National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 3, 2009 • Volume 6 / Number 21

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Cancer Research Highlights

Even With Very Small Breast Tumors, Studies Find HER2 Status Matters

Two retrospective studies have found that women with HER2-positive breast tumors (that is, tumors that produce too much of the HER2 protein) that are 1 centimeter or smaller had a higher risk of their disease returning within 5 years than women with similarly small HER2-negative tumors. The findings, published online November 2 in the Journal of Clinical Oncology, may shed some light on an area of clinical uncertainty: Whether women with small, HER2-positive tumors should receive post-surgical, or adjuvant, treatment with the targeted agent trastuzumab (Herceptin). Few patients with these small tumors took part in the large clinical trials that established adjuvant trastuzumab in combination with chemotherapy as a standard treatment for women with HER2-positive, early stage breast cancer.

The studies included women treated at the University of Texas M.D. Anderson Cancer Center and the European Institute of Oncology in Milan, respectively. In each study, the researchers reviewed the medical records of women with these small tumors treated at their respective institutions. Although the researchers excluded patients who had received adjuvant trastuzumab, some patients included in the analyses had received other adjuvant treatments, particularly those in the Milan group. Both studies found an approximately 2.5-fold higher risk of recurrence in women with small, HER2-positive tumors than in women with small, HER2-negative tumors, and the M.D. Anderson study showed a more than 5-fold increase in risk of developing metastatic disease.

The findings echo those of two earlier studies, noted Drs. Harold Burstein and Eric Winer of Dana-Farber Cancer Institute, in an accompanying editorial. And the findings add to the mounting evidence that, while women with small HER2-positive breast tumors still have a good prognosis, they may benefit from adjuvant treatment with chemotherapy and trastuzumab.

Given the lack of data from randomized clinical trials on the effect of trastuzumab on outcomes in women with small, HER2-positive tumors, Drs. Burstein and Winer caution that “treatment options should still be tailored to the underlying risk of recurrence.” This is particularly true for women with the smallest of these tumors, 5 mm or less, for whom the recurrence risk is “still uncharacterized.” In these patients “it seems hard to justify the rare but potentially serious risks of adjuvant chemotherapy and trastuzumab,” they wrote. In women for whom adjuvant treatment is being considered, they concluded, “Given the potency of trastuzumab-chemotherapy combinations, it seems likely that abbreviated courses of treatment might suffice.”

Risk of Contralateral Breast Cancer Estimated for BRCA Families

Women with inherited forms of breast cancer are at an increased risk of developing a second cancer later in life, often in the opposite (contralateral) breast. German researchers have now estimated the risk of contralateral breast cancer for these women and identified two factors that are associated with risk: a woman’s age when she was first diagnosed with breast cancer, and whether she has inherited a mutation in the BRCA1 or BRCA2 genes. The findings were reported online in the October 26 Journal of Clinical Oncology.

In a retrospective analysis of 2,020 German women with known or suspected BRCA1/2 mutations, the risk of contralateral breast cancer was highest among women with mutations in the BRCA1 gene who were initially diagnosed before the age of 40. For this group, the cumulative contralateral breast cancer risk after 25 years was nearly 63 percent, the researchers found.

Older age at the diagnosis of first breast cancer was associated with a smaller increase in risk. For those with BRCA1 mutations whose first cancer was diagnosed after age 50, the cumulative contralateral breast cancer risk after 25 years was 19.6 percent, and for their BRCA2 mutation-carrying counterparts, it was 16.7 percent, approximately the same as the risk among women from the general population.

For all women in the study, however, the overall risk of contralateral breast cancer at 25 years after a breast cancer diagnosis was nearly 50 percent and continued to rise thereafter. Though the risk estimates are lower than reported previously for this group, the findings suggest that “contralateral breast cancer risk is relevant even a long time after diagnosis of first breast cancer,” the researchers wrote.

Many high-risk women are seeking genetic counseling and BRCA1/2 mutation testing prior to diagnosis or at the time of diagnosis, in the hope that knowledge of their mutation status will improve their medical care. Although the findings need to be confirmed, they could potentially inform decisions about treatment, the authors said. This study may be the first to show that patients from families with BRCA1 mutations face a significantly higher risk of contralateral breast cancer than patients with BRCA2 mutations.

In an accompanying editorial, Drs. Judy Garber and Mehra Golshan of Brigham and Women’s Hospital said that for high-risk women diagnosed at a young age, the estimates “provide powerful figures that should compel the breast cancer care team to consider the issue of management of the opposite breast.” Equally important, the risk of contralateral breast cancer is “less compelling” for BRCA1/2 carriers who are older (i.e., over age 50) at diagnosis, they wrote.

Lower Total Blood Cholesterol Levels Are Not Linked to Higher Cancer Risk

A study published November 2 in Cancer Epidemiology, Biomarkers & Prevention has yielded new insight into the relationship between cholesterol and cancer. Previous studies have suggested that lower total blood cholesterol levels are associated with increased cancer incidence and mortality, but it has been unclear whether these studies observed a cause-and-effect association or if lower cholesterol can in some cases be a product of metabolic changes caused by very early cancer.

To better understand the associations between blood cholesterol and cancer risk, researchers from NCI’s Division of Cancer Epidemiology and Genetics examined prospective data from 29,093 male smokers who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Total blood cholesterol levels and HDL (so-called good cholesterol) levels were measured at the beginning of the study and 3 years later. The participants were followed for 18 years, during which time 7,545 cases of cancer occurred.

The researchers observed an overall association between higher blood cholesterol and decreased overall cancer incidence; however, when cancer cases diagnosed during the first 9 years of the study were excluded, this association disappeared, indicating that the association is not causative and was more likely due to existing early cancers in many cases. “Our data come down very strongly in support of low cholesterol not being a risk factor for cancer,” said Dr. Demetrius Albanes, senior author of the study.

The researchers also saw an association between higher levels of HDL and a lower risk of cancer overall. Unlike for total cholesterol, this association was slightly stronger when cases diagnosed through the first 9 years of follow-up were excluded. “We saw an 11 percent lower risk for all cancers over the entire observation period for the highest HDL levels,” said Dr. Albanes. “That became a 15 percent lower risk after excluding cases diagnosed during the first 9 and even 12 years of follow-up. If these new findings are confirmed by other researchers, higher HDL levels may be beneficial not only for preventing cardiovascular disease but also for inhibiting cancer,” he concluded.

Tests for Catching Cervical Precancers Show Equivalent Accuracy

The two most common methods for identifying cervical cancer precursors are equally accurate, according to the results of the largest randomized study ever comparing the two tests. The study found that liquid-based cytology, now the most commonly used approach for cervical cancer screening in the United States, was not superior to the conventional Pap test for the detection of abnormal cells that can precede cancer development. The results were published in the October 28 Journal of the American Medical Association.

ALSO IN THE JOURNALS

A new study led by Dr. Robin Yabroff of NCI’s Division of Cancer Control and Population Sciences indicates that the practice of cervical cancer screening using Pap tests varies by physician specialty. Published today in the Annals of Internal Medicine, the study involved a survey of more than 1,200 clinicians. While the large majority of physicians offered Pap tests to their eligible patients, the frequency of Pap tests recommended by physicians was often inconsistent with recommended national guidelines.

The trial included approximately 90,000 women aged 30 to 60 who were screened at nearly 250 medical practices in the Netherlands that participate in the Dutch cervical cancer screening program. The medical practices were randomly assigned to use one of the two tests; physicians who followed up on women with positive test results were blinded to the type of test used and the test result. Both tests had nearly equivalent rates of detecting precancerous lesions—called cervical intraepithelial neoplasia—and had equivalent positive predictive value, which is the likelihood of precancerous cells being present following a positive test.

The liquid-based test is more expensive than a conventional Pap test, wrote the study’s lead author, Dr. Albertus G. Siebers, and colleagues. “But in equivocal cases it has the possibility of concomitant testing on the residual material for the presence of [HPV DNA] or other molecular cell cycle-related biomarkers,” the authors noted.

The trial results “are unlikely to have a major effect on cytology screening in the United States,” wrote Dr. Mark Schiffman of NCI’s Division of Cancer Epidemiology and Genetics and Dr. Diane Solomon of NCI’s Division of Cancer Prevention in an accompanying editorial. Liquid-based cytology is preferred by most laboratories because the specimen is easier and quicker to scan under the microscope. And, as the study found, there are fewer unsatisfactory specimens with liquid-based cytology.

“Cytology is now competing against primary and other secondary cervical cancer preventive strategies,” they wrote, including the HPV vaccine and HPV DNA testing. “Even though an increasingly powerful set of prevention tools is available, no combination of vaccination, cytology, HPV testing, colposcopy, and novel methods will be suitable for all settings.”

Nicotine Patch and Lozenge Combination Helps Smokers Quit for Longer

In a comparative effectiveness study testing five different smoking-cessation aids, researchers found that a combination of the nicotine patch plus the nicotine lozenge was most effective at increasing smoking abstinence. The results appeared yesterday in the Archives of General Psychiatry.

Clinical trials have shown that a variety of smoking cessation aids, including nicotine replacement products (such as the nicotine patch) and non-nicotine medications (such as bupropion), can help people quit smoking. However, the lack of research directly comparing the efficacy of these products has made it difficult for smokers to choose and doctors to recommend one aid over another.

The trial, led by Dr. Megan Piper of the Center for Tobacco Research and Intervention at the University of Wisconsin, enrolled 1,504 smokers and randomly assigned them to one of 10 treatment groups: the nicotine lozenge, nicotine patch, a combination of the nicotine lozenge and patch, bupropion, bupropion plus the lozenge, or a placebo for one of the five active treatments. All patients, including those in the placebo groups, received intensive smoking-cessation counseling.

Although all five active regimens helped people immediately quit smoking compared with their placebo controls, only three—the nicotine patch and the two combination regimens—increased abstinence at 1 week after quitting, and only the patch plus the lozenge was effective relative to its placebo 6 months after quitting. People who used this combination during the trial were more than twice as likely to remain abstinent at 6 months than those who received the placebo.

While the patch-plus-lozenge combination was the most effective therapy compared with its placebo, the authors caution that when compared head-to-head (instead of against their placebo controls), the five active cessation treatments all provided a relatively similar benefit for sustaining abstinence 6 months after quitting. In addition, the placebo groups all achieved an unusually high rate of success in quitting, perhaps due to the intensive counseling provided.

Personalized Phone Counseling Helps Teens Quit Smoking

In the largest clinical trial of its kind, researchers from the Fred Hutchinson Cancer Research Center have shown that telephone-based counseling that includes motivational interviewing and cognitive behavioral approaches helps older teens quit smoking. The trial is the first to demonstrate a prolonged effect—defined in the trial as lasting at least 6 months—on smoking cessation among adolescent smokers. This finding is consistent with the recommendation in the U.S. Public Health Service’s 2008 Clinical Practice Guidelines, which indicate that counseling can be an effective treatment to help youth quit smoking.

“These results are critically important for supporting and stimulating our nation’s search to find successful ways to help reduce smoking by teens and young adults,” said the study’s lead investigator, Dr. Arthur V. Peterson, Jr., in a press release. The study was published online October 12 in the Journal of the National Cancer Institute (JNCI).

The NCI-funded trial enrolled 2,151 older teenage smokers (identified through surveys) from 50 high schools in Washington State. Half of the schools were randomly assigned to receive confidential counseling, while student participants in the remaining 25 schools received no counseling. A large group of nonsmokers was also enrolled in the trial to mask participants’ smoking status.

Nearly two-thirds of the participants in the counseling group took part in at least one counseling call. The counseling, the research team explained, centered on two techniques: motivational interviewing, which helps give participants the motivation and confidence to quit, and cognitive behavioral skills training, which provides the tools for learning how to quit.

Among all smokers, 6-month quit rates were higher in participants who received the counseling compared with those who did not (21.8 percent versus 17.7 percent). Daily smokers who received the counseling were nearly twice as likely to report 6-month abstinence rates compared with daily smokers who did not receive counseling (10.1 percent versus 5.9 percent). The counseling intervention effects differed for male and female daily smokers. Male daily smokers who received counseling were more likely than male daily smokers who did not receive the intervention to sustain 6-month abstinence rates. However, this was not true for female adolescent smokers.
 
In an accompanying editorial in JNCI, Dr. Scott Leischow and Eva Matthews of the Arizona Cancer Center praised the trial and called for “encouraging in the strongest possible way” state tobacco quitlines “to implement the intervention…to the extent feasible.”

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