Abstract P2-08-15: Clinical, pathologic, and molecular associations of tumor mutational burden in metastatic breast cancer
Authors: Mohamed Mohamed A , Wang Chenghuang , Buckley Morgan , Lehman Jennifer , Canzoniero Jenna , Gocke Christopher D , Nunes Raquel , Park Ben Ho , Smith Karen L , Tao Jessica , Tukachinsky Hanna , Wilkinson Mary , Wolff Antonio C , Stearns Vered , Santa-Maria Cesar A 
Published: March 2022

Abstract
Background: Tumor mutational burden (TMB) is a biomarker approved to predict response to immune checkpoint blockade (ICB) in solid tumors irrespective of their tissue of origin. However, there are limited data in patients with breast cancer and high TMB to support the use of ICB. The goal of this analysis is to describe clinical, pathological and molecular associations with TMB within a cohort of patients with metastatic breast cancer. Methods: We included patients enrolled onto an ongoing prospective study titled Individualized Molecular Analyses Guide Efforts (IMAGE)-II. Patients eligible for IMAGE-II have metastatic breast cancer of any subtype that had progressed on at least one standard-of-care therapy. Genetic profiling of tumor tissue was performed at the discretion of the treating team using one of several commercially available next generation sequencing platforms. For purposes of this analysis, only patients who underwent tissue-based Foundation Medicine analysis are included as TMB assessments are different across different platforms. Data are summarized by descriptive statistics. Linear and logistic regression analyses are conducted to evaluate the association between TMB and other clinical, pathological and molecular factors. We will present data on associations with specific mutations (i.e. ESR1, ERBB2, DNA repair, Pi3K signaling, TP53) and ctDNA TMB at a later time. Results:Of 117 patients in the IMAGE-II database, median age was 57 (range 23-86), 65% were White, 29% Black, and 6% Other. TMB data were available on 62 patients. Of those with both TMB and subtype information, 35 (70%) had ER+HER2- tumors, and 15 (30%) had ER-HER2- tumors. Median TMB was 4 mutations/megabase and ranged from 0 to 27. We did not observe significant differences in TMB in patients with ER+HER2- and those with ER-HER2- tumors (median TMB of 4 [0-27] and 5 [1-25], respectively), nor between White versus Black patients (median TMB of 4 [0-27] and 5 [0-12], respectively). However, we did observe that age was positively associated with higher TMB (p-value = 0.02). Additionally, we observed that the time between metastatic diagnosis and TMB measurement was positively associated with TMB (p-value &lt; 0.01); this significant association was also observed in ER+HER2- patients (p-value &lt; 0.01) but not in ER-HER2- patients. Median time to obtaining TMB since metastatic diagnosis was 1.1 (range -0.8 - 12.8) years. More lines of chemotherapy prior to TMB assessment was not observed to be associated with higher TMB. Conclusions: We observed that TMB was higher in patients who have had a longer disease course. Further research is required to understand changes in TMB over time, and how TMB is correlated with. other genomic and tumor microenvironment characteristics. A deeper understanding of TMB may help refine it as a predictive biomarker for ICB.
Citation Format: Mohamed A Mohamed, Chenghuang Wang, Morgan Buckley, Jennifer Lehman, Jenna Canzoniero, Christopher D Gocke, Raquel Nunes, Ben Ho Park, Karen L Smith, Jessica Tao, Hanna Tukachinsky, Mary Wilkinson, Antonio C Wolff, Vered Stearns, Cesar A Santa-Maria. Clinical, pathologic, and molecular associations of tumor mutational burden in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-15.