population consisted of 158 women with metastatic breast cancer (108 HR+, 14 HER2+, 19 TNBC) with a median age of 59 years and a median of 2 prior metastatic breast cancer therapies. Median follow up time was 4.0 months, and median PFS was 15.7 months. Mutation burden was greater in triple negative compared to hormone receptor positive breast cancer (7.5 vs. 4.8, p = 0.02) but no different in patients with &gt; 2 prior metastatic therapies vs. not (5.1 vs. 4.7, p = 0.60) and age &gt;45 vs. not (5.0 vs. 3.9; p = 0.26). In univariate models, high mutation burden (&gt; median of 2) and high MAF (&gt; median of 1.4) were significantly associated with worse PFS (Table). These results were similar in effect size and significance when adjusted for age, receptor subtype, treatment subtype, and number of prior metastatic breast cancer therapies. Impact of mutation burden on response to specific therapies will be presented at the meeting.

VariableHazard Ratio95% Confidence Intervalp valueHigh mutation burden1.991.12-3.540.02High mutant allele fraction1.881.06-3.330.03

Conclusions: Higher ctDNA mutation burden and average MAF is associated with worse progression free survival and possibly reflects a more treatment refractory phenotype. Whether immunotherapy, alone or in combination, could influence the clinical outcomes in metastatic breast cancer patients with high ctDNA mutation burden is unclear and warrants additional research.

Citation Format: Keenan T, Juric D, Niemierko A, Spring L, Park H, Malvarosa G, Beeler M, Moy B, Ellisen L, Isakoff S, Bardia A. Higher mutation burden and mutant allele fraction of circulating tumor DNA corresponds to worse progression free survival in metastatic breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-18.