Male Oncology Research and Education program for men at high risk for prostate cancer

Abstract

Three groups of men are at high risk of developing prostate cancer: men with a strong family history of prostate cancer, men of West African or Caribbean ancestry, and men with a germline pathogenic variant in a prostate cancer–associated gene. Despite the fact that those men constitute a significant portion of the male population in North America, few recommendations for prostate cancer screening specific to them have been developed.

For men at general population risk for prostate cancer, screening based on prostate-specific antigen (psa) has remained controversial despite the abundance of literature on the topic. As a result, recommendations made by major screening authorities are inconsistent (ranging from no psa screening to baseline psa screening at age 45), allowing physicians to pick and choose how to screen their patients.

The Male Oncology Research and Education (more) program is an observational research program that serves as an academic platform for multiple research foci. For its participants, serum and dna are biobanked, medical information is collected, and contact for relevant research-related opportunities is maintained. This research program is paired with a specialized clinic called the more clinic, where men at high risk are regularly screened for prostate cancer in a standard approach that includes physical examination and serum psa measurement. In this article, we describe the goals, participant accrual to date, and projects specific to this unique program.

INTRODUCTION

At a lifetime risk of 15%, prostate cancer (pca) is one of the most commonly diagnosed cancers in men¹. Fortunately, most men are diagnosed with relatively indolent, localized, and low-grade disease, which has a 98.9% 5-year survival rate for clinically detected cancers¹. Although the excellent prognosis in screen-detected pca is likely not solely a result of screening based on prostate-specific antigen (psa), early detection, compared with waiting for symptomatic presentation at a more advanced stage, increases the chances of receiving potentially less-toxic curative treatment.

Although early detection results in high cancer-specific survival rates, treatment of localized pca can result in significant complications affecting sexual, urinary, and bowel function—all known to negatively affect health-related quality of life². Not surprisingly, “overtreatment” for an often-indolent disease has resulted in controversy about the use of psa screening for pca. That controversy raises a question: Should psa screening be offered in the general population or on a personalized basis?

At its 13-year follow-up, the European Randomized Study of Screening for Prostate Cancer identified a 21% relative reduction in pca mortality in men randomized to psa screening³. However, the results of that study must be weighed against the fact that, for every pca death prevented, 781 men had to be screened, and 27 pcas had to be detected (and presumably treated).

In contrast to the findings of the European Randomized Study of Screening for Prostate Cancer, the U.S. Prostate, Lung, Colorectal, and Ovarian cancer screening trial did not identify a statistically significant effect of psa-based screening on lowering pca mortality⁴. That conclusion has been challenged, partly because of concerns about contamination, given the fact that approximately 40% of participants had undergone psa testing before randomization and that more than 80% of the men in the control arm received psa testing outside of the study^5,6.

For many years, the U.S. Preventive Services Task Force⁷ and the Canadian Task Force on Preventive Health Care⁸ have recommended against psa screening for men in the general population, stating that the benefits of screening do not outweigh the harms. As a result there has been considerable controversy^9–12. In 2017, the U.S. Preventive Services Task Force presented a grade C draft recommendation statement suggesting clinician-based discussion of the harms and benefits of psa screening in men 55–69 years of age¹³. Other cancer organizations take a less conservative approach to psa screening. For example, the U.S. National Comprehensive Cancer Network recommends that all men have a baseline psa test at 45 and tailored psa screening based on psa level with the use of clinical judgment¹⁴. The American Urological Association recommends shared decision-making for psa screening in men 55–69 years of age at average risk of pca¹⁵. Men at higher risk of pca should, on an individual basis, discuss annual psa screening with their doctor as early as age 40¹⁵.

A clear definition about what qualifies an individual— or population—as being at “high risk” of developing pca is lacking. Aside from men with consistently elevated psa or an abnormal digital rectal examination, these three groups of men are known to have an elevated risk for pca:

• ■ Family History A family history of pca is one of the most powerful predictive factors for the disease. Men with fathers diagnosed with pca have a relative risk of 2.2 for developing the disease; men with brothers diagnosed have a relative risk of 3.4 (Table i).

• ■ West African or Caribbean (WA/C) Ancestry Data from the U.S. Surveillance, Epidemiology, and End Results program identify nearly twice the rate of pca and more than double the rate of death from pca in men of African ancestry compared with other men in the United States¹. More specifically, men of wa/c ancestry connected to the transatlantic slave trade have the highest incidence of pca in the world¹⁷.

• ■ Known Genetic Predisposition Many genes increase the risk for pca if they contain germline pathogenic variants, with the most well-known being BRCA1 and BRCA2. Men with pathogenic variants in BRCA1 and BRCA2 (“BRCA carriers”) have an elevated risk of developing pca¹⁸. Moreover, outcomes are worse—with higher rates of nodal involvement, early progression to metastatic disease, and decreased overall survival— in men with BRCA2 pathogenic variants than in the general population^19–21. Multiple studies have also shown that pca develops at a younger age and a more advanced stage in men with a BRCA2 pathogenic variant than in those from the general population^22–26. The prognosis of men with BRCA1-associated pca is less clear; some data suggest an association with a more aggressive course than is seen in the general population²⁷, but other data show little difference²⁸.

TABLE I.

Relative risk (RR) of prostate cancer (PCa), given a family history of PCa diagnosis¹⁶

Risk group	RR
Brother diagnosed at any age	3.4
Father diagnosed at any age	2.2
Affected 1st-degree relatives
One diagnosed at any age	2.6
Diagnosed at <65 years	3.3
Diagnosed at >65 years	2.4
Two or more diagnosed at any age	5.1
Affected 2nd-degree relatives
One diagnosed at any age	1.7

Given the controversy in pca screening recommendations for the general population, screening recommendations for men at higher risk of pca remain unclear. For example, the U.S. Preventive Services Task Force strongly encourages that additional research be done before psa screening is recommended for men at high risk for pca⁷. The dearth of research has left men at high risk of pca vulnerable to inconsistent or no pca screening. The Sunnybrook Male Oncology Research and Education (more) program seeks to address that void in this field of study by collecting data about men at high risk of pca who undergo pca screening in the Sunnybrook more clinic.

MORE PROGRAM

The MORE Clinic

The goal of the more clinic is to optimize clinical care for men at high risk of pca, while also providing a research platform to investigate relevant research topics both independently and with collaborating partners. The more clinic began in 2012 with the accrual of male BRCA carriers identified through the Sunnybrook Cancer Genetics program. It has been reported in the literature that male BRCA carriers are as likely as female carriers to be advocates for research studies²⁹, and that trend has been corroborated by our experience as brothers, uncles, and cousins of participants who, as BRCA carriers, were referred for screening.

At the establishment of the more clinic, referrals for men at high risk for pca—including men with a strong family history of pca and men of wa/c ancestry—were accepted. Today, men with a BRCA1 and BRCA2 pathogenic variant are referred to the more clinic from the Sunnybrook Cancer Genetics and High Risk program and from 6 genetics clinics in the Greater Toronto Area and surrounding cities. The clinics were made aware of the more clinic through outreach efforts (presentations, information packages, and so on). Men with a family history of pca and men of wa/c ancestry are referred to the more clinic by oncologists in the Sunnybrook Odette Cancer Centre and as a result of additional outreach efforts and word of mouth. The volume of referrals is continually increasing, and clinics have doubled from monthly to twice monthly to accommodate that increase.

Specialized clinics that follow male BRCA carriers are not unique^25,30–32; however, clinics that follow all men at high risk of pca, including men with a family history and men of wa/c ancestry have not yet been described in the literature. In the more clinic, unaffected patients are seen annually for follow-up, which involves serum psa screening and digital rectal exam, starting at 40 years of age. All men have a detailed 3-generation family history drawn up by a genetic counsellor, and all non-BRCA carriers undergo a risk assessment for genetic testing of BRCA1 and BRCA2. In Ontario, there are 13 criteria for BRCA1 and BRCA2 testing, many of which are reserved for women or do not address the current landscape of multiple-gene testing in cancer genetics. When appropriate, male BRCA carriers receive clinical breast examinations and a discussion of mammography under a research criterion. The more clinic currently has 270 participants, almost 197 of whom are followed annually (Table ii).

TABLE II.

Summary of patients enrolled in the Male Oncology Research and Education (MORE) program

Participant characteristic	Participation type
	Overall (n)	Blood and serum biobanked		Followed annually in MORE Clinic
		(n)	(%)	(n)	(%)
BRCA carrier	152	126	83	118	78
Family history	105	72	69	78	74
WA/C ancestry	36	21	58	27	75
TOTAL	270	231	86	197	73

WA/C = West African or Caribbean.

These are the eligibility criteria for inclusion in the more program:

• ■ wa/c ancestry

• ■ Family history of prostate cancer

• ■ Germline pathogenic pca-related gene variant (ATM, BRCA1, BRCA2, CHEK2, HOXB13, and NBN, among others)

• ■ First- or second-degree relative with a pca-related pathogenic gene variant who declined genetic testing

The MORE Program

The more program is an observational research initiative that collects clinical and biologic data from consenting participants. The goal of the more program is to act as the academic foundation for addressing research questions relating to the underserved and understudied populations of men at high risk for pca. Most men involved in the more clinic participate in the more program, providing a unique opportunity for the research participants to be seen annually while they are visiting for clinical screening. It is during those visits that participants often consent to participating in ongoing and new academic studies at the more program or through a network of collaborators.

The more program maintains a biobank of blood samples collected from consenting participants (Table ii). Per a standard operating procedure, dna and serum are extracted from blood samples and are stored on-site under a research ethics board–approved protocol. In addition to blood samples, all men in the more program consent to provide urine samples and access to tissue samples (for example, prostate biopsies). Plans are in place to eventually expand the biobank to include other biologic samples, such as prostate epithelial cells harvested from urine samples obtained after a digital rectal examination.

ACADEMIC INITIATIVES

Can PCa Risk and Aggressiveness Be Predicted in High-Risk Populations?

There is evidence to support the use of serum biomarkers such as human kallikrein 2, early pca antigen, urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor, transforming growth factor β1, and interleukin 6 and interleukin 6 receptor to predict aggressive high-grade disease³³. In addition to serum markers, tumour genetic biomarkers that have been cited as potential predictors of aggressive high-grade disease include BRCA1 and BRCA2, PTEN, KLK6, cellular Myc, NKX3-1, and copy-number variation^33–35. Commercially available single nucleotide polymorphism panels have not had widespread uptake in multiple jurisdictions (including Canada) given they have not been proved to be more effective than current clinical staging at predicting aggressive disease or affecting long-term outcomes³⁶. Our serum and tissue biobank provides a foundation to identify novel (or to validate existing) diagnostic, predictive, and prognostic biomarkers of aggressive disease.

What Is the Underlying Cause of PCa in High-Risk Populations?

As many as 5%–10% of pca cases are thought to be hereditary, but until recently, no “pca gene” has emerged. Instead, pca susceptibility genes have lived in the shadow of the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2^18,37. A growing body of literature is demonstrating that pathogenic germline variants in other non-homologous dna repair genes such as PALB2, CHEK2, and ATM are associated with aggressive pca³⁸. Evidence has also associated the mismatch repair genes responsible for Lynch syndrome (MSH2, MSH6, MLH1, PMS2, and EPCAM) with pca-related risk, but again, as part of a syndrome of cancer risks^39–41. In contrast to those syndromic cancer conditions, the germline variant G84E in HOXB13 is thought to confer a risk solely for pca, increasing that risk by as much as a factor of 4.5^42,43.

The more program aims to further evaluate families with a strong history of pca for germline susceptibility loci such as those described here. Men in the more program who have a personal and family history of pca would be offered a pca gene-susceptibility panel. The goal would be to evaluate the utility of current pca panels for identifying pathogenic germline variants and for establishing preliminary guidelines for offering screening using those panels to men.

Should Screening Be Different for Men at High Risk Than for the General Population?

Prostate magnetic resonance imaging (mri) is quickly coming into regular use for pca diagnosis and treatment. Currently, multiparametric 3 T mri is being used for guided biopsies in many active-surveillance populations around the world, including ours⁴⁴. In Sunnybrook’s active-surveillance population, mri has been evaluated for predicting reclassification into a higher risk category, with positive and negative predictive values of 83% and 81% respectively⁴⁵. Furthermore, a recent study from our group showed that, compared with systematic transrectal ultrasound–guided biopsy, mri-fusion biopsy was 6.3 times more likely to identify an upgrade to Gleason 7 or greater disease⁴⁶. The use of mri-fusion biopsy as a first-line tool in diagnosis has been investigated by multiple groups and was recently systematically reviewed⁴⁷; however, its clinical benefit in the general population is still a matter of debate. Yet, as advances in mri lead to improved detection of significant pca, the question arises of its utility as a screening tool in men at high risk for pca.

One group followed in the more program that might benefit from earlier detection, given their poor prognosis, are male BRCA carriers. We are therefore currently investigating the use of multiparametric 3 T mri imaging in male BRCA carriers 50 years of age and older, independent of psa (see NCT01990521 at http://ClinicalTrials.gov). The results of that study might provide evidence about the utility of mri as a screening tool in this at-risk population, as is similarly performed as the standard of care for female BRCA carriers.

Can Diet or Exercise, or Both, Lower the Risk of PCa in High-Risk Populations?

The correlation of diet and exercise with pca risk and prognosis has long been researched and debated, and it remains largely inconclusive today. Inconsistent findings in diet and exercise studies have led to generalized conclusions supporting a heart-healthy diet⁴⁸ and an active lifestyle⁴⁹. Despite ambiguity about the effects of diet and exercise in pca prevention in the general population, information about such effects in men at high risk for pca—particularly BRCA carriers—is notably lacking. Understanding the biology of BRCA-related cancer allows researchers to investigate how lifestyle factors might influence cancer risk. Take, for example, a study led by Kotsopoulos⁵⁰, demonstrating upregulation of BRCA1 gene expression in women with germline BRCA1 pathogenic variants after oral supplementation with 3,3′-diindolylmethane. The more program has a research arm evaluating the effects of diet and lifestyle on men at high risk for pca, with the aim of establishing definitive forms of lifestyle-related pca prevention.

What Are the Psychosocial Needs of Men at High Risk for PCa?

In North America, media coverage of BRCA genes as a women’s issue has been solidified by famous women publicly discussing their BRCA genetic status⁵¹. That phenomenon has opened up the question of whether the BRCA genes are “gendered,” and if so, what is it like being a man with a mutation in a gendered gene? Qualitative literature exploring experiences specific to men who are BRCA carriers, such as having a mammogram or living with an increased risk of developing pca, is lacking. Instead, the literature is focused on men’s experiences with genetic counselling and testing, or cancer risk perception^52,53. The more program uses qualitative analysis to understand the long-term effects on men of their known BRCA status, with the goal of increasing an understanding on the part of health care providers about patient conceptualizations of self in the context of inherited biomarkers.

SUMMARY

The more program is an academic program and specialized clinic initiated by a genetic counsellor (JL) and an oncologist (DV) specializing in genitourinary cancers. It monitors and screens men at high risk for pca. The goal of the more program is to create a foundation for research about men at high risk for pca and to optimize clinical care for such men. The program has 270 men enrolled, and it continues to enrol 6–8 new patients each month.

The more program collaborates with local researchers to identify new biomarkers and pathogenic germline variants and to deliver pca screening and general and psychosocial aspects of health care to these groups of men at increased risk for pca. We invite collaborations, and we aim to grow our program into a leading national database for men at high risk for pca. Please contact the corresponding authors for more information, or visit our Web site at http://www.sunnybrook.ca/MOREclinic.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: DV has received fees as an advisory board member for AbbVie and Astellas. The remaining authors have no conflicts to disclose.