colon cancer: BMI as risk factor for early cancer

 A recent article suggested that much of the risk of early-onset colorectal cancer (CRC) may be related to increasing BMI in young people (see colon cancer BMI as risk factor Gastro2022 in dropbox, or https://doi.org/10.1053/j.gastro.2021.12.239) 

 

 

Details: 

-- 6602 patients with CRC and 7950 matched controls were compared in a population-based case-control study from Germany 

    -- of these, 747 patients and 621 controls were younger than 55 years old and included in the analysis 

-- BMI was self-reported (height and weight) at ages 20 and 30, and at approximately 10 years before diagnosis (in CRC cases) or similarly timed interview (in controls)

    -- patients and controls participated in personal interviews with trained interviewers assessing social demographics, medical, and lifestyle history 

    -- community-based controls were selected randomly from population-based registries, matched with respect to age, sex, and county of residence. But they were excluded if they had a history of CRC 

-- CRC cases (total of 747): 

    -- age 30-39: 59 cases (8%) 

    -- age 40-49: 280 cases (37%) 

    -- age 50-54: 408 cases (55%) 

-- demographics: cases had less education (42% versus 24% had <10 years), were more likely to smoke (current smokers in 32% of cases versus 24% of controls), were more likely to drink (180 were moderate or heavy drinkers in cases, versus 114 controls), physical activity was more in cases, history of a first-degree relative with CRC was higher in cases (15% versus 7%), previous colonoscopy was higher in controls (32% versus 16% in cases). No difference in the rate of diabetes or NSAID use 

-- results were adjusted for age, sex, education, family history of CRC, previous colonoscopy, ever being a regular smoker, alcohol consumption, use of NSAIDs (including aspirin), physical activity, and diabetes 

 

Results: 

-- BMI increased steadily from age 20 to 10 years before diagnosis among cases or and controls 

-- BMI >30 was strongly associated with a higher risk of early-onset CRC, irrespective of prior BMI recordings

-- as compared with participants with BMI <25, risk of early-onset CRC: 

    -- BMI of at least 30 at age 20: 2.56-fold increased risk of CRC (1.20-5.44) 

    -- BMI of at least 30 at age 30: 2.06-fold increased risk (1.25-3.40) 

    -- BMI of at least 30 approximately 10 years before diagnosis/interview: 1.88-fold (1.30-2.73) 

-- as compared with participants with BMI <25, risk of early-onset CRC: 

    -- BMI of 25-30 at age 30: 1.34-fold increased risk of CRC (1.02-1.77) 

    -- BMI of 25-30 approximately 10 years before diagnosis/interview: 1.46-fold (1.13-1.90) 

 

-- If using a cutpoint of 50 years old (vs 55yo) for defining early-onset CRC (though only total of 339 cases vs 747 cases if use <55yo): 

    -- BMI of at least 30 at age 20: 3.29-fold increased risk of CRC (1.08-10.09) 

    -- BMI of at least 30 at age 30: 2.15-fold increased risk (1.16-4.01) 

    -- BMI of at least 30 approximately 10 years before diagnosis/interview: 1.75-fold (1.02-2.99) 

 

-- by site of cancer, as compared to BMI <25:  

    -- rectal cancer:

       -- at age 20, adjusted OR 3.41 (1.46-7.95) 

       -- at age 30, adjusted OR 2.51 (1.41-4.48) 

       -- BMI approximately 10 years before diagnosis/interview: OR 2.06 (1.32-3.27)

    -- colon cancer: 

        -- BMI >30 at age 30, OR 1.75 (0.97-3.14), not quite statistically significant  

        -- BMI approximately 10 years before diagnosis/interview: OR 1.77 (1.08-2.92)

 

-- Overall the associations were stronger among women than men 

-- CRC was basically restricted to those with no prior colonoscopy 

 

Commentary: 

-- it has been well-documented that obesity has increased over time; in Germany from 1999 to 2017 obesity prevalence increased in all age groups, such that by 2015, 54% of adults in Germany were overweight or obese, and 18.1% were obese (18.3% of men and 18% of women) 

    -- the above study confirmed that the prevalence of overweight and obesity increased steadily from age 20 to approximately 10 years before the diagnosis of CRC or interview among controls 

-- this study was developed to see if there was an association between increased obesity and increased early-onset CRC risk. Many other studies have found some association but this study does have the advantage of assessing  BMI over time, and not just a single baseline value. This study also has the advantage of assessing  BMI  about 10 years before diagnosis of CRC, at a time that decreases potential confounding (since cancer can cause weight loss) 

-- there was notably an increased incidence of rectal cancers than colon cancers in younger people, and overall obesity was more strongly associated with CRC among women than men 

-- In terms of purported mechanisms for a CRC association with obesity: changes in hormone metabolism, insulin and insulin-like growth factors, different pathophysiology of cancer by age, and activation of inflammatory pathways (obesity itself is associated with chronic inflammation, as is metabolic syndrome, diabetes, NAFLD, depression, many rheumatologic diseases, chronic infectious diseases, etc).

--there may also be CR C associations with lifestyle, environment, nutrition, genetics and epigenetic predisposition.

-- findings in this study that are consistent with a causal relationship between obesity and CRC:

    -- there was a strong trend to higher risk of CRC at a young age in those whose BMI >30 at age 20, and to decreasing risk as obesity began later in life. it seems that the length of time with obesity (the "area under the curve") is related to higher incidence of CRC

    -- also, there was an increased incidence with higher BMIs (>30 was worse than 25-30), though there were overlapping confidence intervals

 

-- One potential consequence of this relationship between obesity and early CRC, especially if confirmed in other studies, is that it may be possible to do CRC risk stratification leading to different screening strategies (i.e., perhaps there could be later initial screening in those with BMIs of less than 25???, or perhaps different screening strategies, such as FIT testing vs colonoscopy in those with lower BMIs???)

 

Limitations: 

-- though this is a large cohort of patients, there were relatively few patients who had early-onset CRC, straining the ability to show strong statistical relationships. Many of the above relationships had overlapping confidence intervals between the different ages of reported BMIs 

    -- and, given the small numbers of events, they used the higher cutpoint of age 55 to define early-onset CRC. The analysis was similar with the more traditional cutpoint of 50yo, though many fewer CRC cases and larger confidence intervals

-- BMIs were self-reported as both height and weight approximations at the various ages above, and are potentially not so accurate 

-- there were limited granular data on other components of lifestyle that might have affected CRC incidence, most specifically diet (meat and vegetable intake) for which it were only some data on current and not past habits (and, did those having obesity at age 20 have a terrible prior diet but had improved some when they reached the age of 20?? would confound the results)

-- other "lifestyle" issues may also be involved in risk for CRC, including sedentary lifestyle, alcohol, smoking, etc. They did incorporate these issues in their mathematical adjustments, but in general these behaviors are treated as binary issues, and it is hard to know with certainty the relationship based on that (ie, what is sedentary life? at what point does it become nonsedentary? we really need to assess physical activity, for example, as a more continuous variable to know what the relationship is with CRC)

-- of the 866 controls contacted for this study, only 628 agreed to participate with an interview. This may reflect a selection bias into those controls who were willing to be involved in the study, and could conceivably distort the results 

 

So, it is quite concerning that CRC is becoming more common in those <50yo, so much so that many guidelines are using 45yo as the time to begin screening (eg American Cancer Society, the May 2021 USPSTF guidelines, and the American College of Gastroenterololgy. The issues are:

--what is the cause of the decreasing age for diagnosis of CRC? Is the cause fixable? Do the screening guidelines need to change for everyone or just those at higher risk? more studies are needed to answer these questions definitively, but a few points:

    -- to the extent that overweight/obesity is a major issue, we do know that it is much easier to gain weight than to lose it. Diet and exercise work for some people, but certainly not a very large number (and studies on diabetes prevention in high risk individuals have found limited success with advocating diet and exercise in clinical practice)

    -- which means that a public health challenge is to create an atmosphere wherein diet and exercise take on a primary role (as well as smoking and drinking). This is hard to do in the US and other market-driven economies, since the populations have been brought up to be able to make their own choices (though, of course, those choices are often largely defined by for-profit corporations who saturate the airwaves/social media/billboards/stocking grocery store shelves optimally for consumption of their products/etc). But this imperative is so important for health overall, not just CRC prevention. And many public health measures will not change so much without aggressively addressing these issues

    -- there are some medical/surgical interventions that might help some who are unable to lose weight by lifestyle changes alone, such as semaglutide (see http://gmodestmedblogs.blogspot.com/2021/03/semaglutide-for-weight-loss.html ) or a new agent tirzepatide (see http://gmodestmedblogs.blogspot.com/2021/07/diabetes-and-weight-loss-tirzepatide.html ). of note, these meds lead to weight loss for at least 1 year (limits of the studies) and of similar magnitude to surgical sleeve gastrectomies

        -- it is lamentable that we often need to resort to medical interventions to deal with these social issues.......

geoff

 

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