Risk Factors for Prostate Cancer

Prostate cancer is becoming an increasingly important public health problem in the United States. Prostate cancer is now the most commonly diagnosed cancer in men in the United States as well as the second leading cause of male cancer deaths [1, 2]. It is projected that in 1992 there will be 132 000 new cases of prostate cancer diagnosed as well as 34 000 deaths from prostate cancer; these numbers are expected to continue to increase as the population ages [1, 3, 4]. Epidemiologic and screening studies performed in the past several decades have raised several important questions about the pathogenesis of this disease, but a definitive cause for prostate cancer has not been established. It has been apparent for several years that the age-adjusted incidence rates as well as death rates from clinical prostate cancer vary dramatically from country to country, even if one allows for differences in and availability of screening programs (Figure 1) [5, 6]. For example, Waterhouse and Muir [5] found a 25-fold difference between incidence rates in American black men living in San Francisco and in Japanese men. In 1988, the age-adjusted death rates per 100 000 population were 15.7 for men in the United States and 3.5 for men in Japan [7]. Figure 1. Age-adjusted death rates due to prostate cancer per 100 000 population. The clinical effect of prostate cancer is growing. The advent of newer screening procedures such as the prostate-specific antigen blood test and growing public awareness have raised questions concerning the cause of prostate cancer as well as ways to screen for and prevent this disease [8-12]. The ultimate goal of epidemiologic studies is to identify risk factors to guide disease prevention strategies. This review examines the current data on the identification of potential risk factors that may be important in the development of prostate cancer. Clinical Compared with Histologic Prostate Cancer The prevalence of both clinical and histologic prostate cancer increases with age. After age 50 years, both incidence and mortality rates from prostate cancer increase at a nearly exponential rate. Prostate cancer increases faster with age than any other major cancer and, with an aging population, the burden of illness from prostate cancer will probably continue to increase in the future [13]. It remains unclear why this cancer increases with age so much more than do other cancers. Although the clinical incidence of prostate cancer varies greatly around the world, the prevalence of histologic cancer is remarkably similar. Autopsy study data from many countries demonstrate that 15% to 30% of men older than 50 years have histologic evidence of prostate cancer [14-37]. The presence of histologic cancer increases with age so that by age 80 approximately 60% to 70% of men have evidence of histologic carcinoma at autopsy [14-37]. It is now generally accepted that the development of a fully malignant cancer cell requires multiple malignant genetic events, including those that initiate cell transformation as well as those that promote or encourage the transformation process [38-40]. If histologic cancer represents a step in the development of clinically evident prostate cancer, then the data suggest that the initiation event of prostate cancer appears to occur at approximately the same rate independent of race or place of birth of the individual [1]. Carter and colleagues [1] have shown that although the age-specific prevalence of histologic prostate cancer is similar in Japan and the United States, there is a marked difference in the age-specific prevalence of clinical prostate cancer between Japanese and American men (Figure 2). These data suggest that the initiation rate of prostate cancer may be the same in both groups but that there appear to be differences in the rate of promotion or progression to clinically evident prostate cancer. This interpretation is further supported by the observation that immigrants who move from low-risk areas to the United States gradually assume the higher risk of the U.S. population [3, 41-46]. Therefore, whereas the presence of histologic cancer appears to be related to age, other risk factors that increase the development of prostate cancer probably affect the promotion steps of the transformation pathway. Figure 2. Comparison of the age-specific prevalence of prostate cancer in the United States and Japan. Top panel. Bottom panel. Risk Factors Family History Several studies have suggested that the incidence of prostate cancer in male relatives of patients with prostate cancer is increased [47-59]. Thiessen [47] has reported a higher incidence of prostatic cancer among male relatives of patients with breast cancer. Cannon and colleagues [48] found a familial clustering of prostate cancer in Utah Mormons. Their analysis demonstrated a high kinship coefficient for patients younger than 65 years with their brothers younger than 65 (age-specific relative odds, 5.97). Spitz and colleagues [49] showed an increased risk among men with first-degree relatives with the disease (odds ratio, 2.41). Carter and colleagues [50-53] have done a series of analyses that show that men with a father or brother with prostate cancer are twice as likely to develop prostate cancer as men without affected relatives and that risk increases with an increasing number of affected relatives. These authors have gone on to show through segregation and linkage analyses that early-onset prostate cancer may be inherited in an autosomal-dominant fashion of a rare high-risk allele and suggest that the autosomal-dominant form of prostate cancer accounts for a significant number of early-onset cases. Overall, however, these cases only represent a small proportion of prostate cancer. Together these data show an increased risk for the development of clinical prostate cancer in men with affected relatives. It remains unclear if the current National Cancer Institute prostate cancer screening guideline of a digital rectal examination yearly after age 40 should be altered for men with affected family members. The American Cancer Society screening guidelines for prostate cancer consist of a yearly digital rectal examination and a prostate-specific antigen test starting at age 50. It is suggested that men with a positive family history of prostate cancer initiate screening at an earlier age, but a specific age is not recommended at this time. Race Wide variation in the reported incidence of clinical prostate cancer has been reported between different ethnic groups. It is clear from both incidence and mortality data that the incidence of clinical prostate cancer is low in Asian men and higher in Scandinavian men [7]. Incidence rates vary 120-fold between Chinese men and African-American men living in San Francisco [5, 60]. It is unclear if this is based on genetic or environmental factors; however, migration studies demonstrate that men tend to take on the risk for their host countries [3, 40-45]. These data, unfortunately, are confounded by differences in life expectancy, diet, socioeconomic status, and reporting. African-American men have a higher incidence of prostate cancer than do black men in Africa or Asia [3, 5]. A recent study from the National Cancer Institute based on data extracted from the Surveillance, Epidemiology, and End Results Program (SEER) as well as census data reveal that African-American men living in the United States have a higher incidence rate of clinical prostate cancer than do white men of similar education and socioeconomic classes [61]. The age-adjusted invasive prostate cancer incidence rates in the tri-county metropolitan Detroit area, as measured by the SEER database in 1990, showed a 30% greater incidence among African-American men compared with white men (Figure 3). African-American men have a higher incidence of prostate cancer at all ages (Figure 4). Furthermore, African-American men are routinely diagnosed with later-stage disease, and survival rates are uniformly shorter for African-American men, even when corrected for stage. The 5-year survival rates for all stages of prostate cancer are 62% for African-American men and 72% for white men. Figure 3. Prostate cancer incidence rates for the years 1973 to 1990. Figure 4. Incidence rates by age and race for invasive prostate cancer. If the prevalence of histologic prostate cancer is essentially the same in different racial populations [13-36], these data suggest that African-American men are either more susceptible to prostate cancer-promoting events or are exposed to different promoting agents. Interestingly, Whittemore and colleagues [62] note that the transformation rate from histologic to clinically evident cancer is similar for African-American and white men, but that African-American men appear to have a larger volume of latent prostate cancer. These investigators believe that the larger-volume latent cancers are the carcinomas that progress more rapidly to become clinically evident. These data suggest that events that account for racial differences in prostate cancer incidence may occur early in cell transformation [37-39]. Socioeconomic Factors Differences in socioeconomic status, especially those between African-American and white men, have been suggested as a reason for the differences in prostate cancer incidence between these two groups. This issue has been especially difficult to resolve given that minority populations in many studies come from low socioeconomic groups. Baquet and colleagues [61] at the National Cancer Institute, however, recently investigated the incidence of prostate cancer in African-Americans and whites by correlating cancer incidence with population density, education, and income level. Using incidence data from SEER, these authors found that incidence was generally higher in African-American men than in white men but that no statistically significant association exists between socioeconomic status and prostat