Not Even Best Tx Mitigates Obesity Effect on Breast Cancer

August 27, 2012 — There is now more evidence that obesity can worsen breast cancer outcome. The association occurs even when overweight women receive optimal treatment in a major clinical trial, according to a study published online August 27 in Cancer.

However, the retrospective analysis of 3 clinical trials did not find that the negative association held for all subtypes of breast cancer.

Women who were overweight or obese at the time they were diagnosed with hormone-receptor-positive operable breast cancer had an increased risk for recurrence and death, despite receiving optimal treatment, according to the authors of the analysis.

The results of the analysis of 6885 women clearly establish this deleterious relation, "specifically in hormone receptor-positive, HER2-negative disease, which accounts for about two thirds of all breast cancers," write the authors, led by Joseph A. Sparano, MD, from the Montefiore Einstein Center for Cancer Care, Bronx, New York.

"Many previous studies had shown a relation between obesity and higher recurrence and death rates, but the interpretation was confounded by differences in the treatment patients received, other serious medical problems they may have had, and failing to take into account whether the effect varied by the subtype of breast cancer," Dr. Sparano told Medscape Medical News.

"Our study included only patients who were healthy enough to participate in a clinical trial and had no other serious medical issues, who received state-of-the-art chemotherapy and hormonal therapy, and for whom we had information regarding their breast cancer subtype," he said.

Dr. Sparano and his group analyzed data from 3 National Cancer Institute–sponsored clinical trials coordinated by the Eastern Cooperative Oncology Group. Information on participants' body mass index (BMI) was available for all 3 trials (E1199, E5188, and E3189).

All women had operable breast cancer with axillary lymph node metastases (T1 to T3, N1 or N2) or high-risk lymph-node-negative disease (T2 to T3, N0) but no distant metastases.

Chemotherapy was prescribed according to body weight, and included doxorubicin, cyclophosphamide, plus paclitaxel or docetaxel, and endocrine therapy with tamoxifen or aromatase inhibitors.

Multivariate Analysis Is Key

In the E1199 trial, 4770 patients served as the basis for much of the analysis. Of these patients, 1745 (36.6%) were obese, 1540 (32.3%) were overweight, 1447 (30.3%) had a normal BMI, and 38 (0.8%) were underweight.

Patients who were obese or overweight were older and more likely to be postmenopausal and black. They also had primary tumors that were somewhat larger, were more likely to have breast-conserving surgery, and showed different distribution of nodal metastases (although the median number of involved nodes was similar).

On univariate analysis, obesity was associated with significantly inferior disease-free survival (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.04 to 1.31; P = .0077) and overall survival (HR, 1.23; 95% CI, 1.08 to 1.40; P = .0025).

Obese and overweight patients who had hormone-receptor-positive, HER2-negative, or unknown disease fared worse. For disease-free survival, the hazard ratio was 1.31 (95% CI, 1.12 to 1.53; P = .0009); for overall survival, it was 1.46 (95% CI, 1.21 to 1.77, P = .0001).

After adjustment for other variables, including age, race, menopausal status, tumor size, number of positive axillary lymph nodes, and type of surgery, obesity was found to be linked to inferior disease-free and overall survival only in patients with hormone-receptor-positive, HER2-negative, or unknown disease.

The rate of disease-free survival was 24% lower (HR, 1.24; 95% CI, 1.06 to 1.46; P = 0.0079) and of overall survival was 37% lower (HR, 1.37; 95% CI, 1.13 to 1.67; P = .0015).

However, in the E5188 trial, which included only premenopausal women with estrogen-receptor-positive, axillary lymph-node-positive breast cancer, a similar association was observed. Obese women in this trial had poorer disease-free survival (HR, 1.41; 95% CI, 1.19 to 1.67; P < .0001) and overall survival (HR, 1.51; 95% CI, 1.24 to 1.83; P < .0001).

In the E3189 trial, which included only women with estrogen-receptor-/progesterone-receptor-negative disease, there was no link between obesity and outcome.

The analysis also showed that as BMI increased, so did the risk for poorer outcomes in women with hormone-receptor-positive, HER2-negative, or unknown disease (disease-free survival, P = .0006; overall survival, P = .0007). However, this relationship was not observed in women with triple-negative or HER2-positive disease.

"Doctors can now tell people that being obese at diagnosis of breast cancer is associated with a higher risk of recurrence of the disease for the most common subtype of breast cancer," Dr. Sparano explained.

Will Weight Loss Help?

"What remains to be proven is whether losing weight after a diagnosis will reduce the risk of recurrence, but some preliminary evidence suggests that weight loss after a diagnosis can be helpful," he said.

"I hope this leads to greater attention to diet and exercise after a cancer diagnosis. This may not only contribute to reducing the risk of recurrence, but could lead to other health benefits. Further research is needed to determine what specific factors associated with obesity are driving the risk, and whether these factors can be targeted with drugs commonly used to treat other conditions," he said.

The association between excess weight and poorer outcomes has been shown previously in many studies, noted study coauthor Jennifer A. Ligibel, MD, from the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

"There are...probably about 60 of these studies — the first one was published in the 1970s. So the relationship between obesity and poorer prognosis in early-stage breast cancer has been pretty well established," Dr. Ligibel said.

However, our study provides some new information, she said.

"These data were collected in the setting of clinical trials. Some of the criticism of the earlier studies linking obesity to poor outcomes was that the patients may not have gotten adequate therapy if they were overweight or obese. They may have been less likely to get chemotherapy or they may have had reduced dosages of medicines. The nice thing about this dataset is that all these patients had the same exact therapy, so this study really removes potential bias of treatment-related factors," she noted.

Another unique aspect of this study is that it showed that the patients who seemed to be at the highest risk for recurrence related to weight were patients with hormone-receptor-positive tumors, Dr. Ligibel pointed out. "This is not something that has been seen in other trials."

The next steps will be to find out why excess weight is linked to poorer outcomes and whether this risk can be modified, she said. "A lot of groups are interested in trying to figure out what the biologic connection between weight and poor outcomes in breast cancer could be."

If a woman who is overweight or obese at her breast cancer diagnosis loses weight, will this relationship change? "If we could do something about this, I think this would be a really important finding," she noted.

The study was funded by the Department of Health and Human Services and the National Institutes of Health. Dr. Sparano and Dr. Ligibel have disclosed no relevant financial relationships.

Cancer. Published online August 27, 2012. Abstract

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