Science Spotlight

Survival of the fittest or fattest?

Compared to those with normal BMI, higher BMI was associated with: decreased survival (red) among early stage cancers and increased survival (green) among later-stage cancers. Bold indicates a statistically significant Hazard Ratio (HR; p<0.05).
Image provided by Dr. Jonathan Kocarnik

Obesity, an increasingly common phenomenon in developed countries, is associated with increased risk of colorectal cancer (CRC), the fourth most common cause of cancer death. While higher body mass index or BMI is a well-established risk factor for CRC, the association between BMI and survival after CRC diagnosis is unclear.

To address this question, Drs. Jonathan Kocarnik, Polly Newcomb, and colleagues, evaluated whether pre-diagnosis BMI was associated with overall or CRC-specific survival. The investigators also performed cancer stage stratified analyses to assess BMI-survival associations in the context of disease progression at diagnosis. The results from their study were recently published in the International Journal of Cancer.

Participants came from 6 prospective cohort studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The coordinating center for this international consortium is based at the Fred Hutch (Principal investigator: Ulrike Peters; lead statistician: Li Hsu). Participants included 2,249 non-Hispanic white CRC cases followed for a median 4.5 years after diagnosis, 777 of whom died, 554 from CRC-related causes. To limit potential bias due to illness-induced weight loss, participants whose BMI was measured within the 1 year preceding diagnosis were excluded. To reduce potential bias due to misclassification, participants whose BMI was measured more than 10 years before diagnosis were also excluded. The researchers implemented Cox regression models, adjusted for age at diagnosis, sex, study, and smoking status, to examine the associations between pre-diagnosis BMI and survival (overall and CRC-specific).

The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (P- interaction=0.03) and CRC-specific mortality (P-interaction=0.04). Compared to normal BMI (18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2) was associated with increased mortality among those with stage I disease, and decreased mortality among those with stages II-IV disease. Similarly, obesity (BMI ≥30 kg/m2) was associated with increased mortality among those with stages I- II disease, and decreased mortality among those with stages III-IV disease.

Dr. Kocarnik describes the novelty of this study, "in contrast to previous studies, the relationship between pre-diagnostic body mass index and post-diagnostic survival was found to significantly differ according to cancer stage at diagnosis: higher BMI was associated with increased mortality among those with early-stage disease, but with decreased mortality among those with late-stage disease."

The "obesity paradox", as seen in the finding of improved late stage CRC survival at higher BMI levels, is a phenomenon witnessed in other diseases. One explanation for this paradox is that during illness, elevated adiposity may aid in meeting metabolic requirements. For example in late-stage CRC, higher BMI may provide an increased ability to cope with the physiological stresses of treatment (e.g., nausea induced by chemotherapy). These physiologic stresses of cancer may differ by stage at diagnosis.

"As BMI can only serve as a crude estimate of body adiposity, this study raises questions of how differences in body composition or fat distribution may impact CRC survival." Dr. Kocarnik elaborates on future research directions, "Our current study was also only able to look at BMI at a single point in time before diagnosis. We are planning to look into changes in BMI over time, including from pre- to post-diagnosis. This could be useful for identifying the mechanisms and dynamics of this association, with the goal of eventually translating such findings into beneficial clinical recommendations for CRC survivors"

Lastly, Dr. Kocarnik notes, "this study would not have been possible without the significant efforts of the GECCO investigators to bring together so many studies with such a wealth of data.  We were able to leverage these existing studies to address questions that would otherwise not have been possible to evaluate, whether due to sample size, study design, or time requirements."

Funding for this study was provided by the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health.

Kocarnik JM, Chan AT, Slattery ML, Potter JD, Meyerhardt J, Phipps A, Nan H, Harrison T, Rohan TE, Qi L, Hou L, Caan B, Kroenke CH, Strickler H, Hayes RB, Schoen RE, Chong DQ, White E, Berndt SI, Peters U, Newcomb PA. 2016. Relationship of pre-diagnostic body mass index with survival after colorectal cancer: Stage-specific associations. Int J Cancer. 14 MAY 2016, DOI: 10.1002/ijc.30163