Genetic Screening for Inherited Mutations Could Benefit Men With Metastatic Prostate Cancer

• Prostate cancer is one of the most common types of cancer in men
• Inherited mutations are tied to advanced prostate cancer risk
• Screening for mutations in DNA-repair genes and BRAC1 and BRAC2 genes can benefit men with metastatic prostate cancer.

Genetic screening could help men with prostate cancer find better treatment options. Men with advanced prostate cancer could benefit from screening for mutations in DNA-repair genes including the breast cancer genes (BRAC1 and BRAC2). The study published in The New England Journal of Medicine was led by researchers at Fred Hutchinson Cancer Research Center and the University of Washington. ‘DNA repair genes’ help maintain the integrity of the genetic code of the cell. If there is a mutation in the DNA repair genes, the DNA is less likely to repaired when there is an aberration in its code thereby increasing the cancer risk of the cell.

Prostate cancer occurs in the prostate gland of men. Prostate is a small walnut-shaped gland that produces seminal fluid that nourishes and transports sperms after ejaculation. Prostate cancer, when detected early, has a better chance of successful treatment; however most men present late once the cancer has advanced and has metastasized to other organs. When discovered late the prognosis of cancer is poor. The current research addresses this issue to help detect inherited mutations that make a person more prone to metastasis of cancer.

Researchers gathered genetic information from 692 men with metastatic prostate cancer across seven different groups of patients and several institutions including Fred Hutch and the University of Washington through support from StandUp2Cancer and the Prostate Cancer Foundation. Using next-generation sequencing assays, independent screening of mutations in 20 DNA repair genes was conducted.

Key Results

• 11.8% of men with advanced (metastatic) prostate cancer, irrespective of age or family history of prostate cancer have deleterious germline mutations in one of the 20 DNA repair genes.
• Men with metastatic prostate cancer are five times likelier than the general population to carry the inherited mutations
• The risk of carrying a BRCA2 mutation is 18 times higher in men with advanced prostate cancer than men without prostate cancer

Importantly the men used in the study were not chosen because of age or family history, giving an extra reliability to the results. The screening done at different laboratories produced the same results across the board, adding further strength to the study findings.

Medindia interviewed doctors who published this paper to look at the implication of this important research that is likely to help patients with advanced prostate cancer.

Here are excerpts from Dr. Colin C. Pritchard, Associate Professor in the Department of Laboratory Medicine, and Associate Director of the Genetics and Solid Tumors Laboratory at the University of Washington School of Medicine the first author of the study and Dr. Peter Nelson, a member of the Human Biology, Clinical Research and Public Health Sciences divisions at Fred Hutchinson Cancer Research Center and senior and corresponding author of the study


1. Question - You have recommended germline DNA testing as a part of standard care for men with metastatic prostate cancer. Your report also said - in the key results of the study found that 11.8 percent of men with metastatic prostate cancer, regardless of age or family history of prostate cancer, have deleterious germline mutations in one of 20 DNA repair genes.

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Do you believe that this should be true for all ethnic population groups that present with such cancer? We do know that blacks have more aggressive prostate cancer. Do you think that this percentage may be higher in this ethnic group of people?

Dr. Colin Pritchard - This is a good question. It does seem likely that there will be differences in mutation rates in different ethnicities and there are already some prostate genetic markers that have been described in this context. Although we did not see a significant difference in mutation rate according to ethnicity in our series, our study was not powered to detect such differences, so future research will be needed to address this.

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Dr. Peter Nelson added that “It would be useful to replicate our study specifically in other ethnic and racial groups as our study was comprised primarily of Caucasian men.”

2. Question - Your report mentions that - Men with such mutations could benefit from targeted treatment already approved for ovarian cancer patients with these mutations, such as PARP inhibitors or platinum drugs. Could you please elaborate on this and also will gene therapy help such metastatic tumors.

Dr. Colin Pritchard - DNA repair gene mutations, particularly in the subset of DNA repair genes known as “homologous recombination DNA repair” appear to sensitize cancers to certain DNA-damaging drugs such as PARP inhibitors and platinum drugs. There is a recent study published in the New England Journal of Medicine that found that the majority of men whose tumors had DNA repair gene mutations responded to PARP inhibitor therapy, while only a small minority of those without DNA repair gene mutations responded.  This study and another accumulating evidence have led the FDA in the United States to expedite its review of PARP inhibitors for use in advanced prostate cancer. It is important to clarify that DNA repair genes may be inherited, or acquired in tumor, so PARP inhibitors and platinum therapy is likely to benefit more than just the men with inherited mutations.  We estimate that about 20 to 25% of advanced prostate cancers have these mutations, with about half being inherited, and the other half being acquired in the tumor.

On gene therapy for prostate cancer, Dr. Peter Nelson added that “Currently, there is not an effective way to use gene therapy or gene editing to modify the DNA repair process in tumor cells, so at this time gene therapy in the conventional sense would not be applicable.”

Prostate Cancer Facts

• It is the most common cancer among men after skin cancer
• More than 2 million men in the United States count themselves as prostate cancer survivors
• About 6 cases in 10 are diagnosed in men aged 65 or older.
• 176,450 men in the United States are diagnosed with prostate cancer
• 27,681 men in the United States died from prostate cancer
• Prostate cancer is more aggressive in black population than white population

The Future Treatment of Prostate Cancer

This research project could shed light on new cancer risk mutations and find out how a specific mutation may or may not impact risk of cancer. Further research will validate these findings and determine the genetic mutations that predispose men to a most aggressive form of prostate cancer. Once established these will become guidelines in clinical practice. 

References:

1. Key statistics for prostate cancer - http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics)
2. Prostate Cancer - (http://www.cancer.org/cancer/prostatecancer/)
3. Prostate cancer statistics - (http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/prostate-cancer)

Source-Medindia