Does Obesity Reduce Drug Efficacy in Breast Cancer?

Kristin Jenkins

July 10, 2020

Obesity has been shown to have an impact on the risk of developing breast cancer and on prognosis. A new study suggests that it may also have an effect on treatment.

A high body mass index (BMI) at the time of breast cancer diagnosis could reduce the efficacy of taxane-based adjuvant chemotherapy, worsening survival outcomes, the study suggests.

That study investigated docetaxel (Taxotere), which is a "lipophilic drug, suggesting that fat present in the body could absorb part of the drug before it can reach the tumor," commented lead author Christine Desmedt, PhD, of the Laboratory for Translational Breast Cancer Research, Department of Oncology, Leuven, Belgium.

"These results also make us wonder whether other chemotherapy drugs from the same family, like paclitaxel (Taxol), will show the same effect," she said in a statement.

If follow-up research confirms that the findings are related solely to the pharmacologic characteristics of docetaxel, the results may also apply to its use in other types of cancer, including prostate cancer and lung cancer, she added.

The finding that taxane chemotherapy was less effective in overweight patients "is a provocative observation," commented Harold Burstein, MD, PhD, an oncologist and clinical investigator at Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston, Massachusetts.

"It should be explored in other trials that looked at adding taxanes to standard chemotherapy," he told Medscape Medical News.

Worse Outcomes in Patients With High BMI

The study, published online in the Journal of Clinical Oncology, was a retrospective reanalysis of data from the phase 3 BIG 2-98 trial.

It shows that overweight and obese patients treated with a chemotherapy regimen based on docetaxel had significantly worse disease-free survival (DFS) and overall survival (OS) compared with lean patients treated with the same chemotherapy regimen.

Conversely, for patients treated with an adjuvant chemotherapy regimen that did not include docetaxel, there was no difference in DFS, OS, or in the rates of distant metastases in regard to BMI.

The finding "highlights a differential response to docetaxel according to BMI, which calls for a body composition–based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer," say the researchers. "These results now must be confirmed in additional series."

The findings call into question results from earlier randomized clinical trials that did not evaluate the efficacy of most cancer drugs on the basis of patient adiposity, the researchers say.

Desmedt emphasized that more research is needed "before changes in treatment can be implemented."

Experts approached by Medscape Medical News for comment agreed.

"It is important to remember that breast cancer patients needing chemotherapy should still receive the usual chemotherapy regimens, including taxanes, regardless of their weight or habitus," commented Burstein, who is also professor of medicine at Harvard University.

These data highlight a persistent disparity in breast cancer outcomes, he told Medscape Medical News. Previous studies have shown that overweight patients often have less favorable outcomes. "There are many contributors to poor health outcomes in people with higher BMI, including concurrent health issues such as diabetes and/or hypertension, and unfortunately, the clear link between socioeconomic status and obesity," he added.

Megan Kruse, MD, of the Department of Hematology and Medical Oncology at the Cleveland Clinic, in Ohio, said she "would not make changes in my treatment recommendations based on this study alone."

Kruse was surprised that when the analysis was restricted to patients who received a relative dose intensity ≥85% for docetaxel, the same reduced rates of DFS and OS were seen as in patients with a high BMI.

"One may have suspected, based on the overall results, that patients with inferior survival outcomes actually received less chemotherapy due to [the] tendency to cap doses of chemotherapy in patients with high BMIs," she explained.

"Since this analysis keeps dose intensity in mind, the association between BMI and survival outcomes is stronger in my mind. It does not, however, rule out that there are other confounding factors," Kruse told Medscape Medical News.

Whether the results can be replicated in other retrospective clinical trials remains to be seen, she commented. Noting that the investigators plan to develop a prospective pharmacokinetics study across the BMI spectrum, Kruse added: "This will be of great interest as we plan curative-intent chemotherapy trials moving forward."

Study Details

For the current study, the investigators analyzed data from all 2887 breast cancer patients enrolled in the adjuvant BIG 2-98 trial. They compared the survival outcomes of those who received docetaxel-based chemotherapy with those who received non-docetaxel-based chemotherapy in relation to their BMI. Patients with a BMI of 18.5 to 25 kg/m were classified as lean; patients with a BMI of 25 to <30 were classified as overweight; and those with a BMI ≥30 were classified as obese.

The researchers also assessed a second-order interaction on the basis of treatment, BMI, and estrogen receptor (ER) status.

The results showed that in the overweight women compared to lean women, the adjusted hazard ratios (HRs) for DFS and OS were 1.12 (95% CI, 98 – 1.50; P = .21) and 1.27 (95% CI,101 – 1.60; P = .04), respectively. For obese vs lean patients, the HRs for DFS and OS were 1.32 (95% CI, 108 – 162; P = .007) and 1.63 (95% CI, 1.27 – 2.09; P < .001), respectively.

The survival outcomes were similar when only those patients who received a relative dose intensity ≥85% for docetaxel were considered. However, when ER-negative and ER-positive tumors were considered separately, they found evidence of a joint modifying role of BMI and ER status on treatment effect for DFS (adjusted P =.06) and OS (adjusted P = .04).

"[I]t appears that the benefit for docetaxel-based versus non-docetaxel–based treatment could be limited to lean and overweight patients with ER-positive tumors and, possibly, to lean patients with ER-negative tumors…," Desmedt and colleagues comment.

It may even be possible that docetaxel-based treatment could be detrimental for overweight patients with ER-negative tumors, they note, but warn that these results should be interpreted with caution.

The investigators note that worldwide, the proportion of women with increased adiposity has been increasing for decades. In Europe, it is estimated that more than 50% of women are overweight and obese. In the United States, almost 64% of women have a BMI >25 kg/mg2.

Previous studies have shown that in postmenopausal women, a high BMI is associated with a higher risk of developing breast cancer and that in those who do, the prognosis is worse. In addition, a recent study demonstrated that increased adiposity can raise the risk for breast cancer in postmenopausal women whose BMI is in the normal range.

The study was funded in part by Fondation Cancer Luxemburg and Associazione Italiana per la Ricerca sul Cancro AIRC. Desmedt has disclosed no relevant financial relationships. A number of study coauthors reported relationships with industry.

J Clin Oncol. Published online July 2, 2020. Abstract

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