Kristen Whitaker, MD, MS
Lori J. Goldstein, MD, FASCO
The rate of obesity is rising dramatically in the United States and Europe, with more than 60% of women in the United States1,2 and 50% of women in Europe3 classified as overweight or obese based on their body mass index (BMI). Obesity is associated with an increased risk of hormone receptor–positive breast cancer in postmenopausal women.4 Women who are obese and overweight at the time of breast cancer diagnosis also have an increased risk of breast cancer–specific and all-cause mortality.5,6 A prior study evaluated the relationship between BMI and breast cancer outcomes in patients enrolled in three adjuvant chemotherapy trials. The findings demonstrated that increasing BMI with obese and overweight ranges was associated with inferior disease-free and overall survival in hormone receptor–positive, HER2-negative disease but not in HER2-positive or triple-negative disease.7
Given the fact that patients with breast cancer are increasingly obese or overweight, it is critically important to understand whether increasing BMI affects the efficacy of breast cancer treatments, such as chemotherapy. Dosing of chemotherapy in patients with cancer who are overweight or obese presents a unique challenge, as these patients often receive limited chemotherapy doses that are not based on their actual body weight or dose reductions due to toxicity concerns, despite national guidelines recommending that they receive chemotherapy based on their actual body weight.8 Consequently, patients who are overweight or obese often receive reduced dose-intensity chemotherapy, which is especially problematic. Prior studies have demonstrated that, in patients with breast cancer, reduced dose-intensity chemotherapy is associated with increased disease recurrence9 and mortality.10-13
Closer Look at BIG 2-98 Trial
In a study by Desmedt et al, reviewed in the October 10, 2020, issue of The ASCO Post, the investigators analyzed data from the 2,887 patients with breast cancer enrolled in the adjuvant BIG 2-98 trial.14 They compared breast cancer outcomes, including overall survival, disease-free survival, and development of distant metastases, between those who received docetaxel-based chemotherapy and those who received non–docetaxel-based chemotherapy according to their BMI. Most patients (> 75%) received chemotherapy dosing based on their actual body weight rather than ideal body weight. However, after a patient with obesity experienced a toxicity-related adverse event, a protocol amendment reduced the chemotherapy dose to a maximum body surface area of 2 m2.
The study found that, for patients who received non–docetaxel-based adjuvant chemotherapy, no difference in disease-free survival, overall survival, or rate of distant metastases was reported regardless of BMI. Conversely, patients who were overweight or obese treated with a docetaxel-based chemotherapy regimen had significantly worse disease-free and overall survival and increased distant metastases compared with patients who were not overweight or obese and treated with the same chemotherapy regimen. These findings were most notable in the patients with estrogen receptor–positive breast cancer.
“Future studies should ensure that all patients with obesity receive chemotherapy based on their actual body weight.”— Kristen Whitaker, MD, MS, and Lori J. Goldstein, MD, FASCO
Tweet this quote
Because there was a statistically significant increase in the proportion of patients with obesity receiving docetaxel-based chemotherapy regimens with a relative dose intensity of less than 85%, a cutoff commonly used to define reduced dose intensity, the study investigators evaluated whether the decreased disease-free and overall survival and increased rate of distant recurrences in patients with obesity compared without those without receiving docetaxel-based chemotherapy may have been due to reduced dose intensity by performing separate analyses for patients who received a relative dose intensity of less than 85% and for those who received a relative dose intensity of more than 85%. The findings of reduced disease-free and overall survival in patients with obesity compared with those without remained regardless of whether patients had a relative dose intensity for docetaxel of at least 85% or a relative dose intensity for docetaxel of less than 85%.
Difference in Outcomes From Other Studies
In contrast to this study, demonstrating inferior breast cancer outcomes for patients who were overweight or obese treated with docetaxel-based adjuvant chemotherapy, prior studies that have investigated retrospectively whether BMI affects survival in patients with breast cancer treated with adjuvant chemotherapy regimens with or without taxanes, including regimens containing paclitaxel or docetaxel, did not demonstrate a difference in breast cancer outcomes based on BMI. One study examined the effect of BMI on disease-free and overall survival among 4,996 patients with node-positive early-stage breast cancer. The investigators found that BMI did not impact disease-free or overall survival among women treated with or without taxane-based chemotherapy.15
Another study examined the impact of BMI on breast cancer outcomes in a retrospective analysis including 5,683 patients with operable breast cancer treated with or without taxanes who were enrolled in four adjuvant randomized clinical trials. These investigators also found no difference in recurrence, overall survival, or breast cancer–specific survival between patients with and without obesity.16
Food for Thought
The findings of the study by Desmedt et al are thought-provoking and timely given our current obesity pandemic and highlight the need for future studies to evaluate the impact of BMI on the efficacy of taxane-based chemotherapy administered in the adjuvant setting. Of note, since there is compelling evidence that chemotherapy dose intensity impacts breast cancer recurrence and survival, future studies should ensure that all patients with obesity receive chemotherapy based on their actual body weight. In addition, the criteria for dosing should be maintained throughout the study to more clearly exclude the possibility that reduced dose intensity of chemotherapy is not contributing to the inferior breast cancer outcomes seen in patients with obesity compared with those without.
Furthermore, because the decreased efficacy of docetaxel in patients with obesity is thought to be the result of the drug being lipophilic, and consequently being absorbed by fat in the body before it reaches the tumor,17 it seems likely that paclitaxel, another lipophilic drug commonly used in breast cancer, may also be subject to this effect. Thus, future studies should also investigate the impact of BMI on breast cancer outcomes in patients receiving adjuvant paclitaxel chemotherapy. Additionally, as weight gain after diagnosis has been associated with an increased risk of all-cause mortality compared with those who maintained their weight,18 it will be important for future studies to provide longitudinal BMI assessments. Finally, it is essential that information about other types of adjuvant therapy (anti–HER-2 agents and/or endocrine therapies), as well as adherence to those therapies, be included in the analyses of future studies examining the impact of BMI on chemotherapy efficacy, as these factors will also influence breast cancer outcomes.
For now, the findings of this study should make clinicians question whether obesity does in fact alter the efficacy of taxane-based chemotherapy but should not cause clinicians to alter the adjuvant chemotherapy regimens given to patients with breast cancer regardless of their BMI. Further investigations of the impact of BMI on the efficacy of taxane-based chemotherapy are needed to validate the findings of this study before clinicians should consider altering adjuvant chemotherapy recommendations for patients with breast cancer.
DISCLOSURE: Dr. Whitaker reported no conflicts of interest. Dr. Goldstein has received honoraria from Daiichi Sankyo, Genomic Health, Roche/Genentech, and Teva; has served as a consultant or advisor to Aduro Biotech, Amgen, Eisai, Genentech, Genomic Health, Immunomedics, Merck, Mylan, Myriad Genetics, NanoString Technologies, Puma Biotechnology, and Syndax; has received institutional research funding from Genentech/Roche and Merck; and has held other relationships with Daiichi Sankyo.
1. Hales CM, Carroll MD, Fryar CD, et al: Prevalence of obesity among adults and youth: United States, 2015–2016. NCHS Data Brief 288:1-8, 2017.
2. NCD Risk Factor Collaboration: Trends in adult body-mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387:1377-1396, 2016.
3. Marques A, Peralta M, Naia A, et al: Prevalence of adult overweight and obesity in 20 European countries, 2014. Eur J Public Health 28:295-300, 2018.
4. Neuhouser ML, Aragaki AK, Prentice RL, et al: Overweight, obesity, and postmenopausal invasive breast cancer risk: A secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncol 1:611-621, 2015.
5. Chan DSM, Vieira AR, Aune D, et al: Body mass index and survival in women with breast cancer: Systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 25:1901-1914, 2014.
6. Protani M, Coory M, Martin JH: Effect of obesity on survival of women with breast cancer: Systematic review and meta-analysis. Breast Cancer Res Treat 123:627-635, 2010.
7. Griggs JJ, Mangu PB, Anderson H, et al: Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 30:1553-1561, 2012.
8. Sparano JA, Wang M, Zhao F, et al: Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer 118:5937-5946, 2012.
9. Early Breast Cancer Trialists’ Collaborative Group: Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: A patient-level meta-analysis of 37,298 women with early breast cancer in 26 randomised trials. Lancet 393:1440-1452, 2019.
10. Lyman GH: Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 7:99-108, 2009.
11. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 90:1205-1211, 1998.
12. Chirivella I, Bermejo B, Insa A, et al: Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients. Breast Cancer Res Treat 114:479-484, 2009.
13. Zhang L, Yu Q, Wu XC, et al: Impact of chemotherapy relative dose intensity on cause-specific and overall survival for stage I-III breast cancer: ER+/PR+, HER2– vs. triple negative. Breast Cancer Res Treat 169:175-187, 2018.
14. 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.
15. Ladoire S, Dalban C, Roché H, et al: Effect of obesity on disease-free and overall survival in node-positive breast cancer patients in a large French population: A pooled analysis of two randomised trials. Eur J Cancer 50:506-516, 2014.
16. Pajares B, Pollán M, Martín M, et al: Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: A pooled analysis. Breast Cancer Res 15: R105, 2013.
17. Sparreboom A, Wolff AC, Mathijssen RHJ, et al: Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 25:4707-4713, 2007.
18. Playdon MC, Bracken MB, Sanft TB, et al: Weight gain after breast cancer diagnosis and all-cause mortality: Systematic review and meta-analysis. J Natl Cancer Inst 107:djv275, 2015.
Drs. Whitaker and Goldstein practice at the Fox Chase Cancer Center, Temple Health, Philadelphia.