Bevacizumab May Increase Blood Clot Risk

Bevacizumab (Avastin), the first FDA-approved drug designed to inhibit the growth of new blood vessels to tumors, significantly increases the risk of venous thromboembolism (VTE) in cancer patients, according to a meta-analysis in the November 19 Journal of the American Medical Association.

Pooled results from nearly 8,000 patients with a variety of advanced solid tumors in 15 randomized trials published since 2003 showed that patients taking bevacizumab were
33 percent more likely to develop VTE than those who did not. Incidence among those taking bevacizumab was 11.9 percent for VTE of all grades, and 6.3 percent for high-grade VTE. Those taking the drug had a 38 percent greater risk of developing high-grade VTE.

A dosage as small as 2.5 mg/kg per week was enough to pose a risk, which the authors believe "suggests that the so-called low dose of bevacizumab may already be reaching the saturation level to induce thrombosis." Based on the greater risk found in patients with mesothelioma and aerodigestive malignancies such as non-small cell lung cancer, the authors advised that patients with these conditions receive concurrent prevention for VTE.

"It may be appropriate to add a black box warning [to the package insert currently required by the FDA]," noted the study authors, led by Dr. Shobha Rani Nalluri and colleagues at Stony Brook University. Other angiogenesis inhibitors such as thalidomide and lenalidomide have also been shown to increase risk of VTE, and the authors warned that combining them with bevacizumab could compound the increased risk.

Number of Adult U.S. Smokers Drops, But So Do Quit Attempts

A new report released by the CDC shows that, for the first time in 3 years, the prevalence of cigarette smoking among adults in the United States fell significantly, from 20.8 percent in 2006 to 19.8 percent in 2007. More than three in four adult smokers reported smoking every day, while about one in four reported smoking only on some days. The article appeared in the November 14 Morbidity and Mortality Weekly Report.

Self-reported data were collected through the National Health Interview Survey (NHIS) from more than 23,000 randomly chosen people aged 18 years and over who completed in-person interviews.

Despite overall progress, only two groups of adults showed significant declines in smoking prevalence: blacks (from 23.0 percent to 19.8 percent) and people over the age of 65 (from 10.2 percent to 8.3 percent). Additionally, the percent of "everyday smokers" who attempted to quit in the previous 12 months was lower in 2007 than in 1993; those aged 18 to 24 years were more likely to make a quit attempt than older adults.

The authors suggest that the "lack of funding for comprehensive state tobacco-control programs" is a barrier to achieving greater progress in encouraging adults to quit. They also note that "Clinicians and health-care delivery systems need to consistently identify and document tobacco use status, treat every tobacco user seen in the health-care setting, and promote patients' use of quitlines," as part of a comprehensive tobacco control program. Quitlines are now available nationwide through the toll-free access number 1-800-QUIT-NOW.

PAX2 Protein Mediates Effect of Tamoxifen in Breast Cancer

The protein PAX2 plays an important role in the effectiveness of tamoxifen for the treatment of breast cancer. The presence of PAX2 in tumor cells blocks production of the protein ERBB2 (also called HER2), which fuels tumor growth, and a lack of PAX2 decreases the effectiveness of tamoxifen, British researchers reported online November 12 in Nature.

In experiments using breast cancer cell lines, the researchers identified several new DNA binding sites for the estrogen receptor (ER), including one in the ERBB2 gene. The researchers found that when exposed to tamoxifen, PAX2 forms a complex with the ER and binds to ERBB2, blocking the gene's expression. In normal cells, treatment with estrogen or tamoxifen therefore reduced the levels of ERBB2. But when the researchers blocked the expression of PAX2, the amount of ERBB2 in the cells increased, which subsequently caused an increase in cell growth.

Another protein called AIB-1, which is known to promote tumor formation, was found to bind to the same ERBB2 gene site as the ER-PAX2 complex; AIB-1 and PAX2 appear to compete for this binding site. When PAX2 protein levels fell, AIB-1 preferentially bound to the site, reversing the effects of tamoxifen. In a breast cancer cell line that had reduced levels of PAX2 and was resistant to tamoxifen, the investigators were able to restore sensitivity to the drug by introducing PAX2 into the cells.

The researchers, led by Dr. Antoni Hurtado of Cancer Research UK, confirmed their findings in 109 tissue samples taken from primary breast tumors (from patients who had all been treated with tamoxifen). Patients with PAX2-positive tumors had a significantly improved recurrence-free interval compared to patients with PAX2-negative tumors.

In a press conference accompanying the release of the paper, the researchers explained their hope that this work will eventually be used to help identify women who would not benefit from tamoxifen and who would require an alternate therapy such as an aromatase inhibitor.

Burden of Cervical Cancer Prior to HPV Vaccine Assessed

An estimated 25,000 cancers associated with the human papillomavirus (HPV) occurred annually in 38 states and the District of Columbia between 1998 and 2003, new research suggests. The study is one of 22 new reports coordinated by the CDC to assess the burden of HPV-associated cancers in the United States prior to the introduction of the HPV vaccine Gardasil. The vaccine protects against the two HPV types responsible for 70 percent of cervical cancers and the two types that cause 90 percent of genital warts.

The studies appear in the November 15 supplement of Cancer.

Cervical cancer is the most common HPV-associated cancer, with nearly 11,000 cases in the United States per year. But HPV, which includes more than 100 different types, is also associated with cancers of the vulva, vagina, penis, anus, oral cavity, and oropharynx. (FDA recently expanded its approval of Gardasil to include prevention of vaginal and vulvar cancers.)

The estimates of HPV-associated cancers in the period before the HPV vaccine will give researchers baseline data for measuring the impact of the vaccine and cervical-cancer screening programs in reducing the incidence of cervical cancer and other HPV-associated cancers and precancers, according to Dr. Mona Saraiya of the CDC, who coordinated the studies.

Dozens of investigators authored the 22 articles for project ABHACUS (Assessing the Burden of Human Papillomavirus-Associated Cancers). A range of HPV-cancer related issues, including racial disparities, behavioral risk factors, and cancer mortality, are addressed in the studies.

The results, for instance, confirm recent reports showing higher rates of cervical cancer among black and Hispanic women and women in parts of the South. The mortality data on cervical cancer, one study concludes, are a reminder of the importance of screening and prevention programs, because during each year of the study more than 4,000 women died from this largely preventable disease.