PL 01 - Plenary Session
4 - Androgen Receptor Activity and Radiotherapeutic Sensitivity in African-American Men With Prostate Cancer: A Large Scale Gene Expression Analysis and Meta-Analysis of RTOG Trials
Monday, October 22
2:55 PM - 3:05 PM
Location: Stars at Night Ballroom
Daniel Spratt, MD
University of Michigan
The University of Michigan Cancer Center: Assistant Professor: Employee, Associate Professor: Employee
Androgen Receptor Activity and Radiotherapeutic Sensitivity in African-American Men With Prostate Cancer: A Large Scale Gene Expression Analysis and Meta-Analysis of RTOG Trials
D. E. Spratt1, R. T. Dess1, H. E. Hartman2, B. A. Mahal3, W. C. Jackson1, P. D. Soni4, M. Alshalalfa5, N. Fishbane6, Z. S. Zumsteg7, W. U. Shipley8, T. M. Pisansky9, M. Roach III10, S. G. Zhao1, C. Speers11, E. Davicioni6, M. Schipper2, P. L. Nguyen12, E. M. Schaeffer13, F. Y. Feng14, and H. M. Sandler15; 1Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 2Department of Biostatistics, University of Michigan, Ann Arbor, MI, 3Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA, 4University of Michigan, Ann Arbor, MI, 5GenomeDx, Vancouver, BC, Canada, 6GenomeDx Biosciences, Vancouver, BC, Canada, 7Cedars-Sinai Medical Center, Los Angeles, CA, 8Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 9Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 10Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 11Veteran Affairs Hospital Ann Arbor, Ann Arbor, MI, 12Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 13Northwestern University, Evanston, IL, 14UCSF Department of Urology, San Francisco, CA, 15Cedars Sinai Medical Center, Los Angeles, CA
Purpose/Objective(s): Population data suggests that African-American (AfA) men have an increased mortality from prostate cancer (PCa) compared to Caucasian (C) men. Socioeconomic variables contribute to this disparity, yet intrinsic biological differences remain plausible. Herein, we investigate the interplay of androgen receptor activity (AR-A) and radiotherapeutic sensitivity to provide a molecular rationale to help explain the disparity in outcomes for AfA men with PCa.
Materials/Methods: Transcriptome-wide expression profiles of FFPE tumor samples from 5,831 localized PCa patients were used. Tissue was obtained from a prospective population cohort (n=5,239) and two retrospective cohorts with long-term outcomes (n=592). Predicted radiation sensitivity was measured using the 24-gene post-operative radiation therapy (RT) outcome score (PORTOS). AR-A was defined from the pooled expression of nine canonical AR-target genes. Clinical radiosensitivity was validated using individual patient data from four RTOG trials (92-02, 94-08, 94-13, and 99-10), comprised of 6,011 patients (18.5% AfA). Competing risk adjustments were used for all survival analyses for biochemical recurrence (BCR) and distant metastases (DM).
Results: In men treated by surgery from the prospective cohort, low AR-A tumors were significantly more likely to develop DM (10-year rate: 37% vs 17%, p=0.008). On multivariable analysis after adjusting for Gleason grade, T-stage, PSA, margin status, and lymph node invasion, low AR-A remained independently prognostic for DM (p=0.03). After generating a matched cohort of AfA and C patients, AfA tumors were more likely to have low AR-A (p<0.001). However, AfA tumors had decreased double strand break repair pathway expression (p<0.001) and increased predicted RT sensitivity (p<0.001). This suggests that AfA men may have improved outcomes with RT. To clinically test whether AfA tumors are more radiosensitive, we leveraged four large RTOG trials of men treated with RT. On both unadjusted and propensity weighted cohorts (adjusting for age, performance status, PSA, Gleason grade, T-stage, N-stage, and use/duration of hormone therapy), AfA men had significantly improved outcomes compared to C men (BCR (HR 0.82 [95%CI 0.74, 0.92], p=0.0005) and DM (HR 0.70 [95%CI 0.57, 0.86], p=0.0008)).
Conclusion: Our data suggest that there are population-level differences in AR signaling and DNA repair in AfA and C men’s PCa, which transcriptionally suggest that AfA men may harbor more radiosensitive tumors. To our knowledge, this is the first report demonstrating that AfA men may have improved outcomes compared to C men treated with RT, which is consistent with our hypothesis regarding diversity in AR-A, and warrants further investigation.
Author Disclosure: D.E. Spratt: None. R.T. Dess: None. H.E. Hartman: None. B.A. Mahal: None. M. Alshalalfa: None. W.U. Shipley: Stock; Pfizer. Co-Chair of RTOG FOUNDATION; also Co-Chair of GU D; RTOG. M. Roach: Honoraria; Ferring Pharma, Blue Earth, Myriad. Consultant; Ferring Pharma, Janssen Pharma, International Atomic Energy Agency. Advisory Board; Janssen Pharma, Tolmar, Bayer, Blue Earth, Myriad. Travel Expenses; Ferring Pharma, Janssen Pharma, International Atomic Energy Agency, Tolmar, Bayer, Blue Earth, Myriad. Stock; Abbott, Agilent, Altria, GSK, Hospira. Board Member; NCAB. P.L. Nguyen: Honoraria; Bayer. Consultant; Nanobiotix, Infinity Pharmaceuticals, GI Windows, Astellas, Augmenix. Advisory Board; Ferring, Medivation, Genome DX, Dendreon. Stock Options; Augmenix. Program Committee; Genitourinary Cancers Symposium. E.M. Schaeffer: None. F.Y. Feng: Research Grant; GenomeDx. Advisory Board; GenomeDx, Dendreon, Sanofi. Travel Expenses; GenomeDx. Liaison, GU Translational Research Program; Radiation Therapy Oncology Group. President and Founder; PFS Genomics. H.M. Sandler: Research Grant; ACR-RTOG. Stock; Advanced Medical Isotope Corporation. Committee Chair; NRG Oncology.