New Polygenic Hazard Score Predicts When Men Develop Prostate Cancer

An international team, led by researchers at the University of California San Diego School of Medicine, has developed and validated a genetic tool for predicting age of onset of aggressive prostate cancer, a disease that kills more than 26,000 American men annually.

The tool, described in the January 11 online issue of the BMJ (formerly the British Medical Journal), may potentially be used to help guide decisions about who to screen for prostate cancer and at what age.

Currently, detection of prostate cancer relies primarily upon the prostate-specific antigen (PSA) screening blood test. But PSA testing is not very good as a screening tool. While it reduces deaths from prostate cancer, indiscriminate PSA screening also produces false positive results and encourages over-detection of non-aggressive, slow-growing tumors.

“The existing PSA test is useful, but it is not precise enough to be used indiscriminately on all men,” said the study’s first author, Tyler M. Seibert, MD, PhD, chief resident physician in the Department of Radiation Medicine and Applied Sciences at UC San Diego School of Medicine. “As a result, it may prompt medical interventions like biopsy, surgery or radiotherapy that might not be necessary.”

Seibert, senior author Anders Dale, PhD, professor and co-director of the Center for Translational Imaging and Precision Medicine at UC San Diego School of Medicine, and colleagues in Europe, Australia and the United States, used genome-wide association studies (GWAS) to determine whether a man’s genetic predisposition to developing prostate cancer could be used to predict his risk of developing the aggressive and lethal form of the disease.

GWAS search individual genomes for small variations, called single-nucleotide polymorphisms (SNPs), that occur more frequently in people with a particular disease than in people without the disease. Hundreds or thousands of SNPs can be evaluated at the same time in large groups of people. In this case, researchers used data from over 200,000 SNPs from 31,747 men of European ancestry participating in the ongoing international PRACTICAL consortium project.

Using a method developed at UC San Diego, the researchers combined information from GWAS and epidemiological surveys to assess quantification for genetic risk at age of disease onset. “Polygenic Hazard Score methodology is specialized in finding age-dependent genetic risks and has already been proven to be very useful in predicting age of onset for Alzheimer’s disease”, said study co-author Chun Chieh Fan, MD, PhD, in the Department of Cognitive Science at UC San Diego.

“The polygenic hazard score is very versatile and can be applied to many age-related diseases,” said Fan. “In this case, the polygenic hazard score of prostate cancer captures the age variations of aggressive prostate cancer.”

Genotype, prostate cancer status and age were analyzed to select SNPs associated with prostate cancer diagnosis. Then the data was incorporated into the polygenic hazard score, which involves survival analysis to estimate SNPs’ effects on age at diagnosis of aggressive prostate cancer. The results led to a polygenic hazard score for prostate cancer that can estimate individual genetic risk. This score was then tested against an independent dataset, from the recent UK ProtecT trial, for validation.

“The polygenic hazard score was calculated from 54 SNPs and proved to be a highly significant predictor of age at diagnosis of aggressive prostate cancer,” said Seibert. “When men in the ProtecT dataset with a high polygenic hazard score were compared to those with average PHS, their risk of aggressive prostate cancer was at least 2.9 times greater.”

“And when we account statistically for the effect of the GWAS having disproportionately high numbers of men with disease compared to the general population, we estimate that the risk defined by the polygenic hazard score is 4.6 times greater.”

The study authors note that an individual’s genotype does not change with age, so the polygenic hazard score can be calculated at any time and used as a tool for men deciding whether and when to undergo screening for prostate cancer. This is especially critical for men at risk of developing prostate cancer at a very young age, before standard guidelines recommend consideration of screening.

“This kind of genetic risk stratification is a step toward individualized medicine,” said Dale, who also noted that PSA tests are much more predictive of aggressive prostate cancer in men with high polygenic hazard score than in those with low polygenic hazard score. This suggests that polygenic hazard score can help physicians determine whether to order a PSA test for a given patient, in the context of the patient’s general health and other risk factors.

Investigators caution that further study of the clinical benefits are needed before the polygenic hazard score is ready for routine use.

Estetrol (E4) Shows Promise as a Safe, Effective Drug for Use in Advanced Prostate Cancer

The natural fetal estrogen estetrol, also called E4, is being tested as a new drug that may help treat advanced prostate cancer, according to an ongoing industry-sponsored study from the Netherlands. The final results will be presented in a poster on Saturday, April 1, at ENDO 2017, the annual scientific meeting of the Endocrine Society, in Orlando, Fla.

“E4 for the treatment of prostate cancer would offer a new and affordable option compared to current standard and new therapies. An important advantage of E4 is expected to be the avoidance of the hypoestrogenic side effects that occur with other types of testosterone-suppressing hormone therapy, including hot flushes and sweating, arthralgia, mood, sleep and cognition disturbances, and bone loss and fractures,” said Ellen Dutman, M.Sc., clinical research associate at Pantarhei Oncology BV in Zeist, the Netherlands, the company that is developing the drug.

“Furthermore, E4 treatment may not be as expensive as recently developed new prostate cancer therapies,” Dutman added.

“E4, a steroid produced by the human fetal liver during pregnancy only, is a potential candidate for the treatment of advanced prostate cancer, both as a single entity and for combination treatment with hormone therapy,” she said.

The hormone testosterone stimulates tumor growth and therefore maximal suppression of testosterone levels is the cornerstone of the endocrine treatment of prostate cancer. To test whether oral E4 lowers testosterone levels, Dutman and her colleagues conducted a double-blind, randomized, placebo-controlled study in 45 healthy male volunteers between 40 and 70 years of age at one medical center.

For each group of 15 men, 10 received the E4 and 5 received placebo for 28 days. The 10 men in the first group received one daily dose of 20 mg E4. And after that dose was found to be safe, the 10 men in the second group received 40 mg E4. That dose was found to be safe as well, and a third group of 10 men received a dose of 60 mg E4.

The results of the groups show promise. With 20 mg E4, 40 mg E4, and 60 mg E4 respectively, both total and free testosterone decreased: total testosterone absolute change: -3.74 nmol/L, -11.0 nmol/L, and -13.88 nmol/L respectively; and free testosterone absolute change: -0.059 nmol/L, -0.095 nmol/L, -and – 0.163 nmol/L respectively. Follicle-stimulating hormone (FSH) and estradiol (E2) levels also declined, while luteinizing hormone (LH) levels remained steady and sex hormone-binding globulin (SHBG) levels increased.

All three doses were well tolerated. Body weight and safety parameters did not change but libido decreased and nipple tenderness was reported.

“We expect that in the future, patients with advanced prostate cancer will have the opportunity to choose to be treated with E4, especially in combination with their current therapy,” Dutman said. “The addition of E4 will further improve the efficacy of their current therapy and have a positive impact on the quality of life of the patients.”

Estetrol is also being developed by Pantarhei Oncology for the treatment of advanced breast cancer. Mithra Pharmaceuticals in Belgium is developing E4 for contraception and menopausal hormone therapy in women.

Prostate Cancer Clinical Trial Shows Treating with Precision Radiotherapy Reduces Course of Treatment by 50%

An Ontario-led international clinical trial with 1,206 men with localized prostate cancer shows that compressing radiation treatments into four weeks from eight delivers similar outcomes.

The findings, published online today in the Journal of Clinical Oncology, provide a new standard of care worldwide, which the participating centres have already adopted, says co-principal investigator Charles Catton, radiation oncologist, Princess Margaret Cancer Centre, University Health Network. Dr. Catton is also a Professor, Department of Radiation Oncology, University of Toronto.

“We conducted a randomized clinical trial looking at a way of improving radiation therapy for men with intermediate-risk prostate cancer. Using modern radiation therapy techniques that are very precise, we determined there was no noticeable difference between eight- and four-week treatment regimens in terms of cancer control or side effects of treatment,” says Dr. Catton. The trial participants were followed for six years.

“In fact, for some men, the shorter regimen meant slightly fewer side effects (particularly regarding bowel function) and therefore improved quality of life. The compressed course of treatment is of great benefit to patients and also to the system in terms of being able to treat more patients in less time,” he says. In Canada, 20,000 men are diagnosed with prostate cancer every year; many of whom have intermediate-risk disease that has not spread.

The trial was conducted with co-principal investigator Himu Lukka, radiation oncologist, Juravinski Cancer Centre, and Professor, Department of Oncology, McMaster University, and coordinated by the Ontario Clinical Oncology Group, Hamilton, Ontario. Twenty-seven cancer centres in Canada, Australia and France participated in the study, which began in 2005.

Dr. Catton says the trial further improved patient care by standardizing quality delivery of precision radiation techniques among participating institutions.

The research was funded by the Canadian Institutes for Health Research and The Princess Margaret Cancer Foundation.