Presentation Authors: Arnav Srivastava*, New Brunswick, NJ, Isaac Kim, Providence, RI, Sinae Kim, Biren Saraiya, Tina Mayer, New Brunswick, NJ, Mark Stein, New York, NY, Wun-Jae Kim, Cheongju, Korea, Republic of, Isaac Kim, New Brunswick, NJ
Introduction: Approximately one-third of castration resistant metastatic prostate cancer patients have a dysregulated DNA damage response (DDR) pathway. However, DDR pathway alteration rates in localized prostate cancer have not been fully elucidated. Characterizing these alteration rates offers both insight into prostate tumorigenesis as well as opportunities for targeted therapy.
Methods: Patients with localized prostate cancer were analyzed using The Cancer Genome Atlas (TCGA) database. Based on 12 genes identified a priori, we tabulated the proportion of men with DDR pathway alterations. Survival analysis in patients with and without predictors of recurrence (Gleason score 4+4=8, >pT3a, pre-operative PSA> 20ng/ml) was carried out and further stratified by DDR pathway status.
Results: 136 of 455 patients (29.9%) had DDR pathway alterations, of which BRCA2 constituted the largest proportion (Figure 1). By Gleason score, a much larger percentage of alterations were found in those with Gleason 7 (49.3%) and 8 (44.1%) disease versus Gleason 6 (6.6%). Additionally, survival analysis demonstrated worse survival among patients with DDR pathway alterations in men with a high-risk disease (Figure 2).
Conclusions: DDR pathway alterations may be present in almost 30% of those with localized prostate cancer. Thus, a dysregulated DDR pathway may contribute to tumor biology and progression, even in localized disease. Furthermore, patients with the pertinent alterations often experience inferior outcomes to their normal counterparts. Our data also suggests the potential for therapeutic expansion of poly(adenosine diphosphate-ribose) polymerase (PARP) 1 inhibitors, such as olaparib, in the treatment of localized disease.
Source of Funding: Marion and Norman Tanzman Charitable Foundation