In an attempt to gain a deeper understanding of the relationship between weight and survival in patients with cancer, other explanations have, over the past decade, been posited, such as the notion that patients with cancer with low BMIs are likely to be sicker, as weight loss is associated with progressive disease and toxic treatments.8 Weight loss might also be linked with comorbidities or behaviors linked with worse survival, including smoking, across cancer types.9
These explanations, while plausible, don’t account for the reduced rate of cancer-specific mortality noted in obese patients with colorectal cancer. Whether this is a special case is unknown — but it is likely that a more profound explanation for this phenomenon is still needed.
One potentially revolutionary hypothesis relates to the evolutionary processes involved in oncogenesis.10 In a recent paper published in Evolutionary Applications, researchers suggested that people with low BMI are at a lower risk of cancer because their naturally evolved defenses to the disease create a poor environment for oncogenesis. This is not the case in obese patients, who “present more favorable conditions for malignant transformation, because of several weight‐associated factors and less efficient natural defenses, leading to a larger quantity of neoplasms comprising both nonaggressive and aggressive ones to regularly emerge and progress,” wrote the authors.
This theory suggests that healthy people with a normal BMI are at a lower risk of cancer incidence, but offers that cancers that develop within them are more likely to overcome their natural defenses, suggesting more aggressive phenotypes than those of the more common cancers found in obese patients. This explanation supports findings that obese patients with cancer have improved survival compared with patients with a normal BMI, as cancers in the latter group are more likely to be an aggressive or deadly variety.
Further, the researchers argued, obese patients with cancer may have several non-aggressive tumors, which may be competing with one another and therefore growing more slowly — posing a smaller risk to the patient in question.
“In obese patients,” the authors wrote, “the faster dynamics of oncogenesis together with lower defenses…favor, at least sometimes, the early development of more benign tumors that exert negative effects on subsequent neoplasm formation — thus, emergence of aggressive tumors could be reduced.”
Whether this evolutionary explanation will prove to be correct is yet to be determined. It does, however, appear plausible, and may be more easily tested compared with several of the previous hypotheses offered on this topic. It’s possible, therefore, that the obesity paradox isn’t really a paradox at all, and in light of evolutionary development, we can take a step further in understanding the etiologies of the different manifestations of this disease.
- Strulov Shachar S, Williams GR. The obesity paradox in cancer-moving beyond BMI. Cancer Epidemiol Biomarkers Prev. 2017;26:13-16. doi:10.1158/1055-9965.EPI-16-0439
- Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet. 2014;384:755-765. doi:10.1016/S0140-6736(14)60892-8
- Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71-82. doi:10.1001/jama.2012.113905
- Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med. 2006;355(8):763-778. doi:10.1056/NEJMoa055643
- Charette N, Vandeputte C, Ameye L, et al. Prognostic value of adipose tissue and muscle mass in advanced colorectal cancer: a post hoc analysis of two non-randomized phase II trials. BMC Cancer. 2019;19:134. doi:10.1186/s12885-019-5319-8
- Greenlee H, Unger JM, LeBlanc M, Ramsey S, Hershman DL. Association between body mass index and cancer survival in a pooled analysis of 22 clinical trials. Cancer Epidemiol Biomarkers Prev. 2017;26:21-29. doi:10.1158/1055-9965.EPI-15-1336
- Meyerhardt JA, Kroenke CH, Prado CM, et al. Association of weight change after colorectal cancer diagnosis and outcomes in the Kaiser Permanente Northern California population. Cancer Epidemiol Biomarkers Prev. 2017;26(1):30-7. doi:10.1158/1055-9965.EPI-16-0145
- Gioulbasanis I, Baracos VE, Giannousi Z, et al. Baseline nutritional evaluation in metastatic lung cancer patients: Mini Nutritional Assessment versus weight loss history. Ann Oncol. 2011;22:835-841. doi:10.1093/annonc/mdq440
- Klesges RC, Meyers AW, Klesges LM, La Vasque ME. Smoking, body weight, and their effects on smoking behavior: a comprehensive review of the literature. Psychol Bull. 1989;106(2):204-230.
- Ujvari B, Jacqueline C, Misse D, et al. Obesity paradox in cancer: Is bigger really better? [published online ahead of print March 15, 2019]. Evol App. doi:10.1111/eva.12790