Comprehensive genomic profiling reveals potential biomarkers for targeted therapies in prostate cancer

Jon H. Chung

Routine comprehensive genomic profiling identified genomic alterations that are under investigation as biomarkers for targeted therapies in more than half of tumor samples from nearly 3,500 men with prostate cancer, according to results of a prospective study.

The findings show that analyzing tumors for genomic alterations and signatures — including microsatellite instability, tumor mutational burden and genome-wide loss of heterozygosity — “can inform targeted therapy options, as well as potential therapy development targets, for patients with advanced or metastatic prostate cancer,” Jon H. Chung, PhD, associate director of clinical development at Foundation Medicine, said in a press release.

Early detection techniques have led to a 5-year survival rate of nearly 100% for men with prostate cancer who have localized tumors. However, only about 30% of men with advanced disease survive at least 5 years.

Chung and colleagues used the validated assay FoundationOne (Foundation Medicine) to analyze 3,476 unique tumor samples, including 1,660 from primary sites and 1,816 from metastatic sites of unmatched patients, for genomic changes that could inform targeted treatment strategies.

Median age of the patients was 66 years (range, 34-94).

Results showed an average of 4.5 genomic alterations per tumor in the primary and metastatic sites, including TP53 (43.5%), PTEN (32.2%), TMPRSS2-ERG (31.2%), AR (22.5%), MYC (12.3%), BRCA2 (9.8%), RB1 (9.7%), APC (9.3%), MLL3/KMT2C (7.8%), SPOP (7.7%), PIK3CA (6%) and CDK12 (5.6%).

Overall, 57% of cases had genomic alterations under investigation as biomarkers for targeted therapies. Potentially targetable genomic alterations often appeared in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways.

Alterations in the DNA repair pathway included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%) and mismatch repair (4%).

Alterations in BRCA1, BRCA2, ATR and FANCA genes appeared associated with high genome-wide loss of heterozygosity, which was infrequently high in CDK12-altered tumors and has been associated with benefit from poly(ADP-ribose) polymerase, or PARP, inhibitors.

Researchers observed median tumor mutational burden of 2.6 mutations/Mb. A subset of cases (3%) had high tumor mutational burden. Of those, 71% had high microsatellite instability. Men in this subset could be candidates for immunotherapies, according to researchers.

Limited access to patient-level clinical data prevented researchers from further breaking down samples into subgroups by castration resistance status, which served as the study’s primary limitation. Additionally, primary samples may be biased toward men who received prior treatment because they were collected for routine clinical testing.

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Neeraj Agarwal

“This is the largest study of its kind done to date and gives a very encouraging message in the fact that more than half of the study patients’ tumors have characteristics for which drug targets exist,” Neeraj Agarwal, MD, prostate cancer physician at Huntsman Cancer Institute and professor of medicine at University of Utah, said in a press release. “This information provides major insights into how we can design new clinical trials or drugs that will better treat men with advanced prostate cancers.” – by John DeRosier

Disclosures: Chung reports employment with Foundation Medicine. Agarwal reports consultant/advisory roles with Argos Therapeutics, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Medivation, Merck, Nektar, Novartis, Pfizer and Roche. Please see the study for all other authors’ relevant financial disclosures.

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Source:

Chung JH, et al. JCO Precis Oncol. 2019;doi:10.1200/PO.18.00283.