Liquid Biopsy Reveals Differences in DDR Genes in Prostate Cancer - Targeted Oncology

Alexander Wyatt, PhD

Liquid biopsy results that identify DNA damage repair (DDR) genes in prostate cancer may be a useful tool in clinical-deci­sion making, espe­cially because these genes can elucidate therapeutic vulnera­bilities that could be exploited by current treatments.

The recognition of the role of alterations in the DDR pathway—notably the BRCA1/2, ATM, and CDK12 genes—marks a major milestone in recent prostate cancer research. BRCA2 mutations, in par­ticular, have been associated with more aggressive disease, poor prog­nosis, and poor clinical responses to systemic therapy for patients with castration-resistant prostate cancer.^1,2

An estimated 10% of primary tumors and 25% of meta­static prostate cancer harbor DDR defects.^3,4

Alterations in BRCA2 are most relevant in a cancer cell when both alleles are rendered incapable of pro­ducing functional protein.1 Evidence suggests that the majority of patients with a BRCA2 germline alteration will have a deletion of the second allele, often called loss of heterozygosity (LOH) in the tumor. The use of next-generation sequencing studies is making pos­sible the characterization of rarer mutations in other members of the homologous recombination repair (HRR) pathway.

Alexander Wyatt, PhD, and colleagues at the Vancouver Prostate Centre, University of British Columbia, used liquid biopsy testing to distinguish between monoallelic and biallelic DDR defects in a sample of 882 men with metastatic prostate cancer.⁵ The investigators focused on the BRCA2, ATM, and CDK12 genes because they are most frequently altered in prostate cancer. Results were presented in a poster at the Advances in Liquid Biopsies meeting hosted by the American Association for Cancer Research, held January 13 to 16, 2020, in Miami, Florida.

“Over the last few years, it has become apparent that DNA repair defects are widespread in metastatic pros­tate cancer. This is characteristic of metastatic prostate cancer and not localized, curable disease,” said Wyatt, an assistant professor in the Department of Urologic Sciences, during an interview with Targeted Therapies in Oncology.

Disruptions in ATM and CDK12 can lead to a genomic landscape that is distinct from BRCA2-deficient dis­ease, according to the investigators. “Three or 4 years ago, it was thought that all DNA repair genes were sim­ilar to each other and had the same biology and same effect on therapeutic response. But that’s not the case,” Wyatt said.

This revelation is especially important, noted Wyatt. “Treatment approaches such as PARP inhibitors are most effective in the presence of HRR defects. If your DNA repair gene is not actually in the pathway, then the therapeutic window for PARP inhibition may not be present,” he said.

For patients with >1 deleterious mutation in BRCA2, ATM, and CDK12, the second allele was disrupted in 97%, 85%, and 91% of cases, respectively. This disrup­tion could be attributed to mutation, deletion, or copy-neutral LOH.

For BRCA2, biallelic loss occurred through a deletion of the second allele. The investigators reported 8 cases of somatic biallelic deletion of BRCA2. Biallelic loss in ATM occurred through either mutation or deletion of the second allele. Disruption of CDK12 occurred almost exclusively through secondary mutations, though the investigators noted several cases of copy-neutral LOH.

A total of 277 somatic mutations were detected in patients with loss of BRCA2, ATM, or CDK12. Patients with BRCA-mutant tumors displayed a higher median number of mutations than a control cohort of DDR-intact patients (3.6 vs 2.2; P <.01).

DNA repair defects are most relevant when both cop­ies of the gene are lost, called biallelic loss. “Many DNA repair genes are haplosufficient, so having 1 working copy [of the allele] results in the cell functioning as if it had 2 copies. Our work suggests that the majority of DNA repair defects are biallelic, which is probably good news from a targeted therapies standpoint,” Wyatt said.

Wyatt said an opportunity exists to encourage com­munity oncologists to take advantage of liquid biopsy assays as more tests become available. These tests will be able to detect different types of defects, which have different therapeutic vulnerabilities.

Germline defects are another factor for community oncologists to consider. Wyatt noted that National Comprehensive Cancer Network guidelines on prostate cancer recommend screening of patients for germline alterations in DNA repair genes.⁶ The guidelines recom­mend genetic testing for the germline variants MLH1, MSH2, MSH6, and PMS2 (for Lynch syndrome) and homologous recombination genes BRCA1, BRCA2, ATM, PALB2, and CHEK2. “It’s not enough to just consider the tumor when testing; you’ve got to understand the familial implications that go beyond prostate cancer,” Wyatt said.
 

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References

1. Warner EW, Yip SM, Chi KN, Wyatt AW. DNA repair defects in prostate cancer: impact for screening, prognostication, and treatment. BJU Int. 2019;123(5):769-776. doi: 10.1111/bju.14576.
2. Lang SH, Swift SL, White H, Misso K, Kleijnen J, Quek RGW. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol. 2019;55(3):597-616. doi: 10.3892/ijo.2019.4842.
3. Armenia J, Wankowicz SAM, Liu D, et al; PCF/SU2C International Prostate Can­cer Dream Team, Schultz N, Van Allen EM. The long tail of oncogenic drivers in prostate cancer [erratum in Nat Genet. 2019;51(7):1194. doi: 10.1038/s41588-019-0451-6]. Nat Genet. 2018;50(5):645-651. doi: 10.1038/s41588-018-0078-z.
4. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer [erratum in Cell. 2015;162(2):454]. Cell. 2015;161(5):1215-1228 doi: 0.1016/j.cell.2015.05.001.
5. Warner E, Yip S, Annala M, et al. Frequency and etiology of ctDNA-positive meta­static prostate cancer with BRCA2, ATM, or CDK12 mutations. Poster presented at: American Association for Cancer Research Advances in Liquid Biopsy; January 13-16, 2020; Miami, FL. bit.ly/2GrVAh0. Accessed January 28, 2020.
6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Prostate Cancer (version 4.2019). bit.ly/2UmvuUK. Accessed February 4, 2020.