Prostate Cancer Risk Assessment Program

Introduction

An estimated 184,500 new cases of prostate cancer were diagnosed in 1998, and almost 40,000 men died from the disease.[1] Because of the high burden of morbidity and mortality from prostate cancer, the federal government, through the Medicare reform bill recently passed by Congress, has committed significant resources to expand efforts to improve the control and prevention of prostate cancer. The bill will cover annual prostate cancer screening for men over age 50 years beginning in the year 2000.

Despite this governmental support for prostate cancer screening, the issues of who, how, and when to screen for prostate cancer, and even whether such screening should be done at all, are still being debated at both the state and federal levels. These debates are due, in part, to conflicting and/or vague screening recommendations issued by medical organizations, such as the American Urologic Association, the American Cancer Society, and the American College of Physicians.

Divisiveness over prostate screening recommendations has arisen because, despite the development of sensitive and reliable screening methods, such as the prostate-specific antigen (PSA) level, questions have been raised about the cost-benefit of prostate cancer screening in asymptomatic

men and the cost-benefit of diagnosis and treatment of localized prostate cancer.[2-4] Most of the controversies center around two arguments: (1) that screening of asymptomatic men leads to the detection and costly treatment of latent tumors that would have remained clinically silent and would have been discovered only on autopsy; and (2) that treatment confers only a small survival benefit while having a large negative impact on patients’ quality of life.

Arguments in favor of continued screening include pathologic evidence that most of the cancers detected by screening are clinically significant tumors, and that only a small percentage (10% to 15%) are insignificant or latent tumors.[5,6]

Nevertheless, with the steadily rising cost of health care, resources for screening have come under close scrutiny. A more cost-effective approach to prostate cancer screening may be to screen only those men at high risk for the disease.

Based on these considerations, Dr. Gerald E. Hanks founded the Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP) at Fox Chase Cancer Center in 1996. This risk assessment program offers a unique opportunity for high-risk men to obtain information regarding their risk for prostate cancer within a defined research protocol that will study their risk factors within a biopsychosocial framework. After a brief discussion on risk factors for prostate cancer, this article will describe the establishment of the PCRR and PRAP, their objectives and aims, and preliminary results relating to two of those aims.

Defining “High Risk”

Primary Risk Factors

Men at “high risk” for prostate cancer have been defined by the American Cancer Society as those who have a strong family history or who are African-American.[7] Despite the fact that prostate cancer has a high prevalence (ie, there are many individuals whose prostate cancer results from a variety of causes), it has been theorized that the disease has a genetic component. Family history and a genetic predisposition to develop this common disease have been documented.[8-13] Hereditary prostate cancer is associated with a pattern of cancer distribution consistent with Mendelian inheritance of a susceptibility gene.[14-16] This inherited prostate cancer gene could be autosomal-dominant, x-linked, or recessive.[17]

Segregation analysis suggests the existence of a dominant susceptibility locus accounting for 9% of all prostate cancers and more than 40% of early-onset tumors.[9] The increased risk conferred by family history has been seen in men of all ages but is more pronounced in younger men (ie, those < 65 years old).[11]

The Human Genome Project, an international research program designed to map the human genome and to localize the estimated 50,000 to 100,000 genes within the human genome, has already had an impact on common cancers, such as breast and colon cancers, by localizing specific chromosomal regions.[18] This project recently supported the genome-wide scan of high-risk prostate cancer families, which led to the identification of a genetic locus, HPC1, on chromosome 1, which is associated with prostate cancer predis position.[19] In 1996, Smith et al undertook a linkage analysis to search for evidence of loci contributing to risk for prostate cancer in 66 high-risk prostate cancer families.[19] This analysis showed linkage to the long-arm of chromosome 1 (1q24-25), thus providing strong evidence for a major prostate cancer susceptibility gene. New evidence indicates that a second prostate cancer susceptibility locus resides on chromosome X (Xq 27-28),[20] a finding consistent with results of previous population-based studies suggesting an x-linked mode of inheritence. Recommendations have been made to target future efforts at positional cloning of the gene in families who meet the proposed clinical criteria for hereditary prostate cancer.[21]

Advances in the isolation of genes associated with hereditary cancers not only will elucidate the basic mechanisms of carcinogenesis but also will provide precise tools for assessing an individual’s risk for cancer. The incorporation of genetic information into clinical cancer risk assessment paradigms is being proposed as a way of targeting preventive strategies to the most appropriate individuals and maximizing their effectiveness.[22]

Independent of family history, African-American males have the highest incidence of and mortality from prostate cancer in the world.[23] Mebane and colleagues[24] reported that black males have a two to three times higher rate of being diagnosed with prostate cancer before age 65 years, whereas the mean age at diagnosis among white men is 72.3 years.[25] In 1993, prostate cancer accounted for 9.4% of cancer deaths in African-Americans but only 6.2% of cancer deaths in Caucasians. Black men have a 9.6% risk of being diagnosed with prostate cancer and a 3% risk of dying from the disease, as compared with a 5.2% risk of diagnosis and a 1.4% risk of dying from the disease for US white men.[26]

Prostate cancer survival rates from the last period for which data are available (1986 to 1992) also show marked racial differences; the 5-year survival rate is 73% for blacks, as compared with 89% for whites.[27] Finally, the proportion of patients diagnosed with metastatic disease is higher in black compared with white Americans.[28]

Age is the primary risk factor for prostate cancer. Indeed, the age-adjusted incidence rate of prostate cancer among men ³ 65 years old increased by 82% according to a population-based study derived from Medicare claims data and National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) statistics accumulated between 1986 and 1991.[29] For men at high risk due to other factors, it is not only their age at the time of screening that heightens that risk but also the age of onset of prostate cancer in a first-degree relative.[14] For example, if a man is diagnosed before age 62 years, his brother or brothers have a four times higher relative risk of developing a malignancy.[30]

Additional Risk Factors

In addition to family history, ethnicity, and age, it has become clear that lifestyle risk factors are associated with the development of prostate cancer. Several studies have demonstrated an association between animal fat intake[31-33] and the risk of developing prostate cancer. Although other studies have not supported this association,[34-36] the strong correlation between national consumption of fat and national rates of prostate cancer has led to continued interest in the relationship.

Weaker associations have been found between the use of tobacco and occupational exposure to cadmium, a trace mineral found in alkaline batteries, and subsequent development of prostate cancer.[37]

Rationale for Family Cancer Programs

Since the multifactorial nature of prostate cancer makes it unlikely that the alteration of any one risk factor will prevent the disease, a great deal still needs to be learned about the etiology, biology, and genetic regulation of the disease. The recent growth of genetic information about prostate cancer and the imminent identification of a gene or genes responsible for prostate cancer susceptibility, coinciding with the efforts of the Human Genome Project, will have major public health implications. These implications include the development and evaluation of genetic screening policies, patient treatment preferences, quality of life (QOL) data, patient and physician education, counseling strategies, and health care policy. The demand for genetic testing, as well as confusion about the meaning of prostate cancer susceptibility, is likely to grow, and the need to educate men about their individual and familial risk for prostate cancer will become more acute.

Attempting to meet some of these needs, family cancer programs that offer a wide range of services, including risk analysis, screening, DNA testing and storage, chemoprevention, and assistance with treatment decision-making, are being developed at medical centers throughout North America and Europe. One of the most cost- and labor-efficient ways to approach the definition of prostate cancer risk is to study persons known to be at increased risk for the disease.