Body Mass Index May Impact Docetaxel-Based Treatment Regimens in Breast Cancer

July 9, 2020

“By retrospectively analyzing data from the adjuvant BIG 2-98 trial, we demonstrated that overweight and obese patients treated with a docetaxel-based chemotherapy regimen presented with a worse disease-free and overall survival compared with average weight patients treated with the same chemotherapy regimen."

A differential response was observed with docetaxel according to body mass index (BMI) in patients with breast cancer, according to a retrospective analysis of a large adjuvant clinical trial, BIG 2-98. These findings suggest a body composition-based re-evaluation, which can be used to determine the risk-benefit ratio for use of taxane therapies, but confirmatory studies are recommended.

“By retrospectively analyzing data from the adjuvant BIG 2-98 trial, we demonstrated that overweight and obese patients treated with a docetaxel-based chemotherapy regimen presented with a worse disease-free and overall survival compared with average weight patients treated with the same chemotherapy regimen,” wrote the study authors led by Christine Desmedt, PhD. “We also observed a joint modifying role of BMI and estrogen receptor (ER) status on treatment effect.”

BMI data were calculated by height and weight measurements at the time of enrollment, then categorized based on the World Health Organization definitions of underweight (< 18.5 kg/m2), average weight (≥ 18.5 and < 25 kg/m2), overweight (≥ 25 and < 30 kg/m2), and obese (≥ 30 kg/m2). Patients who were underweight were excluded from the analysis.

Overall, 47.4% of patients were average weight, 33.5% were overweight, and 19.1% were obese. All patients presented with axillary lymph node involvement, but increased involvement appeared to be associated with BMI only in the docetaxel arm. There was also a statistically significant increase in the proportion of patients with an RDI < 85% for docetaxel in the sequential docetaxel arm, in which average weight was 4%, overweight 2%, and obese 8% (P =.003), and this was also observed in the concurrent docetaxel arm, in which average weight was 8%, overweight 13%, and obese 16% (P =.009).

There were no statistically significant differences in terms of disease-free survival (DFS) in the non-docetaxel arm (log-rank test P =.28), but investigators noted a significant reduction in DFS in the overweight and obese patient groups compared with the average weight patients in the docetaxel arm (log-rank test P =.0024). The impact of BMI on DFS appeared statistically significant after adjusting for standard variables as well. A significant increase was observed in the hazard ratios (HRs) in the docetaxel arm.

There were no significant differences in the 3 BMI categories in patients with ER-negative and ER-positive disease in the non-docetaxel arm, but in the docetaxel arm, the curves in the overweight and obese populations had a lower DFS if they had an ER-negative status compared with their ER-positive patients, where only obese patients had a lower DFS. These findings were statistically significant as well in the adjusted analyses. Higher HRs were observed for DFS with increasing BMI in the docetaxel group when BMI was considered a continuous variable, although only in ER-negative patients.

Overall survival (OS) appeared to have consistent results with the DFS when considering BMI in the unadjusted and adjusted analyses. These results also appeared consistent when considering an end point of distant metastasis.

An additional analysis was conducted to compare overweight and obese patients, but there was no evidence of differences between these 2 patient populations in the non-docetaxel group. The docetaxel group, however, demonstrated significant differences, particularly among patients with ER-positive disease for DFS (adjusted HR, 1.37; 95% CI, 1.06-1078; P =.02), OS (adjusted HR, 1.69; 95% CI, 1.14-2.22; P =.006), and distant metastases (adjusted HR, 1.43- 95% CI, 1/06-1.93; P =.02). This was also observed in the global population for OS (adjusted HR, 1.28; 95% CI, 1.00-1.64; P =.05).

This analysis also demonstrated evidence of a second-order interaction of DFS and OS, which supports the joint modifying role of BMI and ER statuses on the treatment effect. The DFS Wald P unadjusted for covariables was 0.05 (adjusted P =.06), and the unadjusted P value for OS was 0.04 (adjusted P =.04).

“In summary, a benefit for docetaxel-based versus non-docetaxel–based treatment seems to be observed only with regard to OS for average weight and overweight patients with ER-positive tumors,” study authors wrote, “whereas docetaxel-based treatment appears to be detrimental for overweight patients with ER-negative tumors.”

In addition to these findings, an exploratory analysis demonstrated that the observed impact of BMI on the docetaxel arm was present in those treated in both the sequential and concurrent docetaxel-based arms.

A total of 2887 patients from the BIG 2-98 trial were enrolled to the analysis from June 1998 to June 2001 and randomized 1:1:2:2 to either the sequential control of 4 cycles of doxorubicin at 75 mg/m2 and 3 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF); the concurrent control of 4 cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600mg/m2 and 3 cycles of CMF; the sequential docetaxel arm of 3 cycles of doxorubicin at 75mg/m2, and 3 cycles of docetaxel at 100 mg/m2, followed by 3 cycles of CMF; or a concurrent docetaxel regimen of 4 cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, and 3 cycles of CMF.

Patients under the age of 71 years with operable, clinical-stage T1-3 invasive adenocarcinoma and > 1 positive lymph node were eligible to enroll to the study, but patients with metastatic disease were ineligible.

“To the best of our knowledge, this is the first time that DFS, OS, and distant recurrences were compared between docetaxel-based and non-docetaxel–based chemotherapy regimens of a trial according to BMI,” the study authors concluded.

Should these results be confirmed in other studies, this could have several implications in the clinical setting, including treating heavier patients with adjuvant docetaxel-based regimens. Other studies may also be able to confirm if similar results could be expected with paclitaxel, which is another lipophilic drug from the taxane family, which is commonly used in breast cancer.

Reference

Desmedt C, Fornili M, Clatot F, et al. Differential benefit of adjuvant docetaxel-based chemotherapy in patient with early breast cancer according to body mass index. Journal of Clinical Oncology. [Published Online July 2, 2020]. doi: 10.1200/JCO.19.01771