HOUSTON, July 7 — Treatment-induced prostate shrinkage likely unmasked high-grade cancers, resulting in a detection bias in the finasteride (Proscar/Propecia) arm of the Prostate Cancer Prevention Trial (PCPT), data from a large patient series suggest.

• Explain to patients that a drug that decreases the size of the prostate might make cancer easier to find.
• The findings were based on a retrospective review of medical records, not a controlled clinical trial.

The value of prostate specific antigen (PSA) as a marker for prostate cancer declined steadily as prostate volume increased. A similar inverse relationship existed for high-grade cancer, Christopher S. Elliott, MD, of Stanford University, and colleagues reported in the July 15 issue of Clinical Cancer Research.

“Decreases in prostate volume over time and the resultant change in prostate-specific antigen performance characteristics may have contributed a bias toward the detection of high-grade disease in the finasteride arm of the Prostate Cancer Prevention Trial,” the authors concluded.

The observations could explain why the increased risk of high-grade cancer in the finasteride arm was limited to the subgroup of men who had symptom-driven biopsies during the trial, they added. The findings also are consistent with those from analyses that PCPT investigators have performed in the six years since the trial ended.

The PCPT involved 19,000 healthy men who were randomized to finasteride or placebo for seven years. The principal finding was a 25% reduction in prostate cancer incidence in the finasteride arm.

However, the beneficial effect has been overshadowed by the finding that finasteride-treated men had a small but statistically significant increase in the rate of high-grade cancer compared with the placebo group.

Closer examination of the PCPT data revealed inconsistencies in the occurrence of high-grade cancer. Specifically, the increase was limited to men who had “for-cause” biopsies, triggered by an abnormal digital rectal exam (DRE) or a rise in PSA. End-of-study biopsies showed an almost-identical incidence of high-grade cancer in the two treatment arms.

Prostate volume at the time of biopsy was 25% lower in the finasteride arm (25.5 cm³ versus 33.6 cm³), the authors noted.

Dr. Elliott and colleagues hypothesized that the increased rate of high-grade cancer in the finasteride arm resulted from the drug’s volume-reducing effect on the prostate. The shrinkage could have improved PSA’s performance characteristics for detecting prostate cancer.

To test their hypothesis, investigators retrospectively reviewed records on 1,304 men referred for an initial prostate biopsy. The referrals were prompted by a PSA value of 4 to 10 ng/mL or an abnormal digital rectal exam.

The study group had a median age of 66, median prostate volume of 42.9 cm³, and median PSA value of 5.5 ng/mL. Digital rectal exam was abnormal in 507 (38.9%).

The investigators calculated receiver-operator curves and positive predictive values for PSA, stratified by diagnosis and prostate volume.

For detection of any cancer, the area under the curve (AUC) decreased from 0.758 to 0.520 as prostate volume increased from <30 cm³ to >50 cm³. For detection of high-grade cancer, AUC decreased from 0.712 to 0.497 as organ volume increased.

A similar pattern emerged from calculations of positive predictive values.

For a prostate volume <30 cm³, the positive predictive value of a PSA of ?4 ng/mL was 25%, declining to 17.3% for a prostate volume >50 cm³. The differences increased for detection of high-grade cancer: 39% for a prostate volume <30 cm³ versus 10.7% for a volume >50 cm³.

Continued analysis of PCPT data has led to similar conclusions regarding the relationships among finasteride, prostate volume, and PSA performance characteristics for detection of prostate cancer, PCPT investigator Catherine Tangen, DrPH, of the Fred Hutchinson Cancer Research Center in Seattle, said in a statement.

Collectively, the data suggest that men should be offered finasteride, if they and their physicians agree that chemoprevention might be beneficial, she added.

Earlier this year, the American Society of Clinical Oncology and the American Urological Association recommended that healthy men ages 55 and older and with no signs of prostate cancer talk to their physicians about taking a 5-alpha reductase inhibitor to prevent prostate cancer. (See Men Encouraged to Consider Medication to Prevent Prostate Cancer)

Neither the authors nor Dr. Tangen reported any relevant disclosures.

Primary source: Clinical Cancer Research

Source reference:

Elliott CS, et al “The influence of prostate volume on prostate-specific antigen performance: implications for the Prostate Cancer Prevention Trial outcomes” Clin Cancer Res 2009; 15(14): 4694-99.

Related Article(s):

• Men Encouraged to Consider Medication to Prevent Prostate Cancer

Researchers have found links between an individual’s genetics and their response to treatment with chemotherapy. The findings, by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues, show how a genetic variation, located in the SOD2 gene, may affect how a person responds to the chemotherapy drug cyclophosphamide. Cyclophosphamide is used in the treatment of breast and other cancers.

The SOD2 gene produces a key protein that protects cells from damage by molecules known as reactive oxygen species, or free radicals. Reactive oxygen species are produced by normal cellular processes and the action of some chemotherapy drugs. The findings represent the first preliminary evidence pointing toward a mechanism and a potential biomarker for cyclophosphamide resistance in breast cancer patients. The study appeared online June 9, 2009, in Clinical Cancer Research.

“This study shows how, with the progress of individualized medicine, a diagnostic test may be developed that determines whether a patient has certain genetic variations that may modify the effect of certain chemotherapies,” said study author Sharon Glynn, Ph.D., of NCI’s Center for Cancer Research.

“In the future, such tests may be used to guide the treatment of patients with the SOD2 variation, ensuring that they receive a therapy that is more effective than cyclophosphamide-based therapies,” added senior author Stefan Ambs, Ph.D., also of the Center for Cancer Research.

Most genes in human cells are present in two copies-one inherited from the mother and the other inherited from the father. These gene copies can vary from one another. Some variations in genes play an important role in how a gene is expressed or how its protein product functions.

The variant identified by the researchers in the SOD2 gene affects both the structure and the function of the encoded protein, an enzyme known as manganese superoxide dismutase (MnSOD) and affects the ability of MnSOD to reach its proper location in the cell and its activity level. MnSOD normally functions inside cellular compartments known as mitochondria and helps protect cells from damage caused by reactive oxygen species formed during cellular metabolism. Excessive levels of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs depend on increased production of reactive oxygen species to kill cancer cells. Furthermore, some studies have indicated that, because MnSOD neutralizes reactive oxygen species, it can modify the effects of chemotherapy drugs. For example, in laboratory and animal models, increased activity of MnSOD protects cells against the toxic effects of doxorubicin, which is a widely used anticancer drug.

In the new study, the research team investigated whether the variation affected survival in two separate groups of women with breast cancer: 248 women in the United States and 340 women in Norway. Some of the women received chemotherapy, and some did not receive chemotherapy. The team first analyzed DNA from the women to determine their genotype, meaning which types of the SOD2 gene they had. The researchers found that, among patients who received chemotherapy, those who had one form had decreased survival and those with another form had the poorest survival. In contrast, the genotype of SOD2 did not affect survival among those who did not receive chemotherapy.

Next, the team looked at the relationship between SOD2 genotype and the type of chemotherapy the women received. The data were analyzed according to which of three types of commonly used chemotherapy drugs were administered: doxorubicin, 5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generate reactive oxygen species in cancer cells during treatment. The researchers determined that the presence of a particular variant was associated with decreased survival of patients treated with chemotherapy regimens that contained any of the three drugs. However, the most significant effects were found with the drug cyclophosphamide. Women with a distinct variant form of SOD2 and who received cyclophosphamide-containing chemotherapy had the poorest survival.

The research team says more work is necessary to confirm these findings and to examine the precise mechanism by which a genotype influences the response of cancer cells to cyclophosphamide. The team plans to examine the influence of several variations on the resistance to other chemotherapies.

For more information on Dr. Ambs’ research, please go here.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Reference: Glynn SA, Boersma BJ, Howe TM, et al. A Mitochondrial Target Sequence Polymorphism in MnSOD Predicts Inferior Survival in Breast Cancer Patients Treated with Cyclophosphamide. Online June 9, 2009. Clinical Cancer Res.

Source
National Cancer Institute