2871 - Prostate Cancer Somatic Mutations and Outcomes of Salvage Radiation and Hormonal Therapy for Post-Prostatectomy Recurrence

K. Otani¹, D. J. Konieczkowski², Y. Otani¹, S. Wu³, E. Davicioni⁴, P. J. Saylor⁵, D. M. Dahl⁶, C. L. Wu³, S. C. Kamran¹, J. A. Efstathiou¹, and D. T. Miyamoto¹; ¹Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ²Department of Radiation Oncology, James Cancer Hospital, The Ohio State University, Columbus, OH, ³Department of Pathology, Massachusetts General Hospital, Boston, MA, ⁴Veracyte Inc., San Diego, CA, ⁵Department of Medicine, Massachusetts General Hospital, Boston, MA, ⁶Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Purpose/Objective(s): Radiotherapy (RT) +/- androgen deprivation therapy (ADT) plays a key role in salvage therapy of prostate cancer (PC) recurrent after radical prostatectomy. However, not all patients benefit, and there is an unmet need for biomarkers to distinguish responders from non-responders (defined as those with second biochemical failure after salvage). We hypothesized that somatic mutations in primary PC are correlated with response to salvage RT+ADT. Materials/

Methods: We retrospectively identified 718 consecutive PC patients treated with post-operative RT at a single institution from 1992-2013, of whom 40 were treated with salvage RT+ADT and had formalin-fixed, paraffin-embedded prostatectomy and matched normal tissues available for DNA extraction. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. Whole exome sequencing (WES) was performed to an average depth of 162X (r, 70.7-219). We tested for association between somatic mutations and clinical outcomes using the log-rank test and Cox proportional hazards model.
Results: Median age at salvage was 64.5 yrs. High quality WES data was available in 31 patients. With a median follow-up of 122 months (range, 29-248), 16 experienced second biochemical failure after salvage while 15 did not. Median time to second biochemical failure was 82.3 months (range, 1.2-140). Overall tumor mutational burden (TMB) was 3.3 mutations/Mb (range, 1.4-12.9). TMB among those with second biochemical failure was 3.8 vs. 2.8 among those without (p=0.22). The most common mutations detected in the overall cohort were ALEC (n=6) and CUX1 (n=5). The presence of mutations in BRCA2, CASZ1, SYNE1, and AFDN was significantly correlated with second biochemical failure after salvage RT+ADT (see Table 1). Local failure after salvage occurred in 3 patients and was correlated with AFDN mutation (p = 0.0002). In contrast, none of the patients with mutations in WIZ (n=4) or FOXA1 (n=3), experienced second biochemical failure during follow-up.
Conclusion: Using WES analysis, we found that mutations in BRCA2, CASZ1, SYNE1, and AFDN correlated with second biochemical failure after salvage therapy with RT+ADT. These findings require validation in larger cohorts, but suggest that somatic mutations could potentially serve as predictive biomarkers for post-prostatectomy salvage therapy.

Abstract 2871 – Table 1

Gene	No. patients with mutation	p-value	HR (95% CI)
BRCA2	1	0.00021	29 (1.8 - 471)
CASZ1	3	0.00060	9.1 (2.0 - 42)
SYNE1	3	0.0031	6.0 (1.6 - 23)
AFDN	3	0.0033	5.9 (1.5 - 22)