Abstract 162P
Background
Germline pathogenic variants (PV) in the BRCA1 gene increase the risk of breast cancer (BC). Yet, the extent to which different types of BRCA1 PV affect BC phenotype and outcomes is poorly understood. In particular, whether BRCA1 large genomic rearrangements (LGR) are associated with distinct clinicopathological features and survival outcomes remains unexplored.
Methods
We conducted a retrospective multicenter study of germline PV BRCA1 carriers diagnosed with BC. Patients with BRCA-associated malignancies prior to BC diagnosis or PV in other BC-susceptibility genes were excluded. Independent samples T-test, X2, and Fisher’s exact tests were used to evaluate associations between variables. After excluding patients with de novo stage IV BC, disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared according to LGR status using the log-rank test.
Results
Among 111 patients, mean age at diagnosis was 38 years (SD 8), 106 (96%) had localized disease, 100 (90%) had triple-negative BC, and 42 (38%) were carriers of BRCA1 LGR. Clinicopathological features according to LGR status are shown in the table. Overall, there were no statistically significant differences between groups. With a median follow-up of 97 months (95% CI 82-112), 10-year DFS rates were not significantly different between the LGR and non-LGR groups (39% and 40%, respectively; p=0.441). However, a notable distinction emerged in OS, as patients harboring BRCA1 LGR demonstrated significantly enhanced 10-year OS rates (95% vs. 57%, p=0.014). Table: 162P
| Non-LGR | LGR | p-value | |
| n | 69 (62%) | 42 (38%) | |
| Age (mean + SD) | 38 + 8 | 38 + 7 | 0.705 |
| Stage at diagnosis | |||
| I | 8 (12%) | 4 (10%) | |
| II | 34 (49%) | 27 (64%) | 0.432 |
| III | 24 (35%) | 9 (21%) | |
| IV | 3 (4%) | 2 (5%) | |
| Molecular subtype | |||
| HR-/HER2- | 62 (90%) | 38 (90%) | |
| HR-/HER2+ | 0 | 2 (5%) | 0.068 |
| HR+/HER2- | 7 (10%) | 1 (2%) | |
| HR+/HER2+ | 0 | 1 (2%) | |
| Use of platinum salts | |||
| No | 42 (64%) | 29 (73%) | 0.347 |
| Yes | 24 (36%) | 11 (28%) | |
| Second primary malignancy | |||
| No | 54 (78%) | 31 (74%) | 0.591 |
| Yes | 15 (22%) | 11 (26%) |
Conclusions
In this cohort of BRCA1 carriers with BC, patients with LGRs exhibited significantly superior survival outcomes. We hypothesize that this survival advantage may be attributed to an intrinsic resistance to reversion mutations in LGR carriers, which have the potential to revert the gene's function, reducing the effectiveness of therapies designed to target BRCA1 dysfunction.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.