Study of Prostate Cancer in Black and White U.S. Veterans

Trial Information

Study of Prostate Cancer in Black and White U.S. Veterans

Primary Objectives: To evaluate the relationship between the length of the CAG repeat
sequence occurring in the androgen receptor gene and major prostate cancer prognostic
determinants (race, age, histologic grade and stage) at the time of diagnosis in black and
white veterans.

Secondary Objectives: To create a secure, organized bank of DNA plasma samples obtained from
newly diagnosed prostate cancer patients and assay the peripheral blood DNA for inherited
polymorphisms of the androgen receptor gene.

Primary Outcomes: The primary outcomes are androgen receptor CAG repeat sequence length and
stage of disease.

Intervention: N/A

Study Abstract: Prostate cancer is diagnosed in approximately 334,500 men each year and
accounts for nearly 41,800 deaths in the United States. Prostate cancer is the leading
cancer affecting veterans and the second leading cancer among all Americans. The causes of
prostate cancer and, particularly, the reasons for the unusually high incidence rates in
African-Americans remain obscure. Dietary factors likely play a role in fatal cases, while
hormones are also important in regulating prostate cancer growth. Dr. Charles Huggins
recognized this effect in the 1940's, with androgen deprivation remaining as the cornerstone
of therapy for advanced disease. Despite the strong circumstantial evidence, neither
epidemiologic studies nor basic sciences have produced clear insight into the etiologic role
of hormones. However, recent observations regarding androgen receptor gene polymorphisms and
their relation to endocrine expression and prostate cancer risk may be providing important
clues as to how an etiologic role might be mediated at the molecular level. Thus, it is
important to attempt to identify genetic markers of high-risk cancer patients for necessary
screening and counseling efforts.

It has been recently demonstrated that the androgen receptor functions as a ligand-dependent
transcriptional regulator, and that this regulation is important in controlling prostate
growth and apoptosis. Heightened androgenic stimulation, a potential by-product of shortened
CAG repeat length, could potentially increase the risk of prostate cancer development and
progression. In particular, a shorter CAG repeat sequence may be associated with cancers
that have features of higher histologic grade, extraprostatic extension, and distant
metastases (stage C or D). Recent evidence indicates that men with shorter CAG repeats are
at particularly higher risk for distant metastatic and fatal prostate cancer. The results
demonstrated that a shorter CAG repeat sequence in the androgen receptor gene predicted
higher grade and advanced state of prostate cancer at diagnosis, metastatic disease, and
mortality. However, these studies have been limited to whites since only a small number of
African American men with prostate cancer were included.

Prostate cancer incidence varies between African-American and white men. African-American
men have the highest known incidence rates in the world, 66% higher than white men in the
U.S. The genetic findings described above raise the possibility that racial differences in
the distribution of androgen receptor polymorphisms may account for the higher rate of
prostate cancer, the more advanced disease, and the younger age at presentation in
African-Americans.

This study created a cohort of prostate cancer patients who are well characterized with
respect to histology, stage of diagnosis, and (over time) mortality. This study is
generating data regarding the length of the CAG repeat sequence occurring in the androgen
receptor gene and major prostate cancer prognostic determinants (histologic grade and state)
at the time of diagnosis in black and white veterans. CAG repeat lengths on the androgen
receptor gene were evaluated for a cohort of 145 African American and 150 white veterans
with prostate cancer.

Results: Mean androgen receptor gene CAG repeat lengths for Caucasians was 21.9 versus 19.8
for African Americans, p=0.0001. However, a truncated CAG repeat length (CAG <= 18 versus
CAG > 18) was not associated with advanced stage of cancer at diagnosis, higher PSA at
diagnosis, or higher Gleason score (each with p>0.5).

Conclusion: The mean androgen receptor CAG repeat length was 2 repeats shorter for African
American versus white prostate cancer patients. These findings raise concern that prostate
cancers in African American men may be less sensitive to hormonal therapy than those in
white men. These findings provide biologic rationale for clinical trials that evaluate the
joint administration of chemotherapy and hormone therapy for African American men with
advanced prostate cancer.