Genitourinary Cancer

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SU_29_2295 - Pathogenic Mutations in ATM Predict for Enhanced Local Control in Prostate Cancers Treated With Radiation Thearpy

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Pathogenic Mutations in ATM Predict for Enhanced Local Control in Prostate Cancers Treated With Radiation Thearpy
C. Lu1, K. L. Pitter1, D. L. Casey1, N. Riaz2, N. Lee2, S. McBride1, J. Reis-Filho1, S. N. Powell1, M. J. Zelefsky1, T. A. Chan1, and J. Setton1; 1Memorial Sloan Kettering Cancer Center, New York, NY, 2Memorial Sloan Kettering Cancer Center, Department of Radiation Oncology, New York, NY

Purpose/Objective(s): Ataxia-Telangiectasia-Mutated (ATM), which encodes a Ser/Thr kinase that plays a central role in the repair of DNA double-strand breaks, is among the most frequently mutated tumor suppressor genes in prostate cancer. Here, we sought to determine whether pathogenic mutations in ATM predict for enhanced response to radiotherapy among pts with primary or metastatic prostate cancer.

Materials/Methods: The study cohort was identified from an institutional database of patients who underwent genomic testing using a capture-based next-generation sequencing assay of 468 key cancer genes. Among 21,675 pts with available genomic data, we identified 1414 pts with prostate cancer, 63 (4.5%) of whom harbored a mutation in ATM. Among these 63 pts, 28 received radiotherapy (RT) at any point during their treatment course--to a total of 71 different sites--and were included in this analysis. Fifteen pts (treated to 40 sites) had a pathogenic ATM mutation (truncating or frameshift mutation), while 13 pts (treated to 31 sites) had a missense ATM mutation of unclear significance. Local control (LC) after RT was compared in pts with pathogenic ATM mutations vs those with missense mutations.

Results: The vast majority (93%) of pts presented with metastatic or high-risk localized disease at the time of initial diagnosis; the modal Gleason score at presentation was 9. At median follow-up of 15 months, actuarial LC at any irradiated site was 89% among pts with pathogenic mutations vs 60% in pts with missense mutations (p=0.006). Improved local control among pts with pathogenic ATM mutation was observed despite such pts receiving a lower mean biological equivalent dose (BED) of RT (Table 1). Among the 71 sites treated with RT, 58 (33 with pathogenic and 25 with missense ATM mutations) were palliatively-treated non-primary sites. Among the 58 sites treated palliatively, the actuarial rate of LC at median follow-up was 85% among pts with pathogenic mutations versus 48% in pts with missense mutations (p=0.01). Thirteen patients received RT to the prostate or prostate bed; crude rates of LC were 100% among pts with pathogenic mutations (n=7) versus 83% among pts with missense mutations (n=6). There were no differences in grade ≥2 acute or late toxicities after RT among pts with pathogenic vs missense ATM mutations.

Conclusion: Prostate cancers harboring a pathogenic ATM mutation were more likely to be controlled with radiotherapy than tumors harboring missense mutations of unclear significance. There was no apparent increase in significant acute or late toxicity after RT for pts with clinically significant ATM mutations. These findings suggest that genetic inactivation of ATM predicts for clinical response to radiotherapy and, if validated, may help guide rational selection of definitive therapy for high-risk localized prostate cancer.
Non-primary sites Prostate/prostate bed
# Irradiated Median BED10 Mean BED10 # Irradiated Median BED10 Mean BED10
Pathogenic 33 28 33 7 85 77
Missense 25 39 36 6 85 80

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

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