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Prostate Cancer Risk Assessment Program

Prostate Cancer Risk Assessment Program

ABSTRACT: Prostate cancer is the most common form of cancer (except skin cancer) in men. Several factors have been associated with an increased risk for prostate cancer, including age, ethnicity, family history, lifestyle, and environmental exposures. Recognition of the importance of the interaction of these factors in prostate cancer has led to an interest in their evaluation as a model both for studying genetic susceptibility patterns and for studying and providing educational tools and preventive interventions. One such model has been developed at Fox Chase Cancer Center. Critical to the implementation of the model has been the establishment of the Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP). Together, they serve as a unique resource for investigating the interaction between environmental factors and genetic susceptibility patterns; exploring the early, premalignant biological markers of prostate cancer; and prospectively assessing the quality of life (QOL) of men at risk. In addition, PRAP facilitates the evaluation of models for prostate cancer risk counseling and screening in the community. This paper describes this model for early detection and risk reduction, along with preliminary data from its first two study aims. 3The program is particularly relevant in view of the wealth of genetic information emerging from the Human Genome Project. [ONCOLOGY 13 (3):325-334, 1999]

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.

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