Update on Early-Onset Colorectal Cancer (EOCRC)

Thomas F. Imperiale, MDIndiana University School of Medicine

Indianapolis, IN, USAWEO Colorectal Cancer Screening (Virtual) Committee Meeting

October 9, 2020

Outline for this talk*

• Review basic epidemiology of EOCRC

• Discuss recent studies on genetic and phenotypic risk factors

– Includes risk prediction models

• Discuss what’s needed and what can be done now

*No relevant disclosures

Siegel RK, et al. Gut 2019

Age-standardized incidence rates, 2008-12, for CRC, adults 20-49 years:- Red – AAPC increased- Gray – stable or insufficient numbers- Blue – AAPC decreased

Siegel RL, et al. Gut 2019; 68:2179-85

Epidemiology of EOCRC (U.S.)• 10-11% of all CRC

• Median age = 44 years

• 75% of all EOCRC occurs in 40-49 year-olds– 50% of all in 45-49 year-olds

• 75% of EOCRC is distal to the splenic flexure

• 17% have a FDR w/ CRC (vs. 8% controls)

• 15% have deficient MMR activityPatel SG and Boland CR. Gastrointest Endoscopy Clin N Am 2020:30:441-455

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Genetic Risk Phenotypic Risk

Contributors to CRC Risk

Study Aim and Methods• Determine whether a “personalized risk score” (PRS) of 95 CRC

associated SNPs is associated with EOCRC• Pooled CRC cases and controls with clinical and genotyping data

– Colon Cancer Family Registry– Colorectal Transdisciplinary Study– Genetics and Epidemiology of CRC Consortium (GECCO)

• Weighed PRS based on # risk alleles for each SNP• Compared PRS between EOCRC & Late-onset CRC, and between

cases and controls• Findings tested in replication dataset of 72,573

– 25 EOCRC, 1,068 Usual-onset CRC, 71,380 controls w/o CRC

Risk estimates for EO vs Late-onset CRC associated with a 95-SNP PRS (Archambault et al. Gastroenterology 2020)

GROUPHazard Ratio (95% CI) per 1 Std deviation

P-value Fold-increase from lowest to highest quintile

All Subjects

< 50 years old 1.73 (1.17-2.56) 0.0056 3.7

≥ 50 years old 1.43 (1.34-1.51) 2.77E-31 2.9

Negative Family History

< 50 years old 1.76 (1.11-2.78) 0.0161 4.3

≥ 50 years old 1.42 (1.33-1.52) 2.85E-25 2.9

Positive Family History

< 50 years old 1.56 (0.75-3.26) 0.23 1.7

≥ 50 years old 1.34 (1.17-1.54) 2.87E-5 2.5

Archambault AN, et al. Gastroenterology 2020

Archambault AN, et al. Gastroenterology 2020

Study summary

• The PRS, derived from common SNPs, stratifies individuals for risk of EOCRC, particularly among those reporting no FDR with CRC.

• The associations between PRS and CRC are greater for EOCRC than for late-onset CRC.

• The PRS may – along with lifestyle and environmental risk factors – contribute toward prioritizing earlier, personalized screening or other interventions.

Selected recent studies on RFs for EO-CRCCountry, yr

Study design Study N Age Group

Outcome (%) Independent Risk Factors

S. Korea, 2017

Prospective XS, screening colonoscopy

2206 40-49 Adv Neoplasia (2.4)

Age (1.16), smoking (3.12) metabolic syndrome (2.00)

China, 2017

Prospective XS, screening colonoscopy

1133 40-49 Adv Neoplasia (2.9)

Male sex, age 45-49, FDR w/CRC, (NNS=18.5) with all 3; diabetes

UK, 2019 Case-control (Clin Practice Research Datalink)

29K cases137K con.

< 50 CRC Penicillin (1.5), Tetracycline (0.90) Atbx use > 10 years prior (1.17)

U.S., 2019

Prospective cohort (Nurses Health Study II)

89,278 women 118 EOCRC

25-42 CRC > 14 hours of TV/wk (vs. ≤ 7 hrs) RR=1.69; RR=2.44 for rectal CA, no FHx

U.S., 2020

Case-control (single center)

269 EOCRC2802 LO-CRC1122 controls

18-49 CRC Male sex, IBD, FHx of CRC – risk factors for EOCRC vs. controls; Male, Black, Asian, IBD, FHx for EOCRC vs LOCRC

Koo JE, J Gastro Hep 2017; 32:98-105; Wong JTC, J Gastro Hep 2017; 32:92-97; Gausman V, Clin Gastro Hep 2019; Zhang J, et al. Gut 2019; doi:10.1136/gutjnl-2019-318593; Nguyen LH, JNCI Cancer Spectrum 2019; 2(4);pky073

Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2019

BMI at an early age and risk of CRC• Meta-analysis of 15 observational studies

– 13 cohort, 2 case-control

• Related body “fatness” prior to age 30 to current risk of CRC - per 5 kg/m2 increase

• Covariates – age, sex, SES, education, physical activity, diet components, smoking, alcohol, OC/exogenous estrogens, FHx CRC, Ht, DM, ASA

Hidayat K, et al. Int’l J Cancer 2018; 142:729-740

Subgroup of studies for persons < 50 years

1st Author Design N Meanage (years)

F/U duration (years)

Adjusted Relative Risk* (95% CI)

Lundqvist Pro cohort 25,565 28.4 28.4 (!) 1.07 (0.98-1.17)

Burton Retro cohort 12,206 20 49 1.16 (0.90-1.50)

Levi Pro cohort 1.1 million 17.3 17.6 1.21 (1.00-1.45)

Kantor Pro cohort 239,658 18 35 1.29 (1.17-1.42)

Hidayat K, et al. IJC 2018

* Per 5 kg/m2 increase

RISK PREDICTION MODELS FOR ADVANCED COLORECTAL NEOPLASIA IN PERSONS < 50

1ST Au, Country, Year

Population(N)

Model variables

Advanced neoplasia (%)

How the model was used

Model metrics and Results

Jung YS, S. Korea, 2017

30-49 year olds, screening colonoscopyN=57,635 derivationN=38,600 validation

Age, sex, BMI, FHx CRC, smoking

1.2 % Cutoff of >= 1.4% predicted probability

AUROC = 0.67 vs. APCS at 0.59, KCS at 0.60, and Kaminski at 0.59

Park YM S. Korea, 2017

40-49 year olds, screening colonoscopyN=2,781

“Older” age (45-49) years, male sex, HDL chol, H. pylori, triglycerides.

2.5% Scoring system of 0 →9; score of ≥ 4 as “high risk” (43%)

“High-risk” had Sensitivity =79%Specificity = 58%AUROC = 0.72

Jung, YS, et al. Dig Dis Sci 2017;62:2518-25 Park YM, et al. BMC Gastro 2017; 17:7

What is needed• Hypothesis-generating research

– Population-based (“ecological”) research – identify candidate risk factors

– Lab-based research on cellular / molecular mechanisms

• Observational research – identify / solidify risk factors– Improve risk stratification (?combine with genetic RFs)

• Large database research examining gene-environment interactions– Consider microbiome

• Promotion of what we can do NOW……

What to do now for EOCRC

• For patients / the public– Report lower GI symptoms, especially bleeding– Look at stools, toilet paper– Adhere to healthy lifestyle – diet, BMI, exercise, no smoking, limit ethanol

• For providers– Take thorough family histories – other cancers, AAs– *ASK* re: lower GI symptoms, constitutional (unintended weight loss)– At least sigmoidoscopy for unexplained rectal bleeding– Appropriate use of colonoscopy (e.g., unexplained Fe-deficient anemia) – Appropriate imaging for unexplained abdominal pain– Consider “early” screening (45) for multiple risk factors (smoking, BMI)

• For systems– Universal testing of CRCs for dMMR (and NGS for all EOCRC)

Thomas F. Imperiale, MD