904MO - Anthracycline-related cardiotoxicity in breast cancer patients carrying mutational signature of homologous recombination deficiency (HRD)

Background

The BRCA proteins play a key role in the homologous recombination (HR) pathway. Beyond BRCA1/2, other genes are involved in the HR Repair (HRR). Due to the prominent role in the cellular repair process, deleterious variants in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. The role of BRCA1/2 as predisposing condition to cardiac dysfunction is debated, and the contribution by no-BRCA genes is still unknown.

Methods

This is a multi-institutional retrospective/prospective study to investigate the risk of heart failure from anthracyclines on adjuvant setting in BC patients carrying germline pathogenic or likely pathogenic variant (PV) in BRCA and no-BRCA HRR pathway genes. We collected genetic and clinical data, and evaluated the left ventricular ejection fraction (LVEF) at cardiac ultrasound, before starting therapy, and at subsequent time points, according to clinical indications.

Results

Five hundred and three (503) BC patients, aging 21 to 82, were included in the study; 201 patients were carriers of germline PV in HRR pathway genes: 77 in BRCA1 gene (38.3%), 73 in BRCA2 gene (36.3%), and 21 in no-BRCA HRR pathway genes (25.4%), including PALB2, CHEK2, ATM, RAD51C, RAD50 and BARD1 genes. In the cohort of 302 patients without PV, 57 showed variant of uncertain significance (VUS), and 245 had genetic testing not informative. When LVEF between the groups was compared, the difference was not significant for the pre-treatment values. Notably, individuals carrying BRCA or other HRR gene deleterious variants, showed a statistically significant reduction in LVEF >5% during monitoring, compared to the LVEF pre-treatment value (p=0.001). A marked LVEF reduction was in mutated patients treated with risk-reducing bilateral salpingo-oophorectomy prior to age 40, BMI>25, and type-II diabetes mellitus.

Conclusions

Our data suggest that PVs in HRR pathway genes can increase sensitivity of cardiac cells to DNA damaging anthracycline in BC patients. In these patients other measurements, such as the global longitudinal strain, could be proposed to optimize cardiovascular risk-management and to improve long-term survival.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Palermo.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.