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The PROMISE of Studying Inherited Genes
“Prostate cancer may be written in some men’s genes, but so are opportunities for discovering new treatments and for understanding family risk.”

If you have prostate cancer, does it really matter whether cancers run in your family?  Cancer is cancer, right?  Not necessarily.  Knowing your inherited genes could make a big difference in your treatment.

Take, for example, “Jim,” a patient of Johns Hopkins medical oncologist, Channing Paller, M.D.  “He was devastated that his prostate cancer had returned after surgery and radiation,” she says.  “He had a rising PSA, with a doubling time of less than six months.  But he really did not want to start androgen deprivation therapy (ADT).” A genetic test revealed that Jim had a germline [inherited] mutation of the gene called BRCA2.  Because of this mutation, Paller got him enrolled in a clinical trial for investigational use of olaparib (a drug in a new class known as PARP inhibitors), originally approved to treat women with ovarian cancer who have a mutated BRCA gene, and now approved to treat metastatic prostate cancer in men who have a mutated DNA damage-repair gene such as BRCA2.

“He’s doing great!”  Paller says.  “He is at 30-plus months, without any progression of the disease.  With his fast PSA doubling time originally, that’s pretty impressive.”  Olaparib does not have the same effect on all men with prostate cancer, but it is known to be more effective in men with a mutated BRCA2 gene.

This is precision oncology: treating subgroups of patients whose cancers share specific genetic features.  Although two men might seem to have the exact same cancer, one’s cancer might respond well to a medication such as olaparib, and the other’s may not, because their genes are different.  “It’s more important today than ever before to make sure patients are tested for potentially actionable mutations for treatments and also for clinical trials,” says Paller.

To that end, Paller and physician-scientist Heather Cheng, M.D., Ph.D., of the Fred Hutchinson/University of Washington Cancer Center Consortium – both PCF-funded investigators – are leading PROMISE, a new registry of patients with inherited mutations in prostate cancer.   This project, says Cheng, “is an ongoing partnership with patients to learn about their genetics, to more rapidly understand treatment responses in the context of specific mutations, and for them to receive updated information and find clinical trials that might be of particular interest.”

To reach these goals, “we will screen 5,000 patients all over the country,” Paller says.  “For 500 patients with specific inherited mutations, we will provide them with information about new standard treatments, as well as precision medicine clinical trials that match their genetic mutation.  The other patients can opt in to learn more about clinical trials and treatment.  This study will help bring a personalized approach to the treatment of prostate cancer.”

One clinical trial, for example, is investigating the timing of starting PARP inhibitors.  “The NCCN guidelines don’t recommend PARP inhibitors until after men have been treated with abiraterone or enzalutamide,” androgen receptor-targeting drugs given in advanced prostate cancer.  But maybe starting PARP inhibitors months or even years earlier, while the cancer is more vulnerable, will make those therapies more effective.

Other research by Paller, Cheng, and colleagues is aimed at shedding light on how men with specific gene mutations respond to therapies, and learning more about which treatments work better for gene mutations that are more rare.  The PROMISE study is investigating 30 genes that are linked to hereditary cancers.   “It’s really important that we go through these mutations one by one,” says Paller, “that we start to look at them more closely in larger groups of patients, to follow these men and, where possible, to find them clinical trials and find the best treatment for each subgroup.”

PROMISE is sponsored by the Prostate Cancer Clinical Trials Consortium, a clinical research group supported by PCF and the Department of Defense Prostate Cancer Research Program.  The study is free, and patients with a diagnosis of prostate cancer can participate from home.  It’s easy:  men enroll online, receive a DNA test kit, and send back a saliva sample.  In six to seven weeks, they will get the results.  “Men who participate will get free, medical-grade, hereditary cancer risk testing and access to a licensed genetic counselor to help them understand the results,” says Paller.  “We hope this will be a resource for people throughout the country.  At its core, it’s a network:  the more people sign up, the more we learn.”

This study is part of a big change over recent years in understanding hereditary prostate cancer.  “When I was in medical school,” Paller recalls, “we used to ask patients, ‘Do you have a family history of prostate cancer?’ but now we know it’s not just prostate cancer, but a family history of ovarian cancer, breast cancer, melanoma, colon, pancreatic, or other cancers that could mean an increased risk of prostate cancer.”

For patients, the discovery of a mutated gene in the family can have a ripple effect:  “Families are incredibly grateful because we found it.”  One man told Paller that his three sisters developed breast cancer before menopause.  “What?  Nobody’s tested your sisters?  Nobody’s tested you?”

Men who have already been treated for prostate cancer are welcome to sign up for PROMISE, as well.  “Even if you think cancer is in the rearview mirror,” says Paller.  “The ideal patient is someone with a family history of cancer, but really we want everybody,” from men on active surveillance to men with metastatic cancer.

“Prostate cancer may be written in some men’s genes, but so are instructions for discovering new treatments and understanding family risk.  That’s why learning more about the genes of men with prostate cancer is so important.”  For more information, go to prostatecancerPROMISE.org.

Janet Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.