National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 22, 2011 • Volume 8 / Number 4

Cancer Research Highlights

Dutasteride May Slow the Growth of Early-Stage Prostate Cancer

For men who are undergoing active surveillance for early-stage prostate cancer, the drug dutasteride (Avodart) could help control the disease and prevent the need for more aggressive treatments. The finding, from a randomized, placebo-controlled trial, was presented during the 2011 Genitourinary Cancers Symposium, which was held February 17–19 in Orlando, FL. Dutasteride is already approved by the Food and Drug Administration (FDA) for the treatment of an enlarged prostate gland, or benign prostatic hyperplasia.

Active surveillance, previously called “watchful waiting,” refers to the practice of forgoing immediate treatment after a prostate cancer diagnosis in favor of regularly scheduled testing and clinical exams to closely monitor the disease. In the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial, 302 men undergoing active surveillance were randomly assigned to receive either dutasteride, which belongs to the class of drugs known as 5-alpha reductase inhibitors, or placebo for 3 years. Biopsy specimens were collected at 18 and 36 months, or as warranted based on evidence of disease progression.

In the dutasteride group, 38 percent of the men experienced some progression of their cancer, compared with 49 percent of the men in the placebo group. This difference translated into a reduction in relative risk for cancer progression of 38.9 percent in the dutasteride group. In addition, taking dutasteride increased the chances that no cancer would be found during a participant’s final biopsy. Thirty-six percent of the men in the dutasteride group and 23 percent of the men in the placebo group had no cancer detected in their final biopsy specimens.

It would be “very reasonable” to give a 5-alpha reductase inhibitor to patients with “ultra low-risk” prostate cancer who elect for active surveillance, said the trial’s lead investigator, Dr. Neil Fleshner of the University Health Network in Toronto, during a press briefing. However, Dr. Fleshner cautioned, this would be considered an “off-label” use of dutasteride. In December, the FDA’s Oncologic Drugs Advisory Committee rejected GlaxoSmithKline's application to approve dutasteride for use in preventing prostate cancer, and Dr. Fleshner said that the company was unlikely to seek an additional approval for the drug.

“The results of REDEEM suggest that dutasteride has an antitumor effect against low-volume, low-risk prostate cancer,” said Dr. Howard Parnes of NCI’s Division of Cancer Prevention, who was not involved in the study. “I think that this class of drugs [5-alpha reductase inhibitors] deserves to be studied further in men undergoing active surveillance.”

The Genitourinary Cancers Symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Bisphosphonate Use May Reduce Colorectal Cancer Risk

Post menopausal women who used bisphosphonate drugs (primarily alendronate) for more than 1 year had a 59 percent lower risk of colorectal cancer, according to a study published online February 14 in the Journal of Clinical Oncology. The findings came from a population-based, case-control study of colorectal cancer in northern Israel.

Bisphosphonates are commonly prescribed to treat or prevent osteoporosis and are also used to treat bone metastases in patients with breast cancer. Laboratory studies have shown that these drugs can interfere with steps involved in cancer cell growth and spread, and thus may have anticancer properties in humans. Indeed, previous reports have shown fewer breast cancer cases in women taking bisphosphonates. However, these studies did not rule out whether the reduced breast cancer risk was due to the lower estrogen levels often found in women who have low bone density and who are thus more likely to use bisphosphonates. (Colorectal cancer is not known to be fueled by estrogen.)

Analyzing data from the Molecular Epidemiology of Colorectal Cancer study, Dr. Gad Rennert of Technion-Israel Institute of Technology in Haifa, Israel, and his colleagues compared 933 women diagnosed with colorectal cancer with 933 women who did not have the disease. The women in the two groups were matched by age, ethnicity, and area of residence. The researchers also adjusted for known colon cancer risk factors, including vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statin drugs, vitamin D, and postmenopausal hormones.

“This evidence does not provide a basis for using bisphosphonates for colorectal cancer prevention,” cautioned Dr. Asad Umar of NCI’s Division of Cancer Prevention. “Indications for these drugs may be limited due to their toxic side effects, including rare cases of osteonecrosis of the jaw, esophagitis and esophageal erosion, and a possible higher risk of bone fractures after prolonged use.” A controlled clinical trial would be needed to confirm the connection between bisphosphonate use and colorectal cancer risk, he concluded.

Common Genetic Deletion Found in Brain Cancers

Researchers have identified a gene that is deleted in approximately one out of four patients with glioblastoma, the most common form of brain cancer. In addition, the researchers found that patients whose tumors had lost one copy of the gene, called NFKBIA, tended to have unfavorable outcomes. The results appeared in the February 17 New England Journal of Medicine and on the journal’s Web site in December.

Abnormalities in NFKBIA have been linked to other cancers, including Hodgkin lymphoma and multiple myeloma, but this study is the first to implicate defects in the gene in glioblastoma. NFKBIA appears to be a tumor suppressor gene; it produces a protein that normally helps to block growth-promoting messages from two signaling pathways linked to cancer, the NF-kappa B and the epidermal growth factor receptor (EGFR) pathways.

Approximately one-third of glioblastoma tumors have alterations in the EGFR gene, which can cause cells to proliferate and become cancerous. To identify additional genetic alterations in glioblastoma, the researchers profiled the EGFR and NFKBIA genes in tumors from nearly 800 patients with glioblastoma.

Based on an analysis of the results and additional laboratory experiments, the researchers concluded that the loss of NFKBIA is another way that glioblastoma cells can activate the NF-kappa B and EGFR pathways. The results also suggest that a majority of patients with glioblastoma have alterations in either EGFR or NFKBIA; very few tumors had abnormalities in both genes.

“We have identified a gene that is known to play a role in cancer, and there are substantial efforts under way to target that NF-kappa B pathway,” said lead author Dr. Markus Bredel of Northwestern University’s Feinberg School of Medicine. “So there are high hopes that we’ll be able to target this alteration.” 

The researchers are developing a clinical test that could be used to detect the deletion in patients and potentially guide the selection of therapy in the future.

More DNA Rearrangements Found in Prostate Cancers

The first study to compare the genomic sequences of multiple prostate tumors has found recurring rearrangements of DNA that may contribute to the development of the disease. Using tumor samples from seven patients, the researchers confirmed the existence of previously identified genetic changes associated with prostate cancer and discovered other alterations that could lead to new treatments for the disease.

Drs. Levi Garraway of the Dana-Farber Cancer Institute and Mark Rubin of Weill Cornell Medical College and their colleagues reported the findings February 10 in Nature. The study was funded in part by NCI’s Early Detection Research Network.

Previous studies have shown that many prostate tumors have fused genes, changes that occur when DNA sequences from different parts of the genome are linked together inappropriately. In the current study, three of the seven patients had the fusion gene TMPRSS2-ERG, which occurs in approximately half of all prostate cancers, and according to a 2008 study, may contribute to the disease.

In addition, the researchers detected approximately 90 genomic rearrangements per tumor, although these were not all associated with prostate cancer. (A genomic study of breast tumors reported a similar prevalence of rearrangements, but the mechanisms by which they occur may differ in the two cancers, the researchers noted.)
 
An analysis of the chromosomal rearrangements “revealed a distinctive pattern of balanced breaking and rejoining not previously observed in solid tumors,” the study authors wrote. Some of the rearrangements appeared to disrupt multiple genes in parallel, and these changes could affect the regulation of genes associated with cancer, the authors suggested.

“This study underscores the importance of doing systematic whole-genome sequencing in cancer,” said the study’s first author, Dr. Michael Berger, who conducted the research while at the Broad Institute. “Some of these rearrangements would not have been detected by targeted sequencing approaches that focus on just part of the genome rather than the whole.”

Certain Physicians Are More Likely to Refer Patients to Clinical Trials

According to a survey-based study of more than 1,500 physicians treating patients with lung or colorectal cancer, medical oncologists were the most likely and surgeons the least likely to refer patients to, or enroll them in, clinical trials. The study, published online February 11 in the Journal of the National Cancer Institute, evaluated the characteristics of specialty physicians who refer patients to clinical trials, the types of trials in which they participate, and factors associated with physicians who report greater involvement in clinical trials.

Almost 88 percent of the medical oncologists who participated in the survey referred or enrolled one or more of their patients in the previous year, compared with 66 percent of radiation oncologists and only 35 percent of surgeons. Nearly half of the survey respondents were affiliated with NCI’s Community Clinical Oncology Program (CCOP) or an NCI-designated Cancer Center, yet one in three of these physicians reported no enrollments or referrals in that year.

“The role of physicians in recruiting patients to clinical trials is pivotal,” wrote Dr. Carrie Klabunde, an NCI epidemiologist who led the study within the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) in collaboration with her colleagues. These trends reflect opportunities to improve clinical trial recruitment.

Although surgeons had the lowest rate of patient referral or enrollment, they represented more than half of the group that was surveyed. Surgical oncologists and surgical subspecialists (thoracic and other types) were much more likely than general surgeons to refer or enroll patients. Female surgeons and those over age 60 were also more likely to refer or enroll patients.

When medical oncologists or radiation oncologists received monetary incentives, they referred or enrolled 20 percent more patients. Physicians who teach medical students or residents, or who are affiliated with a CCOP or an NCI-designated Cancer Center, were also substantially more likely to refer or enroll patients. In these groups, physicians who saw more than 19 patients per month or who attended weekly tumor board meetings were much more likely to refer or enroll patients.

“Realizing the full potential of clinical research in the 21st century will require…efforts to address the complex factors that shape cancer care in the United States,” wrote the authors. “More research is needed to better understand clinician attitudes toward clinical research and to examine specific features of practice infrastructure…that facilitate or hinder physician participation in clinical trials.”