An estimated 220,000 American men are diagnosed with prostate cancer each year, with 30,000 expected to die of it this year. While androgen deprivation therapy (ADT) is initially effective against metastatic disease, most men develop tumors that ultimately become resistant to ADT, including the most recent ADT regimen (abiraterone acetate and enzalutamide). This condition is known as metastatic castration-resistant prostate cancer (mCRPC). While many studies have cataloged somatic alterations in primary prostate cancers, genomic studies of mCRPC have been limited to either autopsy samples or preclinical models. To address the gap in our understanding of mCRPC, an international and multi-institutional consortium that included Fred Hutch investigators and benefitted from key contributions from Dr. Pete Nelson’s Laboratory (Human Biology, Clinical Research and Public Health Sciences Divisions), sequenced the DNA and RNA from biopsies of bone or soft tissue metastases prospectively from 150 mCRPC affected individuals. This work was recently published in the journal Cell.
This integrative analysis represented an entry point of ongoing clinical trials on combination therapy in mCRPC. The biopsies were obtained from lymph nodes (42%), bone (28.7%), liver (12.7%) as well as other soft tissues (16.7%). Compared to primary prostate tumors, mCRPCs were enriched for mutations in the Androgen Receptor (AR) and the tumor suppressor TP53. Based on both biological and statistical criteria, mCRPCs could be subdivided into discrete molecular subtypes. These subtypes were grouped based on knowledge of biological pathways and alteration clustering and included, among others, the PI3K pathway, WNT pathway, DNA repair pathway and the cell cycle machinery. Accordingly, genes that were most frequently altered were AR (62.7%), genes encoding ETS family transcription factors (56.7%), TP53 (53.3%) and PTEN (40.7%). Importantly, the metastases of most mCRPC cases harbored alterations deemed to be clinically actionable, meaning that they have either diagnostic or prognostic significance or that they predict therapeutic response.
The AR signaling pathway was found to be altered in 73% (107/150) of cases, either by mutation in AR itself, or in regulators of AR signaling such as the NCOR1/2, SPOP and ZBTB16 genes. Because most mCRPCs have AR pathway mutations, they are likely to be dependent on AR for viability. As such, future studies may be able to link specific AR mutations to clinical outcomes. Additionally, while mutations in the PI3K pathway are well described in cancer, this study uncovered novel alterations in the catalytic subunit PIK3CB, suggesting that patients with PIK3CB alterations may benefit from PIK3CB-specific inhibitors.
Additionally, 19/150 (12.7%) cases harbored alterations in BRCA2, that encodes a DNA repair protein best known for its role in inherited breast and ovarian cancer. This prompted further examination of the DNA repair pathway, which revealed alterations in other well-known DNA repair genes, such as BRCA1 an ATM. Interestingly, previous work has demonstrated that cancers with DNA repair mutations might be particularly sensitive to poly ADP ribose polymerase (PARP) inhibitors. Overall, this study demonstrates that prospective genomics of advanced metastatic prostate cancer is not only feasible, but also enabled discovery of novel mutations that had not been observed in multiple prior studies of primary prostate tumors. Finally, this work suggests that prospective genomics of metastatic disease in treated individuals could potentially be applied to other types of cancer. "We were quite excited to find that a majority of metastatic castration resistant prostate cancers (mCRPC) harbor actionable mutations. The findings suggest there is potential clinical utility of genetic testing to guide optimal therapy in the setting of mCRPC. For example, a large number of cases had either somatic or germline DNA repair pathway alterations which may be predictive of favorable response to platinum or PARP inhibitor therapy," said Dr. Colin Pritchard, a UW investigator involved in the study.
Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, Montgomery B, Taplin M-E, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM. 2015. Integrative clinical genomics of advanced prostate cancer. Cell, 161(5),1215-28.