Breast Cancer

SS 21 - Breast 2 - Biology and SBRT

132 - Pathogenic Mutations in ATM Enhance Radio-Sensitivity and Local Control in Patients With Primary and Metastatic Breast Cancer

Tuesday, October 23
7:45 AM - 7:55 AM
Location: Room 214 A/B

Pathogenic Mutations in ATM Enhance Radio-Sensitivity and Local Control in Patients With Primary and Metastatic Breast Cancer
D. L. Casey1, K. L. Pitter1, J. Setton1, L. Z. Braunstein1, M. E. Robson1, J. Reis-Filho1, B. Weigelt1, C. Lu1, S. N. Powell1, T. A. Chan1, N. Lee2, and N. Riaz2; 1Memorial Sloan Kettering Cancer Center, New York, NY, 2Memorial Sloan Kettering Cancer Center, Department of Radiation Oncology, New York, NY

Purpose/Objective(s): Hereditary alterations in Ataxia-Telangiectasia-Mutated (ATM) gene, a key signaling protein in the double-stranded break DNA repair process, is associated with an elevated risk of breast cancer. Here, we sought to define whether pathogenic ATM mutations present in breast cancer are associated with response to radiotherapy and exceptional responses to low dose treatment.

Materials/Methods: We screened our institutional database of 21675 patients who have undergone targeted sequencing with a 468-gene panel, and identified 3773 patients with breast cancer, of whom 78 harbored ATM mutations. Among the 78 patients, 58 were treated with RT to a total of 105 different sites and were included in this analysis. Nineteen patients (33%, treated to 31 sites) had a pathogenic ATM mutation (a truncating/frameshift mutation), whereas 39 patients (67%, treated to 74 sites) had a missense ATM mutation of unknown significance. Local control (LC) after RT and toxicity were compared in patients with pathogenic ATM mutations versus those with missense mutations.

Results: Median age at time of RT was 52.2 years (range, 32.1-83.6), and median follow up among the entire cohort was 3.2 years. Three-year LC at any irradiated site was 83.3% among patients with pathogenic mutations versus 68.2% in patients with missense mutations (p=0.02). Among the 61 sites treated palliatively (median dose 30 Gy), crude rates of LC were 93.4% in patients with pathogenic ATM mutations versus 68.9% in patients with missense ATM mutations. Actuarial rates of LC at 3 years were 75% versus 42.0%, respectively (p=0.02). Among the 44 patients treated to the breast or chest wall for localized disease, crude rates of LC were 93.3% versus 79.3%, although actuarial analysis did not demonstrate a statistically significant difference. Patients with pathogenic mutations treated palliatively were more likely to experience lasting symptomatic relief from RT than patients with missense mutations (p=0.009). There were no differences in grade ≥2 acute or late toxicities among the two groups. Exceptional radiation responses were seen in individual patients with pathogenic mutations; one woman with a nonsense truncating mutation and leptomeningeal disease is now without evidence of disease in the central nervous system >10 years after whole brain RT.

Conclusion: Patients with pathogenic ATM mutations exhibited higher LC rates than patients with missense ATM mutations of unknown significance. There does not appear to be an increase in significant acute or late toxicity after RT for patients with clinically significant somatic ATM mutations. Our findings suggest that ATM may constitute a novel mutation-based marker of radio-sensitivity in breast cancer and may facilitate personalized treatment in the future.

Author Disclosure: D.L. Casey: None. K.L. Pitter: None. J. Setton: None. L.Z. Braunstein: None. J. Reis-Filho: None. C. Lu: None. T.A. Chan: Vice Chair; Memorial Sloan Kettering. N. Lee: Consultant; Lily. Advisory Board; Pfizer, Vertex, Merck. N. Riaz: None.

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