Genomic Architecture of Prostate Cancer at Recurrence Following Radiation Therapy

Abstract

Spatial intra-tumoral heterogeneity of prostate cancer is secondary to differential genomics and multi-clonality, even for tumors with the same Gleason's score. These unique features promote resistance to treatment. Here, we investigated if clonal selection or adaptation of new clones dominates in prostate cancer at the time of recurrence following precision radiotherapy (RT). We identified 11 patients with biopsy-proven multi-focal recurrent prostate cancer following image-guided RT; and performed copy number aberration (CNA) profiling of 34 spatially distinct foci of the recurrent tumors (2-4 samples per patient isolated from salvage prostatectomy specimens). To assess for clonality, matched pre-RT biopsies were available for CNA profiling in four of the 11 cases. We evaluated for recurrent amplifications and deletions, and genomic instability (measured by percentage of genome alteration [PGA]); and compared against 373 sporadic prostate cancers from the Canadian Prostate Cancer Gene Network (CPC-GENE). Radio-resistant tumors harbored increased genomic instability compared to the sporadic CPC-GENE cohort; median CNA was 70 vs 34, P = 3.91 x 10-6, median PGA was 9.5 vs 4.9, P = 0.006. We also observed significant spatial intra-tumoral heterogeneity in PGA (P <0.001), independent of Gleason's score, among the radio-resistant tumors. Multi-region profiling reveals common and non-recurrent CNAs, correlating with levels of PGA, between samples of the same patient; suggesting a common clonal origin with subsequent divergent evolution. Clonal selection is further favored by the main observation that recurrent CNAs, including deletion of NKX3-1, PTEN, TP53, and MYC amplification, were shared between matched pre-RT and radio-resistant tumors for all four cases. Of clinical importance, evaluation of our published CNA-based prognostic signatures (100-loci, 31-loci, and PGA) revealed a positive-test in pre-RT biopsies of three (of four) cases; importantly, signature positivity concurred between single pre-RT biopsies and multi-region samples of the recurrent tumor for all cases, supporting the utility of our prognostic signatures in the context of intra-tumoral heterogeneity. Our findings favor the model of selection of radio-resistant clones as the dominant mechanism in recurrent prostate cancers following precision RT. Taken together, these results validate the current approach of developing biopsy-based biomarkers a priori to treatment, and molecular therapeutic targets for these radio-resistant clones, so as to improve the therapeutic ratio of precision RT.