Study finds what could be a key to prostate cancer progression

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Dr. Chinnaiyan

Where both alleles were defective, it presumably represented the germline mutation plus a second, somatic mutation, says Dr. Chinnaiyan, who is the S. P. Hicks endowed professor of pathology at Michigan. “One allele was defective at the germline level,” he explains, “and in many cases the matched tumor tissue had the germline mutation plus a hit in the second allele, suggesting that that gene was the driver in that tumor.” (If both mutations had been present in the germline, the fetus would have been an embryonic lethal.) One would expect this sequence from the multi-hit hypothesis for cancer (https://en.wikipedia.org/wiki/Knudson_hypothesis).

This study was an extension of earlier work in which most of the same investigators examined the integrative genomics of castration-resistant prostate cancer in 150 patients in what Dr. Chinnaiyan says was “an unbiased way.” (That work and the most recent research were supported in part by a grant from the Stand Up to Cancer–Prostate Cancer Foundation to a consortium Dr. Chinnaiyan leads.) In the earlier study it was observed that the frequency of mutations in BRCA1 and 2 and ATM was much higher in castrate-resistant prostate cancer (Robinson D, et al. Cell. 2015;161:1215–1228). Dr. Chinnaiyan called that group the discovery cohort. In the more recent publication, which he called the validation cohort, that finding was verified.

Of the finding’s therapeutic implications, Dr. Pritchard says that in other cancers, the types of mutations in DNA-repair genes seen in this study have been strongly predicted to respond to platinum-based chemotherapy and PARP inhibitors. Platinum therapy is fairly new in prostate cancer and has been used previously only rarely—and as a last step.

“PARP” refers to the DNA-repair enzyme poly-ADP ribose polymerase. Says Weill Cornell’s Dr. Rubin, “It has been known for many years in hereditary cases of breast cancer with a BRCA mutation, where homologous DNA repair is lost, that tumor cells can repair through non-homologous enzymes in another pathway.” That makes them extremely vulnerable to drugs that target that pathway, which PARP inhibitors do. “The combination of a mutation in a DNA-repair enzyme plus a drug that blocks the alternate pathway creates what is called a synthetic lethal,” Dr. Rubin explains. “Cells can no longer repair DNA mistakes, and they die. It is very important that this option adds one more drug that patients can consider for controlling advanced prostate cancer.”

Inhibitors of the PARP enzyme are now used in patients who have defects in DNA repair due to mutations in BRCA1 and 2, Dr. Chinnaiyan says, adding, “These tumors preferentially respond to PARP inhibitors.” He cites the clinical study he conducted with others that found that patients with metastatic prostate cancer that was no longer responding to standard treatments and who had defects in genes for DNA-repair enzymes preferentially responded to a PARP inhibitor (Mateo J, et al. N Engl J Med. 2015;373[18]:1697–1708).

“Based on those results, earlier this year FDA provided breakthrough status for PARP inhibitors for patients with metastatic prostate cancer who have germline defects in DNA-repair genes BRCA1 and 2 and ATM,” Dr. Chinnaiyan says.

Beyond screening patients who have metastatic prostate cancer for mutations in DNA-repair genes, the findings of the latest study suggest analysis also of family members. “Finding a germline mutation in one of these DNA-repair genes suggests a higher risk in family members to have defects in repair genes that could lead to a predisposition to other cancer types,” Dr. Chinnaiyan says.

In the study, 71 percent of patients with a germline mutation in one of the 20 DNA-repair genes had a first-degree relative with a cancer other than prostate cancer, a significant increase over metastatic prostate cancer patients who did not have a germline mutation in a DNA-repair gene. This information can be used not only for risk management of the patient and for his own therapy but also for family counseling. “We are optimistic that this could be incorporated into practice soon,” Dr. Pritchard says. “Men will be motivated to get tested for their own treatment as well as for the potential benefit of family members.”

This fall, the Seattle Cancer Care Alliance will open a cancer genetics clinic dedicated to prostate cancer. (The Seattle Cancer Care Alliance provides clinical cancer care as a consortium of the University of Washington, Fred Hutchinson Cancer Research Center, and Seattle Children’s Hospital.) “It may be the first of its kind or one of the first,” Dr. Pritchard says. Men with prostate cancer can go in for counseling and find out whether genetic testing is right for them. “It will have experts at all levels and oncologists who can make treatment decisions,” he says.

At a more complex level, how will next-generation sequencing analysis for inherited mutations in DNA-repair genes interact with prostate-specific antigen testing? An ongoing European study has already found a lower PSA threshold to proceed to biopsy if a patient has an inherited mutation in BRCA1 or 2, Dr. Pritchard says. “If I had one of these mutations, I would start PSA screening early. However, we need evidence to make screening recommendations,” he adds.

Dr. Rubin

Weill Cornell Medical College is also poised to act on the findings. “We are very much convinced that this is important,” Dr. Rubin says. “As an academic institution we are doing several prospective studies to evaluate what is the best policy for performing germline testing.” One approach is to do homegrown whole exome sequencing to try to identify mutated DNA-repair genes. Then, too, there are companies that offer inexpensive tests directly to patients or with an oncologist’s order, Dr. Rubin says, and at least one of the tests looks robust and has a rapid turnaround time. “That wouldn’t stop us from performing NGS in the future,” he says, “but it would be a way to get testing done rapidly right now.”

More broadly, Dr. Rubin says, the results of this study are going to require a re-evaluation of germline testing. “We know there is a strong call for women with breast cancer to have germline testing. These results will very much open the question as to which men should be tested and which family members. We need to decide how we are going to handle this.”

He cautions against underestimating the complexity of germline testing. “Although there are some very well-known predisposition genes and mutations defined, there are still many that are not clearly understood as to their significance,” Dr. Rubin says. “So there is still a lot of work to be done when results come back.”
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William Check is a writer in Ft. Lauderdale, Fla.