2778 - Radiation Therapy for Breast Cancer: Impact of DNA Repair Gene Mutations on Oncologic Outcomes
Presenter(s)
F. Kwong1, M. E. Bankston1, T. Reddy2, T. Yap3, Y. Li4, W. A. Woodward1, M. P. Mitchell1, H. R. Garber4, K. Shaw5, and S. F. Shaitelman1; 1Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Baylor College of Medicine Department of Internal Medicine, Houston, TX, 3Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX, 4The University of Texas MD Anderson Cancer Center, Houston, TX, 5Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s): Breast cancer is one of the most prevalent malignancies globally, with radiation therapy (RT) playing a critical role in management. In the preclinical setting, tumors harboring DNA repair gene (DRG) mutations demonstrate increased radiosensitivity. However, the impact of DRGs on oncologic outcomes in breast cancer patients who receive RT is unclear.
Materials/Methods: We analyzed 523 breast cancer patients who received RT and underwent genetic sequencing of DRGs. DRG pathways included homologous recombination, non-homologous end joining, checkpoint, and DNA damage response and repair. Patients were included if they underwent sequencing for at least one DRG and were classified as DRG-mutated if their tumor sample carried at least one mutated gene. Otherwise, they were classified as DRG wildtype (non-mutated). Biologically equivalent dose (BED) was calculated using an alpha/beta ratio of 4.6. Each course of RT received was evaluated separately for response. The primary endpoint was local tumor progression, assessed via imaging and/or physical examination. The secondary endpoint was progression-free survival (PFS), defined as time from RT initiation to death or progression. Kaplan-Meier method estimated progression and PFS. Fine-Gray regression accounted for competing risk of death when analyzing cumulative incidence of progression. Univariate and multivariate Cox proportional hazards models identified factors associated with outcomes, including the presence of DRG mutations, age, tumor stage, and treatment-related variables. Two-sided P < 0.05 was considered statistically significant. Ethical approval was obtained via Institutional Review Board.
Results: Of 523 patients tested between 2015-2019, 70 (13%) were excluded for lacking DRG evaluation. RT was administered from 1983-2019. Among 453 eligible patients, 255 (56%) harbored a DRG mutation vs. 198 (44%) wildtype patients. There was no statistical difference in pathologic stage or age between groups. DRG-mutated patients were more likely to receive endocrine therapy (60% vs. 37.4%, P < 0.001) and immunotherapy (4.7% vs. 0.5%, P = 0.009). No difference was observed between our two cohorts regarding local progression or PFS (both P > 0.05). Higher BED correlated with lower progression on univariate but not multivariate analysis. No significant interactions were found between DRG status and RT characteristics (age, radiation site, exam method, and BED) on progression.
Conclusion: Despite preclinical evidence of increased radiosensitivity, DRG mutations did not significantly correlate with oncologic outcomes in our study cohort. Study limitations include retrospective design and heterogeneous genetic analysis. Further study is needed to clarify interactions between DRG status and radiation characteristics and why preclinical findings do not appear to translate into patient outcomes.