Study finds what could be a key to prostate cancer progression

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William Check, PhD

October 2016—The Gleason classification for prostate cancer is by no means going away. But within the Gleason grade, the presence or absence of a DNA-repair gene mutation may signal who is likely to proceed to invasive cancer, says Colin C. Pritchard, MD, PhD, lead author of a study published Aug. 4 in the New England Journal of Medicine.

In the multicenter study (2016;375[5]:443–453), inherited mutations in DNA-repair genes were found at a significantly higher frequency in men with metastatic prostate cancer (11.8 percent) than in men with localized disease (4.6 percent).

“The biology of these mutations suggests that they are important drivers of prostate cancer progression and important contributors to hereditary components of this disease,” says Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan Comprehensive Cancer Center and a participant in the study.

The results point to the benefit of testing all men with metastatic prostate cancer for these genetic variants, says Dr. Pritchard, an associate professor of laboratory medicine and associate director of the genetics and solid tumors laboratory at the University of Washington. Identifying the mutations associated in this study with metastatic prostate cancer will aid in managing risk for individual patients, he says, and prompt counseling for family members who may be at risk.

“Especially exciting,” Dr. Pritchard adds, “is the therapeutic implication, which is promising in metastatic prostate cancer.” Indeed, the finding published last year that treatment with the PARP inhibitor olaparib led to a high response rate in men whose prostate cancers had stopped responding to standard treatments and who had defects in DNA-repair genes “provides a clear treatment pathway in accordance with precision medicine strategies,” write the authors of the latest study.

Overall, “We believe this is really a very important study that will change clinical practice” for clinicians and molecular laboratories, study participant Mark A. Rubin, MD, Homer T. Hirst professor of oncology in pathology and director of the Englander Institute for Precision Medicine at Weill Cornell Medicine and NewYork-Presbyterian Hospital, told CAP TODAY.

In the study, physicians at four medical centers in the United States and one in England enrolled 692 men with metastatic prostate cancer. Using next-generation sequencing techniques, participating laboratories analyzed the sequences of 20 genes associated with autosomal dominant cancer-predisposition syndromes in both tumor and matched normal tissue. Dr. Pritchard’s laboratory used a targeted panel called BROCA. The laboratories of Dr. Chinnaiyan and Dr. Rubin used whole exome sequencing.

All 20 genes are responsible for DNA repair and maintenance of DNA integrity. “We selected genes that are already known to be part of clinical genetic testing for some cancers,” Dr. Pritchard explains, though prostate cancer was not known to be part of the spectrum for every gene.

Among the 692 patients, 84 germline mutations were found in 82 patients (11.8 percent). Mutations were found in 16 of the 20 genes. The highest frequency of mutations was found in the BRCA2 gene, followed by ATM, CHEK2, and BRCA1.

Dr. Pritchard

“The fact that the prevalence and frequency were so high was a surprise to us,” Dr. Pritchard says. “We thought these mutations were rarer.” Questions about guidance and screening are fairly new in this setting. “Some people are working on that,” Dr. Pritchard says. “Now we can begin to set screening guidelines.”

The difference in frequency of repair-gene mutations between localized and metastatic prostate cancer is not only statistically significant but also clinically meaningful. “To some extent we could ask what is the threshold that should prompt testing,” Dr. Pritchard says. “We can learn from the breast and ovarian cancer community, where testing for BRCA1 and BRCA2 is the standard of care among women who meet certain criteria and have breast or ovarian cancer.” In that situation, he notes, testing anyone in a risk group in which the prevalence of inherited mutations rises above 10 percent is strongly recommended and generally accepted. “So at 12 percent the frequency of mutations in DNA-repair genes may justify routine testing among men with metastatic prostate cancer.”

In this study, DNA was taken from white cells in peripheral blood. Strong evidence supports the interpretation that identified variants were inherited or germline mutations. “We can look at the fraction of variants detected in the white blood cells. If they are found in half of sequences, they are usually heterozygous inherited variants,” Dr. Pritchard explains. “Also, a lot of these mutations, maybe most, have already been described as inherited mutations.” While circulating tumor cells and circulating DNA can be found in peripheral blood, Dr. Pritchard adds, “they only constitute a tiny fraction of cells or DNA in the blood.” Of course, patients were selected to have no evidence of blood cancers.

Among the seven cohorts included in the work (three from the University of Washington and four from other institutions), mutation frequency was similar across individual case series. “This was one of the most encouraging things to us,” Dr. Pritchard says. Groups of patients were accrued for different reasons and none were based on a known family history. “So the result was very convincing and reproducible,” he says. One question that remains to be addressed is whether the result applies to those who are not of European descent, in particular African-Americans, who, Dr. Pritchard notes, have a higher rate of prostate cancer and more aggressive disease.

After identifying patients who had a germline mutation in one of the 20 DNA-repair genes, study investigators went back and analyzed tumor tissue from those men. They found that almost 60 percent of them also had an inactivating mutation in the other allele of that gene in the tumor. Finding that both alleles were mutated in tumor tissue supports the notion that the defects found in those genes were related to tumor biology. “Loss of the second allele is important,” Dr. Pritchard points out. “We can make pathogenic inferences.”