Christine Desmedt, PhD
A retrospective analysis from the BIG 2-98 trial reported in the Journal of Clinical Oncology by Christine Desmedt, PhD, of the Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Belgium, and colleagues showed poorer disease-free and overall survival with increasing baseline body mass index (BMI) for women who received adjuvant docetaxel-based chemotherapy, but not among those receiving non–taxane-containing chemotherapy.1
As stated by the investigators: “Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non–docetaxel-based chemotherapy in patients with breast cancer according to their baseline…BMI.”
In the BIG 2-98 trial, 2,887 women enrolled between June 1998 and June 2001 were randomly assigned to one of four treatment groups in a 1:1:2:2 ratio: (1) sequential control, consisting of four cycles of doxorubicin at 75 mg/m2 and three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF); (2) concurrent control, consisting of four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2 and three cycles of CMF; (3) sequential docetaxel, consisting of three cycles of doxorubicin at 75 mg/m2and three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF; and (4) concurrent docetaxel, consisting of four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2 and three cycles of CMF. Disease-free survival was the primary endpoint, and overall survival was the secondary endpoint.
BMI (kg/m2) was categorized as 18.5 to < 25 = lean, 25 to < 30 = overweight, and ≥ 30 = obese. Among the total of 959 patients who received docetaxel-free treatment, 459 were lean, 319 were overweight, and 181 were obese at baseline. Among the total of 1,880 patients who received docetaxel-based treatment, 887 were lean, 632 were overweight, and 361 were obese.
Outcomes by BMI Status Among All Patients
No significant difference in disease-free survival was observed across lean, overweight, and obese subgroups of patients in the nondocetaxel group (overall P = .28). On multivariate analysis, hazard ratios were 1.07 (P = .56) for overweight vs lean and 1.11 (P = .49) for obese vs lean. In contrast, BMI status was associated with significant differences in disease-free survival in the docetaxel-based group (overall P = .0024). On multivariate analysis, hazard ratios were 1.12 (P = .21) for overweight vs lean and 1.32 (P = .007) for obese vs lean. When BMI was analyzed as a continuous variable in the docetaxel-based group, hazard ratios increased per 5-unit increase on univariate (hazard ratio [HR] = 1.10, P = .006) and multivariate analysis (HR = 1.07, P = .06).
No significant difference in overall survival was observed across BMI categories in the nondocetaxel group (overall P = .44). On multivariate analysis, hazard ratios were 0.96 (P = .78) for overweight vs lean and 1.10 (P =.59) for obese vs lean. Increasing BMI was significantly associated with poorer overall survival in the docetaxel-based group. On multivariate analysis, hazard ratios were 1.27 (P = .04) for overweight vs lean and 1.63 (P = .0001) for obese vs lean. When BMI was analyzed as a continuous variable in the docetaxel-based group, hazard ratios increased per 5-unit increase on univariate (HR = 1.22, P < .0001) and multivariate
analysis (HR = 1.18, P = .0002).
A higher proportion of obese patients in the docetaxel-based group received a docetaxel relative dose intensity of less than 85% compared with other BMI groups. Analysis including only patients in the docetaxel-based group who received a docetaxel relative dose intensity of at least 85% showed similar results for disease-free and overall survival, suggesting the findings were not related to relative dose intensity.
Outcomes According to Estrogen Receptor Status
In the nondocetaxel group,BMI categories were not significantly associated with disease-free survival among patients with estrogen receptor–negative tumors (overall P = .62) or those with estrogen receptor–positive tumors (overall P = .24). Similarly, no significant association with overall survival was observed among patients with estrogen receptor–negative disease (overall P = .19) or estrogen receptor–positive disease (overall P = .56).
In contrast, increasing BMI in the docetaxel-based group was significantly associated with poorer disease-free survival among both patients with estrogen receptor–negative (overall P = .0052) and estrogen receptor–positive disease (overall P = .036). Similarly, significant associations with poorer overall survival were observed in both patients with estrogen receptor–negative (overall P = .0011) and estrogen receptor–positive disease (overall P = .0015).
A potential joint modifying role of BMI and estrogen receptor status on the treatment effect was suggested by an analysis showing a second-order interaction for disease-free survival (unadjusted P = .05, P adjusted for covariates = .06) and overall survival (unadjusted P = .04, adjusted P = .04).
Comparison of Obese vs Overweight Categories
No evidence of differences in disease-free or overall survival between overweight and obese patients in the nondocetaxel group was observed. Significant differences were observed for obese vs overweight categories in the docetaxel-based group, including among patients with estrogen receptor–positive tumors for disease-free survival (adjusted HR = 1.37, P = .02) and overall survival (adjusted HR = 1.59, P = .006).
The authors concluded: “This retrospective analysis of a large adjuvant trial 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. These results now must be confirmed in additional series.”
DISCLOSURE: The study was supported by Fondation Cancer Luxembourg and Associazione Italiana per la Ricerca sul Cancro AIRC. Dr. Desmedt reported no conflicts of interest.
1. Desmedt C, Fornili M, Clatot F, et al: Differential benefit of adjuvant docetaxel-based chemotherapy in patients with early breast cancer according to baseline body mass index. J Clin Oncol 38:2883-2891, 2020.