The Obesity Paradox in Cancer—Moving beyond BMI—Response

We read the letter to the editor from Raffaella Mormile addressing our recent publication regarding body composition–related explanations for the obesity paradox in cancer with great interest (1). Mormile proposed an alternative explanation for the obesity paradox in cancer (2) and suggests that Darwin's theory of natural selection might represent another viable explanation for the paradoxical survival advantage in obese patients with cancer. There is a supporting evidence for this explanation in a recent article on all-cause mortality in Denmark. Using three Danish cohorts from the same general population in Copenhagen across 3 decades, Afzal and colleagues evaluated and compared the body mass index (BMI) value associated with the lowest all-cause mortality over the years (3). The study included more than 100,000 patients across three different timeframes (1976–1978, 1991–1994, and 2003–2013) and demonstrated a U-shaped survival curve with an increasing optimal BMI that increased from BMI = 23.7 in the 1976–1978 cohort to BMI = 27 in the 2003–2013 cohort. However, in this study, the same effect could not be demonstrated for cancer-specific mortality (3). In a different study based on an American cohort, Greenlee and colleagues showed that higher BMI was protective mostly in men and in specific types of cancer in their large pooled analyses of 22 clinical trials (n = 11,724; ref. 4). As Mayede and colleagues suggested, simulations are necessary to evaluate collider stratification bias and heterogeneity to help distinguish real from spurious effects of body weight as they demonstrated in renal cancer (5). Although several explanations have been suggested, Mormile's hypothesis that the obesity paradox might be explained by Darwin's theory as a process of adaption by the organism raises a very interesting question that warrants further investigation. We thank Dr. Murmile for raising our attention to this fascinating proposition and encourage more research efforts in this field.

See the original Letter to the Editor, p. 980