Year 1954 was an important year for cancer epidemiology and the tobacco industry.
It saw the launch of the first large cohort study aimed at investigating the links between smoking and lung cancer [1] and the launch of the most brilliant tobacco advertising campaigns of all times, the Marlboro man. Amazingly, both the cohort study and the publicity stunt proceeded for the remainder of the 20th century and ceased to exist almost at the same time [2] and for the same reason: universal recognition that smoking was an important risk factor for lung cancer, and many other diseases
For regular Joe (Joe Camel[3], the advertising mascot of the Camel brand of cigarettes, whom else?), the story would end here. But for curious minds, like yours and mine, that seek to learn to understand cancer better, this is just the beginning of the journey into the country of “cowboy killers” (US slang term for cigarettes)[4].
The first stop is obesity. If smoking is the leading modifiable risk factor for cancer, obesity (high BMI) ranks third.[5] So smokers that have significant excess weight should be significantly more at risk for cancer in general. Which is true: the risks are not merely additive, they are synergistic.[6]
Except for lung cancer.
Such a paradoxical finding must be taken with a lot of caution, considering all the fuzziness associated with observational studies that span lifetimes of complex and variable metabolic states and exposures to environmental toxicants. Thus, the word “fat” is a gross over-simplification of lipid metabolism and “cocktails of inhaled particles and gases” would be much more accurate than “smoking”. Moreover, the message here is also toxic from a public health perspective. So it is no surprise that cancer epidemiologists have been trying pretty hard to invalidate this finding. To no avail.
Incidentally, the inverse association between obesity and smokers’ lung cancer is part of a bigger picture: excess weight confers better chances at cancer survival in general. There are several explanations for this “obesity paradox”. [7] Firstly, overweight patients have higher metabolic reserves, and this may make them less prone to cachexia, the cause of death in 20 to 30% of cancer patients. They also appear to be more resistant to aggressive chemotherapies with fewer drug-related adverse events. They are thus more likely to complete their medical treatment. Their biology is also different. Fat tissues produce their own set of signal molecules (adipokines), some of which may be anti-inflammatory. Finally, perturbations in metabolism caused by obesity may make some tumors more responsive to therapy. It is all very complex [8], as is always the case with cancer disease mechanisms.
Except that, in the case of lung cancer, the obesity paradox also concerns incidence. This is a completely different story as: the presence of fat, at least in some cases, seems to prevent cancer. And the difference is significant: in a recent study in Japan, every 5 kg/m2 increase in BMI was found to be associated with up to 22% decrease in the risk of lung cancer.[9]
Interestingly, obesity-conferred protection concerns both non-smokers and smokers and ex-smokers. But risk reduction is higher in the latter groups. It thus appears that carcinogens present in tobacco smoke somehow do less damage to the lungs of people that have more fat[10].
Because lung tissues contain very little fat a tempting explanation is that at least some of these carcinogens – the nasty lipophilic ones – leave the lungs faster in obese smokers, because they have somewhere fatty to go (adipose tissues can store toxicants safely [11]).
What do you think?
How could one study this with some precision?
Is it important to find out?
I, for one, think so, because in the real world, a carcinogen never acts alone, but always in combinations with other carcinogens, a cocktail. And the variable partitioning of this cocktail into two fractions – if confirmed – and its impact on cancer incidence may tell us something very important about the root causes of cancer.
References:
[1] The “British Doctors Study” .Doll R, Hill AB (1954) The mortality of doctors in relation to their smoking habits: a preliminary report. BMJ 228: 1451–1455
[2] The Marlboro Man campaign and the British Doctors Study were terminated in 1999, respectively 2001.
[3] https://en.wikipedia.org/wiki/Joe_Camel
[4] https://en.wiktionary.org/wiki/cowboy_killer
[5] GBD 2019 Cancer Risk Factors Collaborators. “The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019.” Lancet (London, England) vol. 400,10352 (2022): 563-591. doi:10.1016/S0140-6736(22)01438-6 https://pubmed.ncbi.nlm.nih.gov/35988567/
[6] Roos, Eira T et al. “Joint associations between smoking and obesity as determinants of premature mortality among midlife employees.” European journal of public health vol. 27,1 (2017): 135-139. https://pubmed.ncbi.nlm.nih.gov/28177439/
[7] Laird, Barry J A, and Richard J E Skipworth. “The Obesity Paradox in Cancer: Is Bigger Better?.” Journal of cachexia, sarcopenia and muscle vol. 13,3 (2022): 1440-1441. https://pubmed.ncbi.nlm.nih.gov/35506563/
[8] Tu, Huakang et al. “Body mass index and survival after cancer diagnosis: A pan-cancer cohort study of 114 430 patients with cancer.” Innovation (Cambridge (Mass.)) vol. 3,6 100344. 18 Oct. 2022, https://pubmed.ncbi.nlm.nih.gov/36353671/
[9] Kawai, Sayo et al. “Body mass index and lung cancer risk: Pooled analysis of 10 prospective cohort studies in Japan.” Cancer science vol. 115,4 (2024): 1346-1359. https://pubmed.ncbi.nlm.nih.gov/38310695/
[10] Mizoue T, Tokunaga S, Kasai H, Kawai K, Sato M, Kubo T. Body mass index and oxidative DNA damage: a longitudinal study. Cancer Sci. 2007 Aug;98(8):1254-8. https://pmc.ncbi.nlm.nih.gov/articles/PMC11158668/
[11] La Merrill M., Emond C., Kim M.J., Antignac J.P., Le Bizec B., Clément K., et al. Toxicological function of adipose tissue: focus on persistent organic pollutants. Environ. Health Perspect. 2013;121:162–169. https://pubmed.ncbi.nlm.nih.gov/23221922/