An Exploratory Study to Determine Whether BRCA1 and BRCA2 Mutation Carriers Have Higher Risk of Cardiac Toxicity

Abstract

Anthracycline-based cardiotoxicity is concerning for women with breast cancer and portends a dose-dependent risk of developing left ventricular dysfunction. Overall, the prevalence of heart failure (HF) is ≈2% of the total US population; however, BRCA-deficient mice have shown increased HF. We evaluated for the inherent risk of HF in women with BRCA mutations to determine whether treatment with anthracycline-based therapy increased this risk. We obtained results on BRCA mutation carriers regarding cancer treatment and HF, identified through the BRCA patient advocacy organization Facing Our Risk for Cancer Empowered (FORCE) and the Moffitt-based Inherited Cancer Registry. In our patient group (232 BRCA1 and 159 BRCA2 patients; 10 with both mutations), 7.7% reported HF, with similar proportions in BRCA1 versus BRCA2 carriers (7.4% and 8.2%, respectively). These proportions are significantly higher than published rates (p < 0.001). There was no statistically significant difference in HF rates comparing anthracycline-treated versus anthracycline-naïve patients however (7.1% vs. 8.3%; p = 0.67). In addition, 9.1% of BRCA1 carriers and 8.2% of BRCA2 carriers reported arrhythmias. BRCA mutation carriers showed increased risk of cardiotoxicity versus the general population and an overall increased risk of cardiotoxicity from anthracycline-based therapy. Our study supports data that BRCA carriers have increased non-cancer mortality from cardiotoxicity. A prospective trial to determine HF and conduction abnormalities in this population is warranted.

The connection between the breast and heart in a woman: Breast cancer and cardiovascular disease

“…Interestingly, these BRCA genes are also involved in preservation of cardiac function, and abnormalities may affect susceptibility to cardiac damage. It has been observed that the presence of either of these gene abnormalities is associated with a higher risk of heart failure in patients receiving anthracycline‐based therapies, irrespective of duration and dosing of anthracycline exposure …”

“…It has been observed that the presence of either of these gene abnormalities is associated with a higher risk of heart failure in patients receiving anthracycline-based therapies, irrespective of duration and dosing of anthracycline exposure. 33,34 Breast cancer survivorship has been increasing and comprises the largest group of cancer survivors in the United States. 35 Despite the increased risk of cardiovascular disease in breast cancer survivors, there are no specific guidelines for the assessment and prevention of cardiovascular risk in these patients.…”

Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging?

“…Limited by small sample size, the patterns yielded in our study were very obvious, yet not clearly significant, hampered by high variability. Aging is also characterized by increased cardiovascular risk, due to endothelial dysfunction via increased generation of reactive oxygen species (ROS), thus elevating oxidative stress that in turn promotes DNA damage and endothelial cell apoptosis [ 41 ]. It had been recently demonstrated that BRCA mutation carriers had increased risk of chemotherapy-induced cardiotoxicity in both mouse and human [ 41 , 42 ].…”

“…Aging is also characterized by increased cardiovascular risk, due to endothelial dysfunction via increased generation of reactive oxygen species (ROS), thus elevating oxidative stress that in turn promotes DNA damage and endothelial cell apoptosis [ 41 ]. It had been recently demonstrated that BRCA mutation carriers had increased risk of chemotherapy-induced cardiotoxicity in both mouse and human [ 41 , 42 ]. The pre-clinical data obtained in mice highlight an unrecognized role of BRCA as a gatekeeper of inflammation-induced endothelial cell function and a target to limit atherosclerosis [ 43 – 46 ].…”

hiPSCs in cardio-oncology: deciphering the genomics

“…Many of these studies were limited by small sample size and identified no significant SNPs. [11][12][13][14][15][16][17][18][19][20][21][22] Among CGAS that identified significant variants, candidate genes were related to drug metabolism (CBR3, 23 UGT1A6, 24,25 and POR 26 ), drug transport (SLC28A3, 25,27 SLC22A17, 28 SLC22A7, 28 ABCC2, 29 ABCC1, [30][31][32] ABCC5, 33 and ABCG2 34 ), iron metabolism (HFE 29,35 ), cell signalling (RAC2, 29,31 NOS3, 33 and PLCE1 36 ), DNA repair (ERCC2, 37 BRCA1, 38 and BRCA2 38 ), splicing regulation (CELF4 24 ), response to oxidative stress (CAT, 39 NCF4, 31,40,41 GSTP1, 42 and CYBA 31,41 ), calcium homeostasis (ATP2B1 36 ), myosin synthesis (MYH7 43 ), and extracellular matrix synthesis (HAS3 24,44 ). Additionally, two exome array analyses identified candidate genes (ETFB 45 and GPR35 46 ) that were significant only when analysed with a gene-based approach.…”