Anti-androgen therapy improves survival for men with cancer recurrence after prostatectomy

Men with prostate cancer who have prostate-specific antigen recurrence following radical prostatectomy have improved survival with radiotherapy and a long-term course of anti androgen therapy.

It is well established that a rising serum prostate-specific antigen (PSA) level is an indication of cancer progression in men diagnosed with prostate cancer and treated with radical prostatectomy (RP). For these patients, adding 24 months of anti-androgen therapy (AAT) during and after salvage radiotherapy (RT) improves overall survival statistically compared with salvage RT alone, according to the long-term results of a clinical trial conducted by the Radiation Therapy Oncology Group (RTOG), now conducting research as NRG Oncology. The RTOG 9601 study results presented today at the plenary session of the 57th Annual Meeting of the American Society for Radiation Oncology (ASTRO) also reveal that the addition of ATT to salvage RT reduces prostate cancer death and the development of metastatic prostate cancer without increasing radiation toxicity.

Over the last 25 years, many men with intermediate-risk prostate cancer have undergone RP, yet many will face recurrence subsequently with a rising PSA,” says lead study author William U. Shipley, M.D., FACR, FASTRO, who is the Andres Soriano Distinguished Professor of Radiation Oncology at the Massachusetts General Hospital and the Harvard Medical School, both in Boston. “Our results show that salvage RT plus peripheral androgen blockade (AAT with bicalutamide), when compared with RT plus a placebo, improved long-term overall survival and reduced death from prostate cancer without adding significantly to radiation toxicity. Because prostate cancer progresses slowly, follow-up of over 12 years was necessary to demonstrate a statistically better patient survival with combined AAT and RT.

With a median follow-up now of 12.6 years, the study results showed the actuarial overall survival at 10 years was 82 percent for the RT plus AAT arm and 78 percent for the RT plus placebo arm (P = 0.036). The 12-year incidence of prostate cancer-related deaths was 2.3 percent for the RT plus AAT arm, compared with 7.5 percent for the RT plus placebo arm. At 12 years, the cancer had metastasized in 51 patients (14 percent) in the RT plus AAT arm, compared with in 83 patients (23 percent) in the RT plus placebo arm. Additionally, late bladder and bowel toxicity were low and similar in both groups, whereas 70 percent of men in the RT plus AAT arm reported swelling of the breasts, compared with 11 percent in the RT plus placebo arm.

Conducted at sites across the United States and Canada from 1998 to 2003, the RTOG 9601 trial enrolled 761 men with prostate cancer who had undergone RP and subsequently developed elevated PSA levels. The patients were randomized to receive either salvage RT plus placebo (377 patients) or salvage RT plus AAT (384 patients).

Further statistical analyses, which are underway, may identify subgroups of patients who may not benefit from hormone therapy added to salvage RT and other subgroups for whom it may be especially beneficial. Also, because anti-androgen therapy, which suppresses testosterone production, is now used more commonly than peripheral androgen blockade with AAT, its use should be evaluated,” says Shipley in regard to next research steps for the population of post-RP patients referred for salvage RT. Shipley also emphasizes the clinical researchers’ gratitude for the willingness of the patients to participate on this and other randomized trials and for the essential role they play in advancing cancer care.

The results of this trial are testament to the importance of phase III randomized controlled trials for determining significant benefits. Congratulations to the trial team for their commitment to obtaining the quality of research data necessary for impacting the clinical care of patients with prostate cancer,” says Walter J. Curran Jr., M.D., an NRG Oncology Group Chairman and Executive Director of the Winship Cancer Institute of Emory University in Atlanta.

57th Annual Meeting of the American Society for Radiation Oncology (ASTRO) 2015 San Antonio, Texas, USA

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Increased radiation offers no survival benefit for patients with low-risk prostate cancer

Increased radiation dose was only associated with higher survival rates in men with more aggressive cancers

Increased radiation dose is associated with higher survival rates in men with medium- and high-risk prostate cancer, but not men with low-risk prostate cancer, according to a new study from Penn Medicine published this week in JAMA Oncology. Already-high survival rates for men with low-risk prostate cancer were unaffected by higher radiation dosages compared to lower radiation dosages.

In 2014, low-risk prostate cancer was the most common type of prostate cancer diagnosed in the United States, affecting about 150,000 patients, many of whom undergo aggressive treatment, either complete removal of the prostate or radiation.

Our study raises the provocative question of whether radiation dose reduction for patients with low-risk prostate cancer could achieve similar cure rates while avoiding the increased risk of side effects associated with higher radiation doses,” said the study’s lead author,Anusha Kalbasi, MD, a resident in the department of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania.

Using data from a National Cancer Database, the study employed specialized analytic methods to compare the survival rates of 42,481 men in the absence of a randomized clinical trial. Some men received standard dose of radiation while others received higher dose radiation. For men with medium- and high-risk forms of prostate cancer, the study found that for every incremental increase in radiation dose, there was a 7.8 percent and 6.3 percent reduction in the rate of death from any cause. For men with low-risk cancer, no differences in survival were found whether they received the standard dosage of radiation or a higher dosage.

The study is the first to link increased radiation dose with higher survival rates. Previous studies have linked increased radiation dose with two key measures: steady PSA scores and the absence of re-growth in tumors of the prostate following successful radiation.

The Penn-led team examined men who were diagnosed with prostate cancer between 2004 and 2006 and followed through 2012. In 2004, 56 percent of these men received higher dosages of radiation. Today, the figure is approximately 90 percent.

Kalbasi and his colleagues found that in the low-risk group of men, seven-year adjusted survival rates were 86 percent for both standard-dose and higher-dose patients. In the medium-risk group of men, seven-year adjusted survival rates were 82 percent and 78 percent for higher-dose and standard-dose patients, respectively. In the high-risk group of men, seven-year adjusted survival rates were 74 percent and 69 percent for higher-dose and standard-dose patients respectively.

Doctors divide localized prostate cancer (prostate cancer that is only in the prostate gland and which has not spread outside of the prostate) into three risk groups. Low-risk prostate cancers are unlikely to grow or spread for many years. Medium-risk cancers are unlikely to grow or spread for a few years. High-risk cancers may grow or spread within a few years. Three criteria are generally used for classifying prostate cancer risk: PSA level, Gleason score, and T stage. PSA is a protein produced by both normal and cancerous prostate cells; a high level of PSA can be a sign of cancer. The Gleason score is a qualitative assessment of any cancer cells that may be present. T stage refers to the size and extension of tumors.

Radiation therapy is associated with side effects and those side effects have been shown to increase with radiation dose, said Kalbasi. For patients undergoing prostate radiation, side effects include, fatigue, urinary frequency and urgency, changes in bowel habits, and erectile dysfunction.

Prostate cancer is the most common cancer diagnosed among American men, and causes more deaths annually among men than any other tumor except lung cancer. However, a large majority of men found to have prostate cancer ultimately die of other causes, prompting researchers to conduct studies to identify who benefits most from treatment and what those treatments should be.

Our findings show that the dose of radiation should be personalized to the specific characteristics of the prostate tumor,” said Justin Bekelman, MD, an associate professor of Radiation Oncology at Penn, and the study’s senior author. “For some patients, personalized treatment will lower the chances of toxicity while maintaining similar survival rates; for other patients, personalized treatment will mean escalating radiation dose to achieve the highest survival while protecting normal tissues, like the bladder and rectum.

Kalbasi et al. Dose-escalated irradiation and overall survival in men with nonmetastatic prostate cancer.JAMA Oncol. Published online July 16, 2015; doi:10.1001/jamaoncol.2015.2316 [Abstract]

New screening method for prostate cancer recurrence

The American Cancer Society estimated that 220,800 new cases of prostate cancer will be diagnosed in the United States in 2015. Approximately 27,540 men will die of the disease, accounting for 5 percent of all cancer deaths.

A common treatment for prostate cancer is a prostatectomy, in which all or part of the prostate gland is removed. Recent studies have shown that this procedure is often over-prescribed. As early as 2010, the New England Journal of Medicine reported that such a procedure extended the lives of just 1 patient in 48. Side effects from the surgery, including urinary incontinence and impotence, can affect the quality of life of the patient.

For every 20 surgery procedures to take out the prostate, it is estimated that only one life is saved,” said Gabriel Popescu, director of the Quantitative Light Imaging Laboratory (QLI) and senior author on the study. “For the other 19 people, they would be better left alone, because with removing the prostate, the quality of life goes down dramatically. So if you had a tool that could tell which patient will actually be more likely to have a bad outcome, then you could more aggressively treat that case.”

On a study funded by the National Science Foundation and Agilent Technologies, researchers employed spatial light interference microscopy (SLIM), a label-free method, to perform localized measurements of light scattering in prostatectomy tissue microarrays. The quantitative phase imaging (QPI) performed by the SLIM examines the anisotropy, or the difference in a material’s physical properties, as light is scattered through the stroma, the tissue surrounding the prostate glands.

The researchers found that the higher value of anisotropy indicated that the tissue is more organized. A lower value indicated that the various components within the tissue are fragmented and disorganized.

We found that for patients who had bad outcomes, the connective tissue around the glands (stroma) is more disorganized than in the case of patients who have better outcomes,” said Shamira Sridharan, a graduate research assistant in the QLI Lab, and the lead author of the study.

Among individuals who undergo prostatectomy, there are a few statistical tools that take various clinical parameters into consideration and then predict the risk for recurrence,” said Sridharan. “But among people who are in the intermediate risk for recurrence, those methods often fail, so this might lead to under- or overtreatment. Clearly, more accurate tools are necessary for predicting recurrence among that cohort.

Picture

Left: Quantitative phase image of an unstained prostatectomy sample from a patient who had a biochemical recurrence of prostate cancer. Right: A zoomed-in region from the quantitative phase image showing a cancerous gland with debris in the lumen. The stroma, or supportive tissue environment, shows discontinuities in the fiber length and disorganization in the orientation of the fibers.

For example, says Sridharan, after a prostatectomy is performed, the tumor is graded by the pathologist and, in combination with other surgical parameters such as the surgical margin positivity, whether the cancer has invaded into the lymph nodes, extra-prostatic extensions, and PSA levels, a recurrence risk is assigned. However, some of this information is only available post-surgery. By examining the quality of the tissue surrounding the cancerous glands, the researchers believe they can determine progression of the disease at the pre-surgical, or biopsy stage.

The study of 181 tissue samples obtained from the National Cancer Institute-sponsored Cooperative Prostate Tissue Resource (CPCTR) were from individuals who had already undergone a prostatectomy, approximately half who had no recurrence and half who did. SLIM was able to identify those in which the cancer would reappear.

The study is the result of collaborative work between the QLI Lab and three board-certified pathologists: Drs. Andre Balla and Virgilia Macias from the University of Illinois at Chicago, and Dr. Krishnarao Tangella from Presence Covenant Medical Center in Urbana, Illinois.

It is rather remarkable that the difference between cancers with bad outcomes and good outcomes is found not in the malignant cells, but in the tissue adjacent to the cancer. Possibly, this is because the body can recognize which tumors are more aggressive and react to them,” said Balla.

An established method of screening for prostate cancer is the prostate-specific antigen (PSA) test.

PSA is a very good tool in terms of predicting the recurrence of prostate cancer in an individual who’s undergone a prostatectomy,” said Sridharan. “But when PSA screening first started, there was a huge spike in the number of prostate cancer cases diagnosed. So if a screening tool is indeed good, you would see an initial spike, but after that the cases would level off. With PSA that leveling off never happened. The number of cases diagnosed remained high, so now the United States Preventative Task Force no longer recommends routine screening for PSA.”

Based on the PSA levels, many patients underwent a biopsy and prostatectomy,” explained Popescu. “After prostatectomy serum PSA levels go to nearly zero because it is produced almost exclusively in the prostate. So PSA is great tool after prostatectomy in terms of predicting recurrence if the level starts to climb up again, indicating that the cancer has spread to other sites in the body. But in that pre-diagnosis stage, it’s not particularly great because it can lead to over-diagnosis.”

“The idea behind our method is that, if we can predict recurrence after prostatectomy, chances are we can predict recurrence at a biopsy level, before any radical surgery is performed.

What SLIM is very good at is to make invisible objects visible with nanoscale sensitivity,” said Popescu. “So we pick these structural details without the need for staining, which can introduce new variables into the specimen.”

Our dream is for everyone to have SLIM capabilities in their labs,” said Popescu. “One can imagine that a SLIM-based tissue imager will scan biopsies in a clinic and, paired with software that is intelligent enough to look for these specific markers, will provide the pathologist with valuable new information. This additional information will translate into more accurate diagnosis and prognosis.”

SLIM has excellent potential to add value to the existing methods available to pathologists and improve the accuracy of prognosis,” said Tangella.

To further that goal, the QLI is working with students based in the lab of Minh Do, a part-time faculty member in Image Formation and Processing at the Beckman Institute, to build software that will find patterns in the tissue that are relevant for diagnosis and prognosis.

We are currently working diligently to validate these initial results on a variety of patient populations.” said Balla.

The next step is trying to help with patient treatment decisions and translating this to the biopsy, pre-surgery stage,” said Sridharan. “This method is very promising and demonstrates the potential to help with determining who should undergo active surveillance versus surgical treatment.”

Sridharan et al. Prediction of prostate cancer recurrence using quantitative phase imaging. Scientific Reports. 2015; 5: 9976 doi:10.1038/srep09976 [Abstract]

Statin drugs can delay prostate cancer progression in patients

Men who went on cholesterol-lowering statin drugs when they began androgen deprivation therapy for prostate cancer had a longer time in which their disease was under control than did men who didn’t take statins, a clinical trial led by Dana-Farber Cancer Institute investigators shows.

In a study published online today by JAMA Oncology, the researchers report that men who had been taking statins since the start of androgen deprivation therapy (ADT) went a median of 27.5 months before their disease began to worsen, compared to 17.4 months for men who didn’t take statins. The trial involved 926 patients, 70 percent of whom had their disease progress during a six-year period.

This median 10-month benefit in delaying disease progression suggests that statins could be a valuable addition to our current therapies for prostate cancer,” says the study’s first author, Lauren Harshman, MD, medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber. “These results are supported by multiple prior epidemiologic studies demonstrating that statin use may be associated with improved outcomes in prostate cancer, but require validation.

The trial grew out of laboratory studies that suggested statins could delay prostate cancer growth in patients receiving ADT. (ADT reduces the amount of androgen in the body, preventing prostate cancer cells from using it to fuel their growth. For many years, it has been the frontline treatment for patients with hormone-sensitive prostate cancer that has spread beyond the prostate gland.)

The laboratory phase of the research focused on a protein called SLCO2B1, which helps a variety of drugs and hormones enter cells. One of these immigrants to the cell is dehydroepiandrosterone sulfate (DHEAS), a precursor of testosterone, the hormone that spurs prostate cancer cell growth. Statin drugs, too, rely on SLCO2B1 to gain entry to cells.

In a series of experiments, the researchers showed that statins could interfere with DHEAS uptake in lab-grown prostate cancer cell lines. By monopolizing the available pool of SLCO2B1 within a prostate tumor, statins essentially deny DHEAS a passkey to the cancer cells. The clinical study results suggest this approach could be effective in patients.

We present a plausible mechanism by which statins may work in prostate cancer by decreasing the tumor’s available androgen pool and thus improving patient outcomes,” says the study’s senior author, Philip Kantoff, MD, leader of the Lank Center for Genitourinary Oncology and chief of solid tumor oncology at Dana-Farber. “Further study is required to validate our findings.”

Harshman et al. Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer. JAMA Oncol.2015;doi:10.1001/jamaoncol.2015.0829 EPub ahead of print [Article]

Detecting cancer cells in blood can give an early warning of treatment failure

A blood test that measures the number of cells shed from prostate tumours into the bloodstream can act as an early warning sign that treatment is not working, a major new study shows. Researchers showed that measuring the numbers of circulating tumour cells in the blood predicted which men were benefiting least from a prostate cancer drug after as little as 12 weeks of treatment.

They hope their work will allow doctors to switch patients to alternative treatments earlier than is currently possible, if these results are confirmed by further studies. The research could also hasten the development of cancer treatments by speeding up clinical trials, since doctors could tell much earlier whether a treatment is working.

The study was led in the UK by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and also involved several leading international institutions. It was funded by a range of organisations including a Medical Research Council biomarkers grant, the companies Janssen Diagnostics, the Prostate Cancer Foundation in the US, and Prostate Cancer UK.

As tumours grow and progress, they shed cancer cells into the bloodstream, some of which can seed new secondary tumours elsewhere in the body. So the researchers wanted to see whether a high number of circulating tumours cells was an indication of a growing tumour that wasn’t responding to treatment, and could predict a lower chance of survival.

The study, published in the Journal of Clinical Oncology, involved the detailed analysis of blood samples from 711 men who took part in a major phase III trial of the prostate cancer drug abiraterone.

Researchers measured numbers of circulating tumour cells at four-week periods after the start of treatment with the drug, along with a range of other biomarker molecules in the blood including lactate dehydrogenase (LDH), high levels of which are a sign of general tissue damage.

The trial itself had used the standard trial end points of average overall survival and survival free of cancer progression to show abiraterone’s effectiveness in late-stage prostate cancer. But the researchers were able to cross-reference those results with data on circulating tumour cells and LDH levels in each man taking part.

They found a correlation between those men who had responded least well to treatment with abiraterone, and higher levels of cancer cells and LDH in the bloodstream, measured 12 weeks after starting treatment. They showed that levels of circulating tumour cells varied independently of a range of other biomarkers.

To prove the effectiveness of a new drug, clinical trials normally need to be run until the cancer is progressing clinically for each patient – and often until many of the patients on the trial have died. But with this new blood test, it might be possible to use circulating tumour cells as an early indicator that a drug is or is not working, and as a predictor of survival.

Study leader Professor Johann de Bono, Professor of Experimental Cancer Therapeutics at The Institute of Cancer Research, London, and Honorary Consultant at The Royal Marsden NHS Foundation Trust, said:
The past decade has seen unprecedented success in the development of new drugs for advanced, metastatic prostate cancer. One of the major challenges we face now is in optimising the use of these new treatments by making sure that the right men receive them, and only for as long as they are benefitting.
Our study showed that circulating tumour cells act as an early warning test for men who are not responding to treatment – potentially allowing doctors to switch patients early to alternative options. We hope our results will not only lead to better use of the current range of treatments, but also speed up the discovery of new drugs by providing an important new tool to the researchers trialling them.”

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:
Using a blood test to assess whether a cancer drug is working would be much easier and more convenient than other methods of monitoring treatment, and might pick up signs that a tumour is not responding weeks or months earlier than is achievable now. It could give doctors a valuable early warning that treatment is not working, and an opportunity to switch the patient promptly to an alternative drug.”

Scher et al. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol. 2015;  doi: 10.1200/JCO.2014.55.3487 [Abstract]

HIV drug blocks bone metastases in prostate cancer

The receptor CCR5, targeted by HIV drugs, is also key in driving prostate cancer metastases, suggesting that blocking this molecule could slow prostate cancer spread.

Although prostate cancer can be successfully treated in many men, when the disease metastasizes to the bone, it is eventually lethal. In a study published online in the journal Cancer Research, researchers show that the receptor CCR5 best known for its role in HIV therapy, may also be involved in driving the spread of prostate cancer to the bone.

Because this work shows we can dramatically reduce metastasis in pre-clinical models, and because the drug is already FDA approved for HIV treatment- we may be able to test soon whether this drug can block metastasis in patients with prostate cancer,” says Richard Pestell, M.D., Ph.D., MBA, Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University and senior author on the study.

The work builds on previous research from Dr. Pestell’s lab that showed in 2012 that CCR5 signaling was key in the spread of aggressive forms of breast cancer to the lungs. Their prior paper demonstrated that breast cancer cells that carried the CCR5 receptor on their surface were drawn to the lung. Given that prostate cancer cells were attracted to the bone and brain, Pestell’s team investigated whether CCR5 could play a role in prostate cancer metastases as well.

The research was complicated by the fact that there was no immune competent mouse model of prostate cancer that reliably developed bone and brain metastases. So the researchers developed a prostate cancer cell line, driven by an upregulated Src gene, that regularly caused bone metastases in immune-competent mouse models. Because the immune system is so important in human prostate cancer it was important to develop a model that reflected human disease.

The researchers analyzed the genes of the metastasized bone and brain tumors and found genes driving the cancer were also involved in the CCR5 signaling pathway. To investigate further, the researchers administered the CCR5-blocking drug maraviroc to the new prostate cancer mouse model. In comparison to control animals, maraviroc dramatically reduced the overall metastatic load by 60 percent in the bone, brain and other organs.

Finally, in order to determine whether a similar mechanism might be at play in human prostate cancer, the researchers mined the genomic data of patients with prostate cancer and found that CCR5 was more highly expressed in prostate cancer tissue compared with normal tissue, and even more highly expressed in metastases compared with primary tumors. “In fact, we noticed that patients who had a lower expression of the CCR5-pathway genes had a longer survival times, whereas high expression of these CCR5 genes was associated with a shorter overall survival,” said co-first author Xuanmao Jiao, Ph.D., and an instructor in the department of Cancer Biology at Jefferson.

Sicoli D et al. CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines. Cancer Res. 2014;EPub Ahead of Print, doi: 10.1158/0008-5472.CAN-14-0612 [Abstract]

Prostate cancer in younger men — More frequent and aggressive?

Early onset prostate cancer is a newly identified, more aggressive subtype often linked to genetic mutations.

The number of younger men diagnosed with prostate cancer has increased nearly 6-fold in the last 20 years, and the disease is more likely to be aggressive in these younger men, according to a new analysis from researchers at the University of Michigan Comprehensive Cancer Center.

Typically, prostate cancer occurs more frequently as men age into their 70s or 80s. Many prostate cancers are slow-growing and many older men diagnosed with early stage prostate cancer will end up dying from causes other than prostate cancer.

But, the researchers found, when prostate cancer strikes at a younger age, it’s likely because the tumor is growing quickly. “Early onset prostate cancer tends to be aggressive, striking down men in the prime of their life. These fast-growing tumors in young men might be entirely missed by screening because the timeframe is short before they start to show clinical symptoms,” says Kathleen A. Cooney, M.D., professor of internal medicine and urology at the University of Michigan.

Peter Rich was 59 when he was diagnosed with stage 4 prostate cancer. His Prostate-Specific Antigen (PSA)  levels were relatively low, but the disease had already spread to his ribs, spine and lymph nodes.

To think of mortality was devastating. It was like any major loss – shock and numbness,” says Rich, who had to retire from his job as a school social worker because of his cancer treatment. Rich was diagnosed six years ago. Average survival for stage 4 disease is generally less than three years.”What we both said when we got the diagnosis was, well, that’s not acceptable,” Rich says of himself and his wife, Carol. “I’m a fighter.”

Cooney and Scott Tomlins, M.D., Ph.D., assistant professor of pathology at U-M, are leading a new study supported by the U.S. Department of Defense to look at DNA of both normal and cancerous prostate tissue of men diagnosed with advanced prostate cancer before age 61. They will be looking at whether these younger men are more likely to have inherited genetic mutations. For more information on this study, contact the U-M Cancer AnswerLine at 800-865-1125.

Men with a family history of prostate cancer have a two- to three-times greater chance of being diagnosed with prostate cancer. That risk increases for young men with multiple affected relatives. Prostate cancer runs in Rich’s family. Like Rich, his brother was diagnosed in his 50s, and a cousin and uncle had prostate cancer as well.

The new analysis, which appears in Nature Reviews: Urology, found that men with early onset prostate cancer had more genetic variants than men diagnosed with prostate cancer at a later age. The researchers suggest that genetic counseling or increased surveillance in younger men with a family history of prostate cancer may be warranted.

American men have a 16 percent risk of developing prostate cancer in their lifetime, but only a 3 percent lifetime risk of dying from it. The challenge, Cooney says, is understanding which subset of prostate cancers are most likely to be aggressive and deadly.

The unexpectedly poor prognosis of advanced stage early onset prostate cancer supports the idea that a new clinical subtype might exist in the subset of men with early onset prostate cancer. This subtype is more aggressive and requires more specialty expertise, including genetic sequencing,” Cooney says.

Salinas et al., (2014). Prostate cancer in young men: an important clinical entity. Nat. Rev. Urology11:317–323 doi:10.1038/nrurol.2014.91 [abstract]