Colon cancers: earlier onset

 A recent highly publicized article highlighted the increasing prevalence of early-onset colorectal cancer, per the New York Times (https://www.nytimes.com/2024/03/27/well/colon-cancer-symptoms-treatment.html?unlocked_article_code=1.gk0._FWp.fK3YTcjI4fOo&smid=nytcore-ios-share&referringSource=articleShare&ugrp=m ), which referenced a recent medical article (see colon ca early onset review Cancers2023 in dropbox, or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341111/ )

 

Details:

-- early-onset colorectal cancer (EOCRC), defined as a colorectal cancer (CRC) diagnosis before the age of 50, has been increasing in frequency despite the fact that overall CRC incidence (and mortality) has been decreasing

-- this medical article reviews the epidemiology, risk factors, clinicopathological features/prognosis, and treatment of EOCRC

 

Epidemiology:

-- CRC is the third most common malignancy and cause of death globally, with an estimated 1.93 million new cases in 2020, and it comprises 10% of the global cancer incidence and 9.4% of all cancer deaths.

-- the overall incidence of CRC has decreased since the mid-1980s, likely attributable to increased screening and improved therapies

-- but the mean age of CRC diagnosis has decreased from 72yo to 66yo, wth 10%-20% happening in  those <50yo (3/4 of them aged 40-49)

-- a few important differences in EOCRC vs later onset CRC:

    -- EOCRC is more aggressive, diagnosed at a more advanced stage and more likely to have metastases at diagnosis

        -- this is likely at least partly from the lack of screening in younger people and the more dismissive approach of clinicians (assuming more often that rectal bleeding in a younger person is from a benign source, such as hemorrhoids)

    -- there is a change in the location of the cancers in EOCRC to more rectal and left-sided ones (rectal cancer has increased >90% from 1990s to 2016, from 2.6 to 5.1/10,000 cases, vs an increase of 40% for colon cancer for this younger group)

    -- there are significant sex differences: CRCs in those 55-74yo are 50% more common in men, but there is no sex difference in EOCRC

    -- there is significant geographical variability: from 3.5/100K people in India to 12.9/100K in South Korea. In the US, there has been an increase in the 20-30yo cohort from 1% to 2.4% annually since the mid-1980s, and In the 40-54yo from 0.5% to 1.3% since the mid-1990s. Similar trend in Europe

 

Risk factors:

-- Hereditary: Lynch syndrome is most common, but also the adenomatouos polyposis syndromes (FAP, etc), and cystic fibrosis; EOCRC is predominantly sporadic (80%) and not hereditary. as an aside, 50% of those people who have germline mutations are unaware of any relevant family history

-- Metabolic syndrome: risk of EOCRC increases from those with 1, 2, or >2 metabolic comorbidities, with a respective higher risk of 9%,12%, and 31%.

    -- obesity is likely the main one here: each 5-unit incease in BMI is associated with a 20% increased EOCRC risk (adiposity generates adipokines, which are implicated in carcinogenesis)

-- Diabetes: 30% increased risk of CRC, and those with  diabetes typically develop CRC five years earlier (likely due to prolonged exposure to hyperinsulinemia, which is associated with oxidative stress and tumor cell  proliferation). and, by the way, this is why we should be using more GLP-1 agonists and SGLT-2 inhibitors instead of insulin and sulfonylureas to treat diabetes. Metformin has been reported to decrease metachronous adenomas or polyps after a polypectomy

 

Diet:

-- red- or processed-meats and sugary beverages are bad, likely from their adverse effects on the microbiome

 

Physical activity:

-- several observational studies have found that physical activity is associated with reduced CRC risk (more so for colon than rectal cancers)

 

Alcohol/tobacco

-- 25% increased risk of EOCRC for 3  drinks/day of alcohol, and 71% increase for smokers 

 

Aspirin/NSAIDs:

-- these are mostly found to be protective of CRC and of EOCRC

 

Chronic inflammation:

-- inflammatory bowel disease (IBD) is associated with CRC, presumably from the chronic inflammation and the associated increase in free radical species, circulating adipokines, up-regulared antiapoptotic and proliferative pathways

 

Intestinal dysbiosis:

-- some microbiome species seem to promote CRC, including Bacteroides fragilis, Fusobacterium nucleatum, Streptococcus bovis, and Escherichia coli

-- antibiotic use is associated with higher risk of CRC: athis is  more so for EOCRC which is associated with a 49% increased risk, vs the 9% increase for those >50yo (see colon ca antibiotic use inc risk early and late CRC BritJCa2021 in dropbox, or https://www.nature.com/articles/s41416-021-01665-7 )

 

Pollution:

-- residing within 1-3km from industries and exposure to air pollutants is associated with increased risk

    -- though, not stated, this might be a factor in the disproportionate CRC incidence in those of lower SES who tend to live in more industrial areas, though other related factors likely also play a part (diet, exercise, access to screening and health care overall…).  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422782/ )

 

Sites of CRC:

-- of note, the proximal colon, distal colon, and rectum have different embryological origins, with each embryological site having specific functions that  might explain differences in risk factors for different colonic sites:

    -- obesity is a stronger risk factor for proximal and distal colon cancer vs rectum

    -- physical activity decreases proximal and distal colon vs rectum

    -- smoking increases risk for distal colon and rectum

    -- alcohol, diabetes and NSAID use do not correlate with any specific site

 

Prognosis:

-- metastatic disease: some studies finding higher survival but other studies have found more disease progression (more studies with the latter finding) for EOCRC. But lots of confounding here:

    -- younger people are not systematically screened, so they present with more advanced tumors than those receiving regular screenings

    -- younger people are often not diagnosed as quickly, so cancers may progress more; the time from the onset of symptoms to cancer diagnosis is 40% longer in younger people

    -- likely related to this, younger patients have more adverse histopathological features than older ones: more poorly differentiated cancers, higher grade tumors with more perineural, lymphovascular, and venous invasion

    -- though younger patients do tend to get more aggressive therapies for their cancers, since they are young, healthier, have fewer comorbidities, and their bodies can handle them better

Molecular Signatures:

-- there are chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) pathways that might be different in EOCRC vs later-onset.  If interested, please see the text.

 

Treatment:

-- the treatment algorithms are pretty much the same for younger vs older people. Younger people often get more aggressive surgeries as noted above (including more resection of liver metastases, for example), though so far there is no clear benefit and perhaps even worse survival outcomes with some of these more aggressive surgeries. Please see text if interested in more details; however,  treatment approaches are likely to change over time, so perhaps best to check at the time it is an issue with the patient

 

Commentary:

-- colorectal cancer incidence has changed pretty dramatically from the mid-1980s:

 

 This chart is from colorectal cancer incidence patterns JNCI2017 in dropbox, or doi: 10.1093/jnci/djw322:

 

 

 

--similarly, breast cancers are increasingly frequent in younger women, also reinforcing the potential utility mammograms earlier: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10289488/. The earlier onset of breast cancers may be similar to the role of pollution, as noted with EOCRC: it is like the environmental toxicity from PFAS, the omnipresent “forever chemicals”, are involved with earlier onset breast cancer, likely related to the fact that >25% of PFAS are estrogenic

  

There are 2 major issues (I think) that are not included in this 23-page paper on “Early Onset Metastatic Colorectal Cancer: Current Insights” (ie, it is missing a couple of really important insights):

--They do not include HPV as one of their risk factors:

    -- HPV infection is remarkably common; per the CDC, more than 42 million Americans are infected with HPV, about 13 million Americans, including teens, become infected each year, and "nearly everyone will get HPV at some point in their lives": https://www.cdc.gov/hpv/parents/about-hpv.html

    -- anal intercourse is increasing in frequency: 30-40% of men and women have had anal intercourse at least once (prior estimates were in the 15%-20% range), and the vast majority of anal sexual encounters are condomless:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949144/  and https://www.theguardian.com/society/2022/aug/11/rise-in-popularity-of-anal-sex-has-led-to-health-problems-for-women

    -- 90% of anal cancers are linked to HPV, and men and women with HPV have an increased risk of developing anal cancer https://www.cancerresearchuk.org/about-cancer/anal-cancer/risks-causes#:~:text=Men%20and%20women%20with%20HPV,and%20goes%20away%20without%20treatment.

    -- a systematic review and meta-analysis of HPV and anal cancer according to sex and HIV status found that HPV16 serotype positivity in particular was associated with increased severity of abnormal anal diagnoses (high grade-lesions and anal cancer), both in HIV positive and negative individuals: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805865/

        -- and, not surprisingly, HPV has been included in other enumerations of the anogenital risk factors: https://pubmed.ncbi.nlm.nih.gov/9217656/ 

    -- HPV vaccination “should effectively prevent anal cancer", reinforcing the huge importance of vaccinations: https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1149274 

--and this review does not include environmental toxins as a risk factor (other than air pollution):

    -- inflammatory bowel disease and chronic inflammation in the intestines seem to be associated with colon cancer

    -- many toxins are associated with chronic inflammation, such as microplastics: https://gmodestmedblogs.blogspot.com/2024/03/plastics-too-many-and-too-bad-for-our.html

    -- exposure to high concentrations of PVC microplastic particles  are linked to liver cancer (https://onlinelibrary.wiley.com/doi/10.1002/ajim.23540 ); workers exposed to PVC in the vinyl chloride industry are at higher risk of lung cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141742/ 

    -- PVC microplastics induce microbiome dysbiosis and gut barrier dysfunction in mice: https://www.sciencedirect.com/science/article/pii/S0147651322006492

    -- and, microbiome changes might be an important factor in the development of early-onset colorectal cancers (see microbiome and early onset colon cancer Cancers2024 in dropbox, or doi.org/10.3390/ cancers16030676, a review article that suggests strongly that younger individuals are exposed to very different toxins than the older generation at the same age, as well as an increased incidence of some of the more traditional colon cancer risk factors (eg diabetes, and especially obesity; this study also elaborates information on the microbiome changes in humans from microplastics)

        -- especially with the excessive rate of ~2000 new chemicals developed each year,  >80,000 chemicals used in commerce in the US, and  >2.5 million tons of toxic chemicals released into the environment by industry every year (https://www.worldometers.info/view/toxchem/#google_vignette), which is increasing over time (https://www.newscientist.com/article/2367026-us-toxic-chemical-emissions-to-air-water-and-soil-increased-in-2021/ ), huge numbers of potential toxins are making their way into our (and other animals, plants etc) air/water/soil/food supply. And, no federal agency is really able to assess the potential toxicity of these chemicals to the human body (at best for the vast majority of them, it is up to industry to do some animal studies).

        --and humans have many ways in which external toxins can affect our health, besides the direct absorption of toxins through ingestions, including the changes induced in our various microbiomes (gut, upper and lower respiratory tract, vagina, skin)  as well as leading to possible epigenetic effects

-- also, the association between chronic inflammation and EOCRC may be even much more of a problem than we know: there are huge numbers of causes of increased inflammation, from diabetes, obesity, atherosclerotic disease, autoimmune disease, COPD, asthma, neurodegenerative diseases, chronic infections and some other cancers, to depression, stress, low SES/income equality (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814496/). And likely many more conditions to be discovered

so, a provocative study:

-- the findings of this study and many others on EOCRC lay bare the rather precarious position we humans (and the rest of most living things) are in now.

-- as with climate change, the focus on short-term issues is coming back to haunt us: releasing large quantities of many toxins into the environment for short-term financial gain for corporations and some population benefits

-- and the global health and social changes (increases in obesity, diabetes, income inequality/stress/depression), with their association with chronic inflammation is another profound change

-- which all means that for the future of humans, we really do need to address these profound  issues aggressively and in a really timely fashion...

geoff

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