Prostate-specific membrane antigen scan has the ability to revolutionize the way we treat prostate cancer.— William Dahut, MD
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The field of prostate cancer is being energized by discoveries in genetics, novel imaging techniques, and the potential of checkpoint inhibitors in the treatment of prostate cancer. Not all of these advances are currently clinically actionable, but all have the potential to change clinical practice in the future.
During a recent YouTube Live event sponsored by the National Cancer Institute, these inroads in the understanding and management of prostate cancer were discussed by William Dahut, MD, of the National Cancer Institute, and Heather Cheng, MD, PhD, of the University of Washington, Seattle.1 The discussion moderator was Ana Fadich, MPH, CHES, of the Men’s Health Network.
Overlapping Genetic Variants
The understanding that a family history of prostate cancer increases the risk of developing the disease is now broadened by the recognition that some men with prostate cancer have inherited germline mutations that overlap with those associated with other cancers, such as breast and ovarian. In particular, a family history of breast cancer may be linked with an increased risk of prostate cancer if the breast cancer is associated with a BRCA1/2 mutation or related gene-involved homologous recombination DNA repair. This has opened the door to rapid development of clinical trials of effective treatments in BRCA-associated breast and ovarian cancers for prostate cancers with the same mutations.
Mutations in BRCA genes increase the risk of prostate cancer. There are exciting new treatment options for men with prostate cancer who carry these mutations.— Heather Cheng, MD, PhD
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“Mutations in BRCA genes increase the risk of prostate cancer. In addition, there are exciting new treatment options for men with prostate cancer who carry these mutations,” Dr. Cheng said.
“Germline mutations or variants (differences in DNA) represent inherited characteristics, which serve as the blueprints of who we are and what makes us unique. Some variants increase the risk of cancers, and some are neutral. It is important to understand these differences when providing counseling and management advice to patients and their families and to offer referral to a genetics expert appropriately,” she elaborated.
Dr. Cheng continued: “Not all family histories of prostate cancer are equal. Simply reporting that a man has a family history of prostate cancer is not enough—details such as grade, prostate-specific antigen (PSA), and course of disease are helpful if known. An example is that having a brother with a stage I Gleason grade 6 prostate adenocarcinoma at 78 years of age is not the same as having a brother with metastatic Gleason grade 8 prostate cancer at 50 years of age. We also need to know the family histories of other cancers, including breast, ovarian, and pancreatic cancers, and the ages of onset and details for those cancers if known. We should encourage our patients to ask their family members if they don’t know.”
“We are learning as we go,” Dr. Cheng acknowledged. “The evolving knowledge relates to treatment implications for prostate cancer patients who carry these mutations, and we should also be thinking about understanding prostate cancer risk in male relatives of BRCA1 and BRCA2 mutation carriers and how we might modify prostate cancer screening strategies,” she added. “These discoveries are new for prostate cancer, and we hope they will improve how we care for men with prostate cancer and their family members. Most likely we have not identified all genes associated with prostate cancer and need to learn more about new genes to provide better counseling,” Dr. Cheng admitted. “With new treatments and management implications, looking for inherited DNA-repair gene mutations may become part of standard testing.”
Therapeutic Implications
“We’ve learned that drugs targeted to a specific pathway, such as the DNA-repair pathway, may work in prostate cancer,” Dr. Dahut predicted. One in five men with metastatic prostate cancer has defects in DNA repair; 50% have germline (inherited) mutations, and the other 50% have genetic changes only in the tumor (not inherited).
Dr. Cheng noted: “We think DNA-repair deficiency confers sensitivity to platinum chemotherapy and PARP [poly (ADP-ribose) polymerase] inhibitors. Currently, there are ongoing trials evaluating these agents in advanced prostate cancer associated with these defects, both somatic (tumor-only) and germline mutations. We think these exciting new treatment options will be effective additions to the treatment options in our current toolbox for men with prostate cancer and DNA-repair deficiency.”
Immunotherapy
Enhancing antitumor activity by blocking immune-related checkpoints has become a standard approach for melanoma and lung cancer, and checkpoint inhibitors are in various stages of development for other cancers, including bladder and some blood malignancies. New data suggest that these agents will play a role in the treatment of some prostate cancers.
“Immunotherapy with checkpoint inhibitors is another exciting treatment option for prostate cancer,” Dr. Dahut said. “We will be studying combinations of immunotherapy with other therapies. Some data suggest that combinations will be beneficial for prostate cancer. Checkpoint inhibitors are less toxic than chemotherapy and achieve more durable responses,” he continued.
Novel Imaging Modalities
Experts believe that new molecular imaging techniques will transform the diagnosis and surveillance of patients living with prostate cancer—and inform treatment decisions. These new techniques include hyperpolarized magnetic resonance imaging (MRI), choline positron-emission tomography (PET)/computed tomography (CT) and prostate-specific membrane antigen PET/CT.
One area in which molecular imaging will make a difference is in advanced cancer. “Traditional bone scans used to assess response in men with castrate-resistant prostate cancer measure uptake of radioisotopes that signal the presence of a metastatic lesion, but these techniques do not measure changes in the metastatic tumor itself,” Dr. Dahut stated. “Now we are using molecular imaging to try to quantitate the cancer and determine early response to treatment.”
Both Drs. Cheng and Dahut are excited about prostate-specific membrane antigen technology. “Prostate-specific membrane antigen scan has the ability to revolutionize the way we treat prostate cancer,” Dr. Dahut predicted. “This technique can pick up lesions earlier and help guide treatment.” Dr. Cheng added: “I have referred patients to clinical trials where prostate-specific membrane antigen imaging is being studied.”
Clinical Trials
Both Drs. Cheng and Dahut emphasized the importance of enrolling patients in clinical trials. “It is critical to know about options throughout the United States,” Dr. Dahut stated. “Results of clinical trials can be positive or negative, and both kinds of results move the field along. Without them, the field would be on a treadmill.”
The advances discussed by Drs. Dahut and Cheng were the fruits of clinical trials. “We move ahead by leaps and bounds when patients volunteer for clinical trials,” Dr. Cheng said. She emphasized the value of both intervention trials as well as patient registries. “The information we gain now from these efforts will improve our knowledge and care of prostate cancer for the next generation,” she said. ■
Disclosure: Drs. Dahut and Cheng reported no potential conflicts of interest.
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