Docetaxel regimen confers shorter DFS, OS for women with breast cancer and elevated BMI
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Women with breast cancer and overweight or obesity had shorter DFS and OS than their lean counterparts after treatment with a docetaxel-based chemotherapy regimen, according to study results published in Journal of Clinical Oncology.
Additionally, researchers observed a joint modifying role of BMI and ER status on treatment effect.
“The proportion of women with increased adiposity, reflected by an elevated BMI, has been increasing in most parts of the world during the past decades, with 64% of women in the United States being either overweight or obese, according to the latest estimates,” Christine Desmedt, PhD, researcher in the Laboratory for Translational Breast Cancer Research at KU Leuven in Belgium, and colleagues wrote. “It is known that differences in the pharmacokinetic/pharmacodynamic activities of drugs, and especially lipophilic drugs, can exist between lean and obese patients. Nevertheless, and despite the high frequency of [patients with overweight and obesity and cancer], the efficacy of most of the anticancer drugs has not yet been thoroughly and systemically evaluated according to patient adiposity.”
In the retrospective analysis of the adjuvant BIG 2-98 trial, investigators sought to assess potential differences in efficacy between docetaxel-based and nondocetaxel-based chemotherapy regimens according to baseline BMI among 2,887 women aged younger than 71 years with early-stage breast cancer.
Researchers categorized 47.4% of women as lean (BMI, 18.5 kg/m2 to < 25 kg/ m2), 33.5% as overweight (BMI, 25 kg/m2 to < 30 kg/m2) and 19.1% as obese (BMI, 30 kg/m2). They excluded 48 women deemed underweight from the study.
DFS served as the primary endpoint. OS served as the secondary endpoint.
Researchers observed no differences in DFS or OS according to BMI among women in the nondocetaxel cohort.
However, they observed shorter DFS and OS with increasing BMI category among women in the docetaxel cohort. For women with overweight vs. lean women, results showed adjusted HRs of 1.12 (95% CI, 0.98-1.5) for DFS and 1.27 (95% CI, 1.01-1.6) for OS. For women with obesity vs. lean women, adjusted HRs were 1.32 (95% CI, 1.08-1.62) for DFS and 1.63 (95% CI, 1.27-2.09) for OS.
Researchers also assessed a second-order interaction among treatment, BMI and ER status. They observed similar results when considering ER-negative and ER-positive tumors separately and when only considering patients treated with a docetaxel relative dose-intensity of 85% or greater. The analysis showed evidence of joint modifying role of ER status and BMI on treatment effect for DFS, which did not reach statistical significance after adjustment for covariables, and for OS (adjusted P = .04).
“This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition-based reevaluation of the risk-benefit ratio of the use of taxanes in breast cancer,” the researchers wrote. “These results must now be confirmed in additional series.”
Perspective
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Debu Tripathy, MD
The interaction of BMI and outcomes in breast cancer has been explored both as a risk factor and as a modifier of disease, with both outcomes being elevated with higher BMI, particularly among postmenopausal women and those with hormone receptor-positive disease. The BIG 2-98 trial, a four-arm study comparing docetaxel and nondocetaxel adjuvant regimens, presents an opportunity to analyze a potential pharmacologic interaction focusing on docetaxel exposure, which is affected by BMI.
As a lipophilic drug, docetaxel exhibits a higher volume of distribution and a lower area under the curve with higher BMI. Researchers tested this hypothesis in a retrospective and post hoc analysis, which showed greater adjusted OS in the lean group compared with overweight/obese groups in the docetaxel-containing arms, but not among the other women. There also was an interaction of this effect with ER status, with docetaxel curiously appearing to be detrimental in ER-negative and obese cases. Of note, the primary outcome measures of this trial showed no differences between arms in the final 10-year follow-up analysis. Of course, this study did not adjust for multiple comparisons because it was an exploratory/hypothesis-generating exercise.
The trend toward precision medicine should include optimization of drug dosing and scheduling, but there are several challenges, the primary of which is the large sample size that would be required for results definitive enough to affect practice. Additionally, serum levels may not be reflective of tumor cell exposure, as drug levels could be different in the tumor microenvironment and micrometastatic sites. Noninvasive ways to measure drug levels directly, or indirectly by drug effects that are built to large scale clinical trials, could greatly accelerate this important mission.
The University of Texas MD Anderson Cancer Center
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