LACK OF SLEEP LINKED TO MORE AGGRESSIVE BREAST CANCER

For the first time, lack of sleep has been associated with more aggressive breast cancers, according tofindings published in the August issue of Breast Cancer Research and Treatment.
The study was conducted in 101 women with early-stage estrogen-receptor-positive breast cancer who were assessed with the Oncotype DX test, which guides treatment in early-stage breast cancer by predicting the likelihood of recurrence.
The worst scores on the recurrence probability test were found in women who reported having the least sleep at night. Specifically, having fewer than 7 hours of sleep a night during the 2 years before the diagnosis was associated with a greater risk for recurrence.
However, this association between less sleep and breast cancers that are more aggressive and more likely to recur was strong only in postmenopausal women (P = .0011), not in premenopausal women (P = .80).
"This is the first study to suggest that women who routinely sleep fewer hours may develop more aggressive breast cancers than women who sleep longer hours," said lead author Cheryl Thompson, PhD, in a press statement. She and her coauthor, Li Li, MD, PhD, are from Case Western Reserve University in Cleveland, Ohio.
The study findings are limited by the "relatively modest sample size," the authors acknowledge.
Nevertheless, the study adds to the literature on sleep duration and breast cancer. Four previous studies, all of which assessed breast cancer risk and did not specifically look at breast cancer aggressiveness, have had "mixed results," according to the authors. Three of these have suggested that sleep can reduce the risk for breast cancer and 1 found no association at all.
Medscape Medical News asked Simone P. Pinheiro, ScD, from the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), for her opinion on this study.
Before joining the FDA, Dr. Pinheiro was the lead author of the large prospective study that "did not find convincing evidence to support an association between habitual duration of sleep and subsequent development of breast cancer" (Cancer Res. 2006;66:5521-5525). However, information on habitual sleep duration was obtained prior to the development of breast cancer in that study, she emphasized.
The study by Drs. Thompson and Li "suggests" a "significant inverse correlation" between sleep duration and breast cancer aggressiveness among women diagnosed with breast cancer, Dr. Pinheiro noted.

"These results could also reflect the effect of subclinical (not yet diagnosed) breast cancer on sleep duration," she said in an email. In other words, a woman's nascent breast cancer might have caused sleep disturbance, she explained.
So, is lack of sleep a new risk factor for aggressive breast cancers?
The authors believe it might be. "Our data suggest that lack of sufficient sleep may cause biologically more aggressive tumors," they write. But they note that "further work will need to be done to more thoroughly characterize the biology underlying this epidemiological association."
Less Sleep and Recurrence Scores Defined 
All of the study participants are enrolled in a larger 412-patient case–control breast cancer study. As such, they were recruited at diagnosis and asked about lifestyle matters, including average sleep duration in the previous 2 years. Many of the breast cancer patients in the study underwent Oncotype DX testing.
The authors designated 3 levels of nightly sleep: 6 hours or less, 6 to 7 hours, and 7 or more hours.
Using previously published data on the recurrence probability test, they determined that scores below 18 predict a low risk for recurrence, scores of 18 to 30 predict an intermediate risk, and scores of 31 or higher predict a high risk.
Overall, less sleep was found to be correlated with a higher score. Risk for recurrence was intermediate in patients who slept 6 hours or less (mean recurrence score, 27.8) or 6 to 7 hours (mean recurrence score, 18.0) and low for patients who slept 7 or more hours (mean recurrence score, 16.4).
Thus, getting an average of less than 7 hours of sleep a night was associated with an intermediate risk and getting 7 or more hours was associated a with low risk. However, this finding was only statistically significant in the subset of postmenopausal women.
The lack of a strong association in premenopausal women is explainable, say the authors.
"It is well known that there are different mechanisms underlying premenopausal and postmenopausal breast cancers," they explain. "Our data suggest that sleep may affect carcinogenic pathway(s) specifically involved in the development of postmenopausal breast cancer, but not premenopausal cancer."
The positive findings in postmenopausal women remained statistically significant after adjustment for possible confounders, including age, physical activity, smoking status, and body mass index.
"Effective intervention to increase duration of sleep and improve quality of sleep could be an underappreciated avenue for reducing the risk of developing more aggressive breast cancers and recurrence," said Dr. Li in a press statement.
This study adds to the literature on lifestyle factors that can affect breast cancer and its related risk. These studied factors are increasingly diverse and include night-shift work, light in the bedroom, and more obvious variables such as obesity.

RISK OF HEART FAILURE WITH TRASTUZUMAB

Clinical trials have already shown that breast cancer patients who receive treatment with anthracyclines and trastuzumab (Herceptin, Genentech/Roche) are at increased risk for heart failure and cardiomyopathy.

Now, an observational cohort study conducted in a "real-world" setting suggests that this risk might be much higher.

The study, led by Erin J. Aiello Bowles, MPH, from the Group Health Research Institute in Seattle, Washington, was published online August 31 in the Journal of the National Cancer Institute.

This study adds to the understanding of the association between trastuzumab and heart failure, writes Ann M. Geiger, MPH, PhD, from Wake Forest School of Medicine in Winston-Salem, North Carolina, in an accompanying editorial. In this study, the median follow-up time is a year longer than that of previous clinical trials, and the incidence of heart failure appears to increase with longer follow-up.

"These results provide additional evidence that heightened risk of heart failure is a long-term effect of previous trastuzumab use rather than a short-term increase associated with current or recent use," she writes.

"This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials," Dr. Geiger notes.

Real-World Community Setting

"Clinical trials have shown that anthracyclines and trastuzumab are not only effective at improving survival, but are also associated with an increased risk of heart failure. However, these studies typically exclude older women and women with chronic diseases, so we really don't know what the real-world estimate of heart failure risk associated with these drugs is," Bowles told Medscape Medical News.

"Our goal was to describe not only the population of women with breast cancer who do and who do not receive these drugs, but also to estimate the risk of heart failure associated with these drugs in a real-world community practice," she said.

In this population-based retrospective study, Bowles and her colleagues from the Cancer Research Network analyzed data from 12,500 women diagnosed with incident invasive breast cancer from January 1, 1999 to December 31, 2007.

The women were patients for at least 12 months before their diagnosis at 6 health maintenance organizations in different areas of the United States.

The risk for heart failure and cardiomyopathy with anthracycline alone, trastuzumab alone, anthracycline followed by trastuzumab, and other chemotherapy was compared with no chemotherapy.

Among the women in the analysis, 5807 (46.5%) received no chemotherapy, 3697 (29.6%) received anthracycline-based chemotherapy alone, 112 (0.9%) received trastuzumab-based therapy without anthracycline, 442 (3.5%) received anthracycline plus trastuzumab, and 2442 (19.5%) received other chemotherapy.

The mean age of the population was 60 years (range, 22 to 99 years), 85.8% were white, and the median follow-up time was 4.4 years (interquartile range, 2.6 to 6.9 years).

The researchers found that women who received anthracycline or anthracycline plus trastuzumab were younger. Of the women who received anthracycline alone, 86.4% were younger than 65 years, as were 89.6% of the women who received both anthracycline and trastuzumab.

Younger women were also diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy than women who received other chemotherapy or no chemotherapy.

The small proportion of women who received trastuzumab without anthracycline were older (more than 65 years) and had more comorbidities.

The researchers also found that the risk for heart failure was higher among women who received anthracycline alone than among those who received no chemotherapy, and that the magnitude of that risk was similar to what has been reported in clinical trials.

For that population, the risk for heart failure or cardiomyopathy was higher than among those who received no anthracycline (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11 to 1.76). The increased risk was similar to that seen with other chemotherapy (adjusted HR, 1.49; 95% CI, 1.25 to 1.77).

However, the risk for heart failure associated with trastuzumab following anthracycline was much higher than has been reported in clinical trials (adjusted HR, 4.12; 95% CI, 2.30 to 7.42)

Overall, for anthracycline, the cumulative incidence at 5 years was 4.3%. But for the women who received anthracycline and then trastuzumab, the 5-year cumulative incidence was 20.1%.

"It is a lot bigger than what has been reported from the clinical trials," said Bowles. "But keep in mind that this is a much broader population that we looked at. We have a lot more older women who are already at an increased risk for heart failure, so that is going to drive up our results."

Bowles said this study can be generalized to other women, whereas the results from clinical trials are only applicable to the populations in those trials.

"We know clinical trials are very well done, they're very controlled and have great internal validity because they control any kind of confounding for age and other characteristics, but their generalizability to people who many not be included in those trials is really limited," she explained.

"Our results are much more generalizable, but at the expense of the internal validity. But we did our best to control for age, comorbidities, and any other things that we thought would affect the results. I think our study provides a nice complement to clinical trials," she said.

Long-term Follow-up

In her editorial, Dr. Geiger notes that the results of this study add to the evidence that anthracycline and trastuzumab (in particular) increases the risk for heart failure or cardiomyopathy as a long-term effect.

Dr. Geiger concludes that there is a need to monitor women who have received trastuzumab on an ongoing basis, and calls for prudence in using trastuzumab outside of clinical trials.

She also highlights a role for observational studies. This study "illustrates how observational studies complement randomized controlled trials by capturing valuable information about treatment outcomes for the vast majority of women who are unable to access a trial."