Germline genetic testing should be offered to men with metastatic prostate cancer, regardless of age or family history, say the authors of a new study.
The incidence of germline mutations in genes that mediate the DNA-repair processes in patients with metastatic prostate cancer was found to be significantly higher than that in men with localized disease (11.8% vs 4.6%).
Almost three quarters of these men also had a first-degree relative with cancers other than prostate cancer.
These cancers include breast, ovarian, pancreatic, and other gastrointestinal malignancies, as well as leukemia and lymphoma.
The findings were published online July 6 in the New England Journal of Medicine.
"This information is important, not only for the patient but for other family members as well, as they too may be predisposed to cancer," said Michael F. Walsh, MD, co-lead author of the study and a geneticist and pediatric oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.
Dr Walsh recommended that family members should also be offered testing, in addition to the patients. "There are preventative and risk reduction options that may be relevant for family members which they should consider if also carrying the same pathogenic germline mutation," he said.
These findings also can potentially change clinical practice. "We are now at a point where we have specific therapies that we can offer people with heritable DNA repair mutations," Dr. Walsh told Medscape Medical News.
These include agents such as poly adenosine phosphate ribose polymerase inhibitors, for which there has been a precedent to try these therapies in women with breast and ovarian cancer. "These are emerging therapies and only available in clinical trials at this time," he said. "And these trials are ongoing now."
Higher Rates in Metastatic Disease
Previously, as part of other research, the authors sequenced germline DNA exomes from a population of men with metastatic prostate cancer. That is when they unexpectedly found that 8% of these men carried pathogenic germline mutations in DNA-repair genes.
Now, Dr Walsh and colleagues have assessed mutations in 20 DNA-repair genes that are associated with autosomal dominant cancer-predisposition syndromes in 692 men with metastatic prostate cancer.
The objective was to confirm the earlier findings and further ascertain the spectrum and prevalence of these mutations in this population.
They identified a total of 84 germline DNA-repair gene mutations that were presumed to be deleterious in 82 men in the cohort (11.8%).
Mutations were identified in 16 genes; these included BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2(10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]).
The frequency of mutations did not seem to be affected by a family history of prostate cancer or the patient's age at diagnosis.
However, it was significantly more prevalent than the 4.6% frequency observed in the 499 men with localized prostate cancer (P < .001). This included patients with high-risk disease.
A family history was available for 72 of 82 men (88%) with mutations in DNA-repair genes and for 537 of 610 men (88%) without them.
In both groups of men, 22% (16 of 72 men with DNA-repair gene mutations and 117 of 537 men without them) had a first-degree relative with prostate cancer (P = 1.0).
But 51 patients with DNA-repair gene mutations (71%) had a first-degree relative with another cancer type compared with 270 patients (50%) without the mutations (odds ratio, 2.4; P = .001).
The authors point out that the 11.8% overall frequency of germline mutations seen in this study is substantially higher than the 1.2% to 1.8% incidence of BRCA2 mutations detected in localized prostate cancer or the 7.3% incidence of mutations in 22 tumor-suppressor genes identified in familial prostate cancer.
Even though testing for gene mutations is becoming increasingly available, Dr Walsh recommends that patients be tested in a comprehensive cancer center, where they will have access to genetic counselors.
"In addition to coming across mutations in the genes that we know are harmful, variants of uncertain significance may also be detected in these genes," Dr Walsh said. "So we need to make sure that patients are being counseled appropriately by an experienced team."
At the current time, it is unknown whether these mutations are prognostic, and that needs to be studied, he added. "This research is ongoing."
The study was funded by a Stand Up To Cancer–Prostate Cancer Foundation (SU2C-PCF) International Prostate Cancer Dream Team Translational Cancer Research Grant, the National Institutes of Health, the Department of Defense, and the Prostate Cancer Foundation (Movember Challenge Awards). Several of the authors also received funding from awards and various foundations as noted in the paper. Dr Walsh has disclosed no relevant financial relationships. Several of the coauthors disclosed relationships with industry.
N Engl J Med. Published online July 6, 2016. Abstract
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