National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
December 15, 2009 • Volume 6 / Number 24

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Cancer Research Highlights

Bone Drugs Linked to Fewer Cases of Breast Cancer

A new analysis from the Women’s Health Initiative (WHI) study has found that the use of drugs called bisphosphonates, which are taken to improve bone health, was associated with a nearly 33 percent reduction in the incidence of invasive breast cancer compared with women who did not take the drugs. Although preliminary, the findings raise the possibility that this commonly used class of drugs may have a role in preventing breast cancer, researchers said at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium.

Bisphosphonates are taken primarily for the treatment of osteoporosis but can also treat bone-density problems in patients with cancer-related conditions. Laboratory studies have suggested that these agents may also have anticancer effects, providing a possible biological explanation for the association.

To find the association, Dr. Rowan Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and his colleagues analyzed data on 151,000 women in the observational component of the WHI. Of the 2,216 women who were using bisphosphonates when they entered the study, 64 developed breast cancer, and most of those cancers (50) were estrogen-receptor positive.

The results translate into 32 percent fewer cases of invasive breast cancer among users of oral bisphosphonates—primarily alendronate (Fosamax)—compared with nonusers. A second study presented in San Antonio found a nearly 30 percent reduction of postmenopausal breast cancers among women in Israel who used bisphosphonates for at least a year compared with nonusers.

Since neither study was a randomized controlled trial, the results should be considered hypothesis-generating and are by no means proof, noted Dr. Leslie Ford of NCI’s Division of Cancer Prevention and the institute’s WHI liaison. “One issue is that women who take bisphosphonates often have low bone density because they are in a low estrogen environment,” she said, “so these women would be at a lower risk for breast cancer than women who did not get bisphosphonates.” This could be an alternative explanation for the result.

An ongoing clinical trial is looking at the role of bisphosphonates in the adjuvant treatment of breast cancer. If the results indicate that women taking the drugs have a lower rate of cancer in the opposite (contralateral) breast than women not taking bisphosphonates, this would “be a very intriguing finding and would make the current observations even stronger,” said Dr. Ford. Nonetheless, randomized controlled trials in the preventative setting would be needed for this to become the standard of care, she added.

Bisphosphonates have been linked to osteonecrosis of the jaw, and the FDA issued a warning about musculoskeletal side effects of these drugs in January 2008. A year later, the FDA’s Dr. Diane Wysowski warned of an increased risk of esophageal cancer and death in patients taking oral bisphosphonates.

U.S. Cancer Cases and Deaths Continued to Decline in 2006

The overall rate of new cancer cases diagnosed (incidence) and deaths from cancer (mortality) continued to decline significantly in the United States through 2006, due largely to lower lung, prostate, and colorectal cancer rates in men and lower breast and colorectal cancer rates in women. New diagnoses for all cancers decreased, on average, almost 1 percent per year between 1999 and 2006. Cancer deaths decreased 1.6 percent per year between 2001 and 2006. Researchers from NCI, CDC, American Cancer Society, and North American Association of Central Cancer Registries reported these findings in the Annual Report to the Nation on the Status of Cancer (1976-2006), published online December 7 in Cancer.

This year’s report featured a special section on colorectal cancer (CRC) trends. Over the most recent data collection period, new cases of CRC fell 3.0 percent per year in men and 2.2 percent in women, while deaths from CRC fell 3.9 percent per year in men and 3.4 percent in women. Using data from NCI’s SEER Program and the CDC’s National Center for Health Statistics, the researchers used a microsimulation model, MISCAN-Colon, from NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET) consortium to estimate the impact of historical changes in modifiable risk factors (obesity, smoking, and diet), screening, and treatment on past CRC incidence and mortality trends and to project future mortality trends through 2020.

Of the 26 percent reduction in CRC mortality from 1975 to 2000, estimates from MISCAN-Colon modeling indicated that slightly more than half was due to increased screening (especially of older adults using the fecal occult blood test, sigmoidoscopy, and colonoscopy), more than a third was due to improvements in risk factors, and the remaining reduction can be attributed to better treatment. The model predicted a “36 percent overall decline in CRC mortality from 2000 to 2020 if current trends in risk factors, screening, and treatment continue,” and, with accelerated cancer control efforts, “an overall mortality reduction of 50 percent by 2020 is possible,” the authors wrote.

“The continued decline in overall cancer rates documents the success we have had with our aggressive efforts to reduce risk in large populations, to provide for early detection, and to develop new therapies that have been successfully applied in this past decade,” said NCI Director Dr. John E. Niederhuber in a statement. “Yet we cannot be content with this steady reduction in incidence and mortality. We must, in fact, accelerate our efforts to get individualized diagnoses and treatments to all Americans and our belief is that our research efforts and our vision are moving us rapidly in that direction.”

Nilotinib Effective and Safe in Initial Treatment of Chronic Leukemia

Preliminary results from a phase III trial testing nilotinib (Tasigna) against imatinib mesylate (Gleevec) as first-line treatment for chronic-phase chronic myelogenous leukemia (CML) indicate that nilotinib is effective and safe as initial treatment for this disease. The findings were presented December 8 at the 2009 American Society of Hematology annual meeting.

Imatinib has been a model for cancer drug developers because it specifically targets a mutant protein called BCR-ABL. Unfortunately, many patients eventually develop resistance to the drug, and this has led to the development of second-generation targeted therapies such as nilotinib and dasatinib (Sprycel) to treat imatinib-resistant CML.

An international group of researchers, led by Dr. Giuseppe Saglio of the University of Turin in Italy, enrolled 846 patients into the ENESTnd trial. Participants were randomly assigned to receive 300 mg of nilotinib twice daily, 400 mg of nilotinib twice daily, or 400 mg of imatinib once a day.

At 12 months of follow-up, patients receiving either dose of nilotinib had fewer white blood cells expressing the mutant BCR-ABL protein and were more likely to have no leukemia cells detected by laboratory techniques (a complete cytogenetic response) compared with patients receiving imatinib. Patients receiving nilotinib were also less likely to have their disease progress to an advanced stage.

Side effects and rates of drug discontinuation due to side effects were similar between the groups. Nilotinib is known to potentially cause problems with heart rhythm and function, but no severe cardiac side effects have been observed to date in the ENESTnd trial, Dr. Saglio reported. Although the investigators cautioned that the trial is still ongoing, the presenters suggested that nilotinib may eventually replace imatinib as the standard first-line therapy for CML.

Androgen Deprivation Therapy Linked to Cardiovascular Disease, Diabetes

Studies have indicated that older men receiving androgen deprivation therapy (ADT) for the treatment of prostate cancer may be at increased risk of cardiovascular disease and diabetes. A new study suggests that ADT can increase the risk of these side effects among all men undergoing this treatment.

ALSO IN THE JOURNALS

Men undergoing androgen deprivation therapy (ADT) lose muscle and strength and can also develop osteoporosis and other musculoskeletal problems. Findings from a small randomized trial published November 30 in the Journal of Clinical Oncology showed that a 12-week program that combined resistance and aerobic exercise was successful in improving strength, endurance, and quality of life in a group of men receiving ADT. Compared with 28 men receiving usual care, the 29 men in the exercise program increased their lean muscle mass, muscle strength, endurance, and balance, and reported better mental function and less fatigue and nausea. The exercise program had no effect on prostate-specific antigen (PSA) values, indicating “that combined resistance and aerobic exercise can safely be undertaken in patients with prostate cancer” receiving ADT, concluded the authors, led by Dr. Daniel A. Galvão from Edith Cowan University in Australia.

To conduct the study, Dr. Nancy L. Keating of Harvard Medical School and her colleagues performed an observational study of 37,443 men treated with ADT through the Veterans Health Administration. The results appeared online December 7 in the Journal of the National Cancer Institute.

“Although the risks associated with androgen deprivation therapy remain incompletely defined, the potential for harm from this treatment underscores the importance of better understanding its benefits,” the researchers concluded.

Of the 37,443 men, 39 percent received some form of ADT as part of their treatment. The majority of these men underwent treatment with a gonadotropin-releasing hormone (GnRH) agonist, a type of drug that blocks the body’s production of testosterone. Only 0.8 percent underwent bilateral orchiectomy (removal of the testicles), 3.3 percent received oral antiandrogen monotherapy (treatment with a drug that blocks testosterone from binding to prostate cancer cells), and 4.9 percent received a combined androgen blockade (the combination of an antiandrogen monotherapy drug and a GnRH agonist). Patients with pre-existing cardiovascular disease or diabetes were excluded from the analyses, and factors such as cholesterol levels and statin use were taken into account.

Treatment with a GnRH agonist was associated with an increased risk of diabetes, coronary heart disease (CHD), heart attack, sudden cardiac death, and stroke. Combined androgen blockade was associated with an increased risk of CHD, and orchiectomy was associated with an increased risk of CHD and heart attack. Oral antiandrogen monotherapy alone, however, was not associated with an increased risk of any of the studied outcomes.

ADT has been shown to extend survival for men with locally advanced prostate cancer, but its benefits for men with less advanced disease are not clear, explained Dr. Peter C. Albertsen in an accompanying editorial. Despite this lack of clarity, its use in men with less advanced cancer has been increasing.

Antioxidant Supplement May Prevent Return of Precancerous Colorectal Growths

Long-term results from a clinical trial conducted in Italy suggest that an antioxidant compound may play a role in preventing colorectal cancer. In the trial, participants were randomly assigned to take a placebo or a selenium-based antioxidant compound supplement for 5 years following the removal of precancerous growths in the colon called metachronous adenomas. Participants who took the supplement had a statistically significantly reduced risk of adenoma recurrence compared with participants who took the placebo. The results were reported at the American Association for Cancer Research Frontiers in Cancer Prevention Research conference in Houston.

The reduction in risk extended out 13 years after participants had stopped taking the supplement, reported Dr. Luigina Bonelli of the National Institute for Cancer Research in Genoa, Italy, and colleagues.

There were 411 participants in the trial, and data on survival and the results of at least one total colonoscopy were available for 311 patients. The supplement used in the trial, manufactured by Pharma Nord, was a combination of selenomethionine, zinc, vitamin C, and relatively high doses of vitamins A and E.

Overall, participants who took the supplement had a 41 percent reduced risk of developing adenomas over the long term. Adenomas returned in 4.2 percent of patients in the supplement arm compared with 7.2 percent in the placebo arm. The reduction was especially pronounced in patients who had previously had advanced adenomas removed, which for this report included 111 participants in the antioxidant arm and 109 in the placebo arm. Among these participants, those who took the supplement had a nearly 90 percent reduction in the risk of developing advanced adenomas compared with those who took the placebo.

Regarding the clinical implications for these findings, Dr. Bonelli said: “We need further information to better target the treatment.” Participants with prior advanced adenomas did appear to obtain the greatest benefit, she added, and there was little to no toxicity associated with the supplement.

The findings, while promising, have to be interpreted with some caution, noted Dr. Asad Umar, chief of the Gastrointestinal and Other Cancers Research Group in NCI’s Division of Cancer Prevention. “Other data from observational and clinical trials examining the effect of selenium on colorectal cancer have yielded mixed results,” showing either a decreased risk or no effect, he said. Selenium also appeared to have no effect in prevention trials for skin and prostate cancer, he added.