1114 - Germline Indicators of Radiation Therapy Response in Both Aggressive and Non-Aggressive Prostate Cancer Subtypes

08:05am - 08:10am PT

Room 155/157

Presenter(s)

David Miyamoto, MD, PhD - Massachusetts General Hospital, Boston, MA

G. E. Cerrato¹, R. Sanjeev¹, I. Pompa², D. E. Kozono³, A. V. DAmico⁴, P. L. Nguyen⁴, D. T. Miyamoto², J. A. Efstathiou², and S. C. Kamran²; ¹Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, ²Massachusetts General Hospital, Boston, MA, ³Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, ⁴Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA

Purpose/Objective(s): Research on the genetic profile of cribriform pattern (CP) and intraductal carcinoma (IDC) prostate cancer (PCa) subtypes is limited. We evaluated germline mutations in PCa patients receiving radiation therapy (RT) to assess the role of familial high-risk (FHR) and DNA damage repair (DDR) mutations on clinical outcomes in both CP/IDC and non-CP/IDC (control) cases.

Materials/Methods: This multi-institutional study included CP/IDC and control PCa patients treated with RT with germline whole exome sequencing (WES). WES was annotated with Ensembl Variant Predictor, ClinVar, and OncoKB for variant classification. Clinical outcomes included overall survival (OS) and biochemical recurrence-free survival (BRFS, no biochemical recurrence post-salvage/definitive RT). Outcome associations were evaluated using the Kaplan-Meier method and log-rank test (Benjamini-Hochberg FDR of 0.1 for multiple hypothesis testing). T-test and Chi-square were used for comparisons.

Results: Of 1392 CP/IDC and 3387 control patients treated with RT between 2010-2024, 49 (12 CP, 24 IDC, 13 CP+IDC) and 352 had WES, respectively. Cohort demographics are listed in Table.

Median follow-up (mFU, months) from RT was 44.5 in CP/IDC and 69.1 in control patients. Five-year OS from diagnosis was 94.8% (95%CI, 80.4-98.7) in CP/IDC and 95.7% (95%CI 92.8-97.4) in control (p=NS). Despite shorter mFU, BRFS was significantly worse in CP/IDC (69%, 95%CI 47.8-83 CP/IDC; 86.2%, 95%CI 81.3-89.8 control; HR 3.1, 95%CI 1.7-5.6, p<0.001).

In total, 98 NCCN FHR and 280 DDR genes were analyzed. Among CP/IDC and control patients, 41% and 3% had DDR variants (p<0.001), 8% and 3% had FHR (p=0.1), 41% and 5% had pathogenic stop-gains or deletions (p<0.001), and 10% and 3% had oncogenic/tumor suppressor variants (p=0.02), respectively.

DDR mutations associated with improved CP/IDC BRFS (HR 0.14, 95%CI 0.03-0.70, p=0.007). Notably, 19 CP/IDC patients had a pathogenic MSH3 deletion associated with improved BRFS (HR 0.17, 95%CI 0.03-0.83, p=0.02).

Among IDC samples, there were five mutated oncogenes, notably SHDA and DPYS, previously implicated in PCa. Of 9 control patients with oncogenic mutations, 5 had a CHEK2 deletion.

Conclusion: Clinical analysis supports the aggressive nature of CP/IDC morphologies in PCa patients. Pathogenic DDR mutations are significantly associated with CP/IDC pathology and improved BRFS. MSH3 deletion was linked to improved BRFS, highlighting the potential role of DDR alterations in therapeutic response of RT patients with aggressive PCa subtypes.

Abstract 1114 - Table 1

	CP/IDC	Non-CP/IDC	P-value
Age at diagnosis, median (range)	64 (50-81)	67 (39-89)	0.04
Gleason Score, median (range)	8 (6-10)	7 (6-10)	<0.001
Pre-treatment PSA, median (range)	7.7 (3.8-111)	7.2 (3.7-212.7)	0.15
Localized Risk Group, No. (%)			<0.001
Low	1 (2)	48 (14)
Intermediate	16 (33)	210 (60)
High	28 (57)	91 (26)
Metastatic	4 (8)	3 (1)	0.002