Abstract P2-03-08: Influence of mutagen exposure on molecular profile in breast cancer

Abstract

Background: Molecular profiling of tumor DNA has changed the management of many cancers. For example, differences in mutations have been observed in lung adenocarcinoma between smokers and non-smokers, with the latter harboring more EGFR mutations. However, there is a paucity of information the influence of mutagen exposure on molecular profile in other cancers. This is a pilot analysis to determine if smoking history or prior adjuvant radiation has an influence on the molecular profiles of women with breast cancer. Methods: Moffitt's Clinical Genomic Action Committee (CGAC) database was used to assess 62 patients with breast cancer treated at Moffitt with targeted deep sequencing of 315 genes as part of clinical care between 4/1/2013 and 12/31/2015. Smoking history was determined by self-report and history of adjuvant radiation therapy was abstracted from the medical record. Tumor sequencing results were analyzed for differential mutational burden (any alteration other than amplifications) and the presence of differentially altered genes between the groups of interest. The groups were similar with regards to percentage of triple negative patients (35.3% vs. 33.3%) between active/prior smokers and never smokers respectively. Results: The most frequently mutated genes across the cohort were TP53 (54.2%), PIK3CA (40.7%), MLL3 (25.4%), CDH1, PTEN, and MLL2 (18.6%), BRCA2 and NF1 (15.3%), BARD1, ESR1, CDKN2A/B, and SPEN (13.6%). There was no difference in the mutational burden between 17 smokers (mean 10.2 alterations; range 1-21) and 42 never smokers (mean 11.5 alterations; range 4-30); p=0.35, with a trend towards more mutations in never smokers. Amongst genes with at least for total alterations, breast cancers of smokers contained a higher frequency of alterations in APC, BLM, and RAD50 (17.6% vs. 2.4%), PIK3CA (58.8% vs. 33.3%), MAP3K1 (23.5% vs. 7.1%), GPR124 (17.6% vs. 4.8%), and TP53 (70.6% vs. 47.6%); although none met statistical significance for multiple comparisons. On the other hand, non-smokers contained increased alterations in MLL2 (5.9% vs. 23.8%), ATM (0.0% vs. 14.3%), as well as FAT1, ATR, AR, and KDM5C (0.0% vs. 11.9%); but also did not differ to a statistically significant degree. There was no difference in the mutational burden between 26 patients without prior radiation and the 34 with prior radiation, each group had a mean of 11.1 alterations. Conclusions: There was no difference in the mutational burden between smokers and never smokers in breast cancer or between breast cancer patients who received prior radiation therapy and those who did not. Smoking StatusMean # of AlterationsRangeAssociated Molecular AlterationsCurrent/Former (n = 17)10.21-21APC, BLM, RAD50, PIK3CA, MAP3K1, GPR124, TP53Never (n=42)11.54-30MLL2, ATM, FAT1, AR, KDM5C Citation Format: Knepper TC, Grabska J, Teer JK, McLeod HL, Solliman HH. Influence of mutagen exposure on molecular profile in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-08.