March 25, 2019

The Evolution of Genetic Testing and Immunotherapy in Prostate Cancer

By Mark T. Fleming, MD

Genetic testing and targeted drug regimens have revolutionized the care of multiple cancers, particularly breast, colon, and lung cancers. Increasingly, we are discovering similar benefits in the diagnosis and treatment of prostate cancer.

High-quality genetic testing now can accurately pinpoint both hereditary and somatic mutations, providing crucial insights into how prostate cancer develops and grows. Simultaneously, new medications tailored to specific mutations have demonstrated great promise in clinical trials, especially in metastatic disease that has not responded to standard androgen-deprivation therapy.

Working with an oncologist and certified genetic counselor, patients can glean important information via blood samples and tumor biopsies. Another evolving technique draws tissue samples from metastatic sites of disease, which further empowers patients to make the most informed decisions.

Evidence for genetic risk factors in prostate cancer continues to grow. About 10 percent of cases are hereditary with known genetic risk factors in 1 of 16 DNA repair genes, including BRCA1 and BRCA2 mutations (associated with hereditary breast and/or ovarian cancer syndrome) and MLH1, MSH2, MSH6, PMS2, or EPCAM mutations (associated with  Lynch syndrome). Men with Lynch syndrome have a 2 to 5.8 increase in risk for prostate cancer; disease in men with germline BRCA mutations appears to occur earlier with a more aggressive clinical course. Therefore, a family history might involve not only prostate cancer but other cancers, particularly if they have emerged before age 50 or 60.

For all high-risk men, genetic testing can highlight the need for risk reduction strategies and regular screening for early detection. This hits home for me: after losing my own father to prostate cancer, I have diligently undergone annual PSA and digital rectal exams.

In patients already diagnosed with prostate cancer, identifying a gene mutation can help ensure the best chance of long-term survival with the best possible quality of life. A patient who harbors a mutation linked to an aggressive form of cancer, for instance, likely would not be a good candidate for active surveillance versus immediate treatment.

A DNA-repair defect is one such mutation that tends to herald a more dangerous form of disease, which may evolve from androgen-sensitive to castration-resistant. However, an emerging class of drugs called PARP inhibitors – already FDA-approved for certain ovarian cancers – has produced positive results in prostate cancer trials. The therapy works by blocking an enzyme that helps repair damaged DNA.

Local clinical trials also are ongoing on multiple targeted medications for additional genetic glitches. Those include AR-V7 and RB1 mutations (androgen receptor and androgen signaling disruptions, respectively) and checkpoint inhibitor mutations, which allow tumors to evade immune system surveillance.

As genomic targets and immunotherapy grow increasingly relevant in prostate cancer treatment, my hope is that all providers treating prostate cancer patients will embrace genetic testing for higher-risk patients. That includes individuals with a personal or family history of:

• Prostate, breast, ovarian, uterine, colon, pancreatic, melanoma or sarcoma, particularly early onset disease

• Prostate cancer with a Gleason score greater than or equal to 7

• Metastatic prostate cancer

• Male breast cancer

• Ashkenazi Jewish ancestry with a history of prostate, pancreatic, breast or ovarian cancer

With a referral, insurance generally covers the cost of genetic screenings. Typical turnaround time is two to four weeks.

Now that genetic testing has become a life-saving tool for women with a history of breast and ovarian cancers, I am excited that the future could be equally promising for men.

Mark T. Fleming, MD, is a Hampton- and Norfolk-based medical oncologist with Virginia Oncology Associates, specializing in Genitourinary (cancers of the bladder, kidney, prostate and testicle). He also is the Medical Director of the Genitourinary Program for US Oncology.