Gerald Rogers had no idea that prostate cancer had already spread to his bones. In 2012, the pain in his hips was so bad that he developed a strange gait. Not only did Rogers have metastatic prostate cancer, he had scary numbers to go with it: His Gleason score was 9 and his prostate-specific antigen (PSA) level was 1000. “I told the oncologist that I didn’t know a PSA could get that high,” recalls Rogers, a psychotherapist in Amarillo, Texas. “He said, ‘I’ve only seen it that high one other time in my career.’ ”
Rogers specializes in marriage counseling and sexual issues. He’s in private practice with his wife, Kay Renshaw, who is also a therapist. Rogers was 63 at the time of his diagnosis; doctors initially told him to get his affairs in order. His oncologist immediately started him on anti-androgen therapies, Lupron (leuprolide acetate) and Casodex (bicalutamide), and on Xgeva (denosumab), an osteoporosis medication to prevent fractures. Shortly after, his PSA dropped to near zero, and his bone scans showed the cancer wasn’t progressing. He decided then to try Provenge (sipuleucel-T), a Food and Drug Administration-approved vaccine treatment for prostate cancer. (Read more about Provenge and other cancer vaccines in “A Shot Against Cancer?” on page 44 in Genome’s spring 2017 issue.)
Rogers says the vaccine therapy didn’t make him sick, but the other medications caused a lot of side effects — low energy, low libido, erectile dysfunction, and hot flashes. “I really learned to appreciate my menopausal patients,” he says. “Everybody thinks women are crybabies when they start having hot flashes. But they’re real, and they’re uncomfortable.”
Men like Gerald Rogers are on the frontlines of a more personalized approach to prostate cancer treatment. Doctors have better tools at hand to evaluate risk and to help distinguish whether the disease will remain idle or turn aggressive and spread. Although androgen-deprivation therapy is still the standard-of-care, genetic discoveries have opened the doors to new treatment for hormone-resistant, metastatic disease. New research shows that prostate cancer can be inherited the same way as breast and ovarian cancers, opening the door to therapies already on the market, and raising the issue of screening family members for the same inherited defects.
The prostate is a gland that sits in front of the rectum and below the bladder; it surrounds the urethra, the tube that carries semen and urine out of the body. The disease starts in cells that make mucous and seminal fluid. Cancers that form in these secretory cells are called adenocarcinomas. The disease is the second-most common cause of cancer in men (behind skin cancer) and is the third leading cause of cancer death among men (behind lung and colorectal cancers), with about 25,000 deaths occurring each year in the U.S.
Age and ancestry are risk factors for developing prostate cancer. It occurs more often in African-American men than in Caucasians, and African-Americans are more likely to die of the disease. (See “Family Roots of Prostate Cancer,” page 61.) American men have a 17 percent chance of developing the disease, but that risk is only 2 percent for Chinese men. Where a man resides can be a risk factor too; for example, Chinese men who move to the U.S. incur prostate-cancer risks on par with those of Caucasian American men.
I told the oncologist that i didn’t know a PSA could get that high. He said, ‘I’ve only seen it that high one other time in my career.’
Screening and Diagnosis
Doctors diagnose prostate cancer with the PSA blood test, with digital rectal exams (DRE), and with biopsies. The PSA test is far from perfect. The test cannot tell doctors whether the cancer is aggressive and needs to be treated or can be ignored. As a result, men have been over-diagnosed and received treatment or biopsies that were perhaps unnecessary, explains Sudhir Srivastava, the chief of the Cancer Biomarkers Research Group at the National Institutes of Health. “A high PSA leads to biopsy, but less than 30 percent of those cases actually detect prostate cancer,” says Srivastava. “Numerous efforts are underway to identify clinically significant cancers to reduce over-diagnosis, as well as new molecular tests, with more and more patients opting for active surveillance and less invasive therapies.”
The year 2017 brought a big change for prostate cancer, when the U.S. Preventive Services Task Force revised its recommendations for prostate cancer screening, giving it a grade “C” recommendation, which means it advises screening only for individual patients “based on professional judgment or patient preferences.” The American Urologic Association (AUA) has also revised its stance and has divided men into two groups, according to age. For healthy men ages 55 to 69, the task force said that benefits of screening outweigh the risks and that men should talk to their doctors about screening. For men 70 years and older, the recommendations suggest that the risks of screening outweigh the benefits, because the cancer is generally slow-growing and the survival rate is high.
Biopsies are challenging because little tumors can spring up throughout the prostate and the biology of those tumors can differ. “Just because you have one area that appears [to be] a low-grade tumor, you can still have a 40 percent chance of higher grade disease in another area,” says Brian Helfand, a urologist at NorthShore University Health System in Evanston, Illinois.
One of the more surprising findings in prostate cancer centers around the genes BRCA1, BRCA2, and ATM, as well as a group of DNA mismatch repair genes, some of which are common in Lynch syndrome, an inherited form of colorectal cancer. Breaks in DNA can be repaired with specialized enzymes that stitch together any damaged strands in the double helix. Without the ability to mend themselves, cells can turn cancerous. Sometimes mutations that we inherit from our parents (called germ-line mutations) can prevent repair genes from mending any damage. Researchers are discovering that men who inherit mutations in these repair genes — especially BRCA1, BRCA2, ATM, and CHEK2 — have an increased risk of developing prostate cancer. Certain variants in these genes also increase the risk of other cancers, including breast, pancreatic, and ovarian cancer.
Over the past 12 years or so, researchers have pieced together how mutations in BRCA1 and BRCA2 mutations affect prostate cancer. In 2005 an ongoing, international effort called the IMPACT trial set out to test the value of targeted prostate cancer screening in men with BRCA mutations. The trial compared men at higher genetic risk of prostate cancer to controls. Men ages 40 to 69 with BRCA1 and BRCA2 mutations and men who do not carry these mutations were given yearly PSA tests. Researchers were able to detect prostate cancer in mutation carriers while the disease was still confined to the prostate. (The IMPACT study is still ongoing; researchers are now studying men with mutations for Lynch syndrome.)
In separate studies, researchers have shown that men who were not screened regularly or early, but who do carry BRCA mutations, have an increased risk of metastatic disease by the time their prostate cancer is diagnosed. When researchers studied BRCA1, BRCA2, and ATM mutations in men who died of prostate cancer and in men who survived it, mutations in those genes showed up more often in the men who died from the disease. Those genetic variants also marked the more aggressive cancers and higher-grade cases of the disease.
Doctors can use these findings to make treatment decisions. “When we combine these two results, it would be logical to conclude that men with mutations who are screened and treated earlier will have improved survival,” explains Helfand, one of the study’s authors.
Helfand says that men with the BRCA and ATM mutations are not the best candidates for active surveillance, a strategy of monitoring men with perhaps PSA or repeat biopsies without actual treatment. “BRCA/ATM carriers have a high risk of aggressive and lethal tumors,” says Helfand. “As such, if you were going to monitor these patients, it makes it much more likely that the window for curative treatment may be missed.”
The presence of those mutations does open an opportunity for treatment with drugs already on the market, however. Patients with BRCA mutations can be treated with PARP inhibitors and also with platinum-based chemotherapies, explains Helfand. PARP (or polyADP ribose polymerase) is an enzyme that helps repair damage to DNA. By keeping PARP from repairing the DNA damage, PARP inhibitors mark cancer cells for death.
Meanwhile, research is turning up mutations in other genes linked to prostate cancer, but the work is still early. “We think that if you have metastatic prostate cancer and if you carry certain gene mutations inherited from one of your parents, there is a greater chance that that specific gene mutation may be relevant to your risk of cancer but need further study,” says Heather Cheng, an oncologist at the Seattle Cancer Care Alliance.
Because some of these gene variants are turning up more frequently than expected in prostate cancer, the concerns reach beyond the patient to his family, says Peter Nelson, a prostate cancer researcher and oncologist at the Fred Hutchinson Cancer Research Center in Seattle. Nelson led a study of 692 men who had already been diagnosed with prostate cancer; he and his colleagues found germline mutations — that is, mutations inherited from one or both parents — in DNA repair genes in 11.8 percent of these men.
“The frequency of between 10 and 12 percent suggests that all men with metastatic prostate cancer should have germline testing,” he says.
Mutations in genes such as BRCA and those involved in Lynch syndrome also increase the risk of other cancers, including breast, pancreatic, and ovarian cancer. If a man with metastatic prostate cancer harbors one of these mutations, other family members of both genders may also need genetic testing. The tricky part is that these mutations aren’t 100 percent penetrant, meaning that, for example, while a woman who inherits a mutation in BRCA2 has a high likelihood she will get breast cancer by around age 70, it’s not 100 percent certain that she will.
“There needs to be counseling for family members before they get tested, because there are implications for so many things, such as health insurance and prophyl-actic therapy. There may be harm in over-detecting some prostate cancers that do not actually require treatment — thus, counseling is essential,” says Nelson.
For now, such testing and screening is not standard care for prostate cancer unless there is a strong family history of cancers, but that may change. The Seattle Cancer Care Alliance has a clinic that evaluates men with prostate cancer and offers patients and their families counseling and testing. And Cheng is setting up a clinical trial to identify men with metastatic prostate cancer and offer them genetic testing for inherited cancer-risk genes. The trial aims to raise awareness and offer men with metastatic prostate cancer access to genetic testing, and identify men with prostate cancer who have inherited cancer-risk associated gene mutations. The team also wants to collect enough data to figure out the best way forward for family members who don’t yet have cancer, but who may be at increased risk. She and her colleagues are working on ways to improve prostate cancer screening in men who inherit cancer-risk genes but don’t yet have cancer –— with the hopes of saving lives. For now, Cheng and her team are reaching out to patients in Washington state, but she hopes to expand the model nationally.
Helfand is all-in when it comes to genetic testing for prostate cancer. “I am someone who advocates a very early germline testing for everyone,” he says. “To get a full risk profile for prostate cancer, or any disease, you need three pieces of information: family history; [knowledge] about the high-penetrance genes, such as BRCA and the DNA repair genes; and a SNP-based risk profile of the common variations.” For prostate cancer, Helfand says this combination gives the “best risk assessment we have in an early time point for who needs to be screened.”
Prognostication with a Capital Pee
Tracking prostate cancer through urine can spare the need for repeat biopsies and it’s non-invasive. The company Hologic offers a urine test called Progensa, which detects PCA3, a gene with variants specific to prostate cancer. The Food and Drug Administration has approved using PCA3 for prostate risk assessment in men with a previous negative biopsy.
The pathology lab at the University of Michigan Medical School offers patients a urine-based test called MiPS (Mi-Prostate Score), which measures the TMPRSS2-ERG gene fusion and PCA3.
“This is a very specific, non-invasive diagnostic for prostate cancer, because the fusion itself gives you some insight into the aggressiveness of the disease,” says Arul Chinnaiyan, the director of the Michigan Center for Translational Pathology. “But this is still a work in progress. We would like to add more biomarkers to pinpoint aggressive forms of prostate cancer versus the indolent, slow-growing form, which probably doesn’t require treatment.”
The fluid-based tests (urine and blood) available now can detect metastasis. In the future, doctors hope to use urine to detect cancer at a very early stage. But detecting tumor DNA before cancer spreads is technologically difficult because the amount [present] is so tiny, says Sudhir Srivastava, chief of the Cancer Biomarkers Research Group at the National Institutes of Health.
“We need a balance between sensitivity and specificity,” says Srivastava. “The higher the sensitivity of any technology, [the more often] you are going to detect … unwanted cancers, and that is over-diagnosis. Therefore we have to have a test that is not only highly sensitive in terms of level of detection but also in terms of specificity, so we know that when a test is negative, the person does not have the disease.”
Deadly or NOT?
Here are some of the prostate-cancer-related biomarkers that doctors can use along with the Gleason Grade to help decide whether a biopsy is necessary.
The 4KScore test (OPKO Health Inc.) is a blood test designed to predict which tumors will be more aggressive when prostate cancer has been detected but before a biopsy has been taken.
The Oncotype DX Prostate Cancer Assay (Genomic Health) is a genetic test to help doctors decide whether early-stage prostate cancer patients are likely to benefit from near-term surgery and/or radiation.
Progensa PCA3 Assay (Hologic) measures levels of the genetic marker prostate cancer antigen 3 (PCA3) in order to help doctors decide whether repeat biopsies are necessary for men who have already undergone more than one negative biopsy.
The Prolaris Genetic Test (Myriad Genetics, Inc.) measures expression of a set of genes linked to prostate cancer cell division. It helps doctors predict how aggressive the cancer will be, which patients will benefit from active surveillance, and which patients have a more aggressive cancer and may need treatment. The test can also help estimate disease recurrence in men who have already had surgery.
to get a full risk profile for prostate cancer, or any disease, you need three pieces of information: family history; [knowledge] about the high penetrance genes, such as brca and the dna repair genes; and a snp-based risk profile of the common variations.
In the early days after his diagnosis, Rogers took Provenge, the only vaccine that’s been approved thus far to treat prostate cancer. It was approved in 2010 for men with metastatic disease. The vaccine is tailored to each patient. Rogers’ blood was sent through a machine three times. The machine removed his white blood cells, which were sent to a lab in California, where the vaccine “trained” them to fight cancer cells. The trained white blood cells were then infused back into his bloodstream. While Provenge extends survival in advanced prostate cancer patients by four months on average, it does not appear to shrink or kill tumor cells.
Other vaccines to treat prostate cancer are currently under investigation in clinical trials. Douglas McNeel, a genitourinary oncologist at the University of Wisconsin, Madison, says that cancer vaccines are an attractive therapy because they can target only the cancer and spare healthy cells in ways that conventional chemo cannot. “They can work for long periods, and any side effects tend to be mild and go away a few days after the infusion,” McNeel says. For his part, Rogers experienced no side effects with Provenge (although a sizable fraction of patients experience mild to moderate side effects).
McNeel has developed a vaccine to stimulate an immune response to prostate cancer cells. The vaccine is designed to pair with a PD-1 inhibitor, a therapy that helps the immune system recognize and destroy cancer cells, while leaving normal cells alone. The aim is to craft an off-the-shelf vaccine to treat prostate cancer. The vaccine is one of several in clinical trials with Madison Vaccines, a company McNeel co-founded. The company is testing several vaccines in combination with current treatments in clinical trials in various stages, including phase 1 and phase 2 trials. Some trials have been completed; some are recruiting patients.
Researchers at the University of Michigan Medical School are going after prostate cancer with an entirely different strategy. Chromosomes can rearrange themselves and fuse together, which can end up fueling cancer growth. In 2005, Arul Chinnaiyan, director of the Michigan Center for Translational Pathology, figured out that a fusion of the ERG gene and a gene called TMPRSS2 were found in 70 percent of prostate cancers. His team has worked on trying to find a way to block the fused genes from triggering prostate cancer.
The Michigan investigators have recently crafted a molecule potent enough to block the fused genes. Chinnaiyan says the molecule is designed to work the same way that the drug Gleevec blocks the gene fusion in chronic myeloid leukemia patients. The next step will be to test the molecule in human trials. “Gleevec has been a poster child for personalized medicine, because it brings a long remission or cure,” Chinnaiyan says. “If we can do the equivalent for some of the prostate cancers, I think that would be huge.”
While Rogers was treated with Provenge more than four years ago, he is still taking Lupron, an anti-androgen therapy. Rogers sees an oncologist in Amarillo, and travels with his wife once or twice a year to MD Anderson Cancer Center for follow-up care and any second opinions. Rogers now spends some of his time counseling men with prostate cancer and their families, because he understands the stress cancer puts on marriages and children, not to mention patients themselves. He connects with prostate cancer patients in nursing homes via telehealth.
“Cancer has given me an added compassion for anyone who has an illness that could potentially be terminal,” he says. “Cancer can reside in any organ in the body; it can metastasize to any other organ in the body, but where it lives is in your mind, because it’s there all the time.”
Family Roots of Prostate Cancer
African-American men face a more than 50 percent higher risk of prostate cancer than Caucasian men, and 200 to 300 percent higher risk than Hispanic men. But the really big numbers are in mortality. Prostate cancer is much more aggressive in African-Americans and starts at an earlier age — between ages 40 and 50, compared to age 60 and higher for Caucasians.
Some African-American men lack access to medical care. Biology is at work, too: Prostate tumors in African-American men have a higher rate of mutations in key genes. “There’s a strong genetic component. We need to find out what’s going on,” says Rick Kittles, a geneticist at the City of Hope in Duarte, California.
Changes in the LSAMP gene, for example, happen more frequently in African-American men with prostate cancer. Variants in this gene are also associated with an increased risk of recurrence after surgery in African-American men.
One study looked at African-American and Caucasian men in the VA health system, where access to oncology care is ostensibly equal. Men in the study had prostate cancer that had not spread, and the treatment and outcomes were similar. “With more awareness, early detection, and informed treatment decisions, disparities, and overtreatment may be reduced,” says Srivastava.
There is a downside to combining race and genetics, says Kittles. For instance, he doesn’t want to subject African-
American men with prostate cancer to genetic discrimination by calling attention to racial differences in risk. When Kittles first started biomedical research with ancestry in prostate cancer, he was sensitive about identifying risk alleles for African-
Americans and prostate cancer, describing them as alleles found all over the world, but more frequently in those with West African ancestry.
“I’m a geneticist, but I am also a black male, and so there is cause for concern, particularly for groups that have been marginalized and stigmatized,” says Kittles. “As scientists, we have to be responsible and show a level of sensitivity and understanding about what we are saying about our results and our data.”
Kittles brings this sensitivity to African Ancestry, a direct-to-consumer company that he co-founded in 2003 to search for ancestry on the maternal and paternal sides for people of African descent. While Kittles and his co-founder were setting up the company, they considered the history of African-Americans being exploited in research that goes back to the Tuskegee Study of Untreated Syphilis in the Negro Male, in which African-American men with syphilis went untreated for 40 years, and the men were misinformed about the study’s purpose.
They decided not to save the DNA swabs or share any of their customers’ personal or genetic data with any third party, because they didn’t want them to be vulnerable to any kind of genetic discrimination. After testing and returning results, the company destroys the swabs.