BMI AND DOCETAXEL BENEFIT IN BREAST CANCER

A retrospective analysis from the BIG 2-98 trial reported in the Journal of Clinical Oncology by Desmedt et al showed poorer disease-free and overall survival with increasing baseline body mass index (BMI) in women receiving adjuvant docetaxel-based chemotherapy but not among those receiving non–taxane-containing chemotherapy.

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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.”

Study Details

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:

• Sequential control: Consisting of four cycles of doxorubicin at 75 mg/m²and three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF)
• Concurrent control: Consisting of four cycles of doxorubicin at 60 mg/m²plus cyclophosphamide at 600 mg/m² and three cycles of CMF
• Sequential docetaxel: Consisting of three cycles of doxorubicin at 75 mg/m² and three cycles of docetaxel at 100 mg/m², followed by three cycles of CMF
• 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 categorized at baseline as lean, 319 were overweight, and 181 were obese. 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 Among All Patients

No significant difference in disease-free survival was observed across lean, overweight, and obese subgroups in patients in the non-docetaxel 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. Analysis of BMI as a continuous variable showed significant increases in hazard ratios with increasing BMI. 

No significant difference in overall survival was observed across BMI categories in the non-docetaxel 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 (P = 1.1e^−.05). On multivariate analysis, hazard ratios were 1.27 (P = .04) for overweight vs lean and 1.63 (P = .0001) for obese vs lean. BMI was also significantly associated with overall survival in this group when considered as a continuous variable. 

A higher proportion of obese patients in the docetaxel-based group received a docetaxel relative dose intensity of < 85% compared with other BMI groups. Analysis including only patients in the docetaxel-based group who received a docetaxel relative dose intensity of ≥ 85% showed similar results for disease-free and overall survival, suggesting that the findings were not related to relative dose intensity.

Outcomes According to Estrogen Receptor Status

In the non-docetaxel group, BMI categories were not significantly associated with disease-free survival among patients with estrogen receptor (ER)-negative tumors (overall P = .62) or those with ER-positive tumors (overall P = .24). Similarly, no significant association with overall survival was observed among ER-negative patients (overall P = .19) or ER-positive patients (overall P = .56).

In contrast, increasing BMI in the docetaxel-based group was significantly associated with poorer disease-free survival among both ER-negative patients (overall P = .0052) and ER-positive patients (P = .036). Similarly, significant associations with poorer overall survival were observed in both ER-negative patients (overall P = .0011) and ER-positive patients (overall P = .0015).

A potential joint modifying role of BMI and ER status on the treatment effect was suggested by 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 difference in disease-free or overall survival between overweight and obese patients in the non-docetaxel group was observed. Significant differences were observed for obese vs overweight categories in the docetaxel-based group, including among patients with ER-positive tumors for disease-free survival (adjusted hazard ratio = 1.37, P = .02) and overall survival (adjusted hazard ratio = 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.”