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AbstractBackgroundThe incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants.MethodsRelying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.ResultsIncreasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores.ConclusionsPersonal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes’ coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84–1.27 and OR: 1.08, 95% CI: 0.86–1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

Abstract Background Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study–specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (Ptrend < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; Pdifference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference < .001). Conclusion Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.

7538 Background: PTEFb/CDK9-mediated transcription of short-lived anti-apoptotic survival proteins and oncogenes like MCL-1 and MYC plays a critical role in a variety of cancers. VIP152 (formerly BAY 1251152), a potent and highly selective CDK9 inhibitor, has been evaluated in a Phase 1 dose-escalation study in patients with advanced cancer. The maximum tolerated dose was 30 mg once weekly administered in consecutive 21-day cycles, based on neutropenia as the dose-limiting toxicity (JCO 2018;36:2507; NCT02635672). DHL is defined as dual rearrangement of the MYC gene and either the BCL2 or BCL6 genes; the resulting overexpression of MYC and BCL2/BCL6 make it particularly difficult to treat. Patients with DHL have a poor prognosis and no standard of care. Considering the impact of CDK9 inhibition on MYC, an exploratory cohort of patients with DHL was added to the study. Methods: Patients with refractory or relapsed DHL were eligible. VIP152 was administered once weekly as a 30-minute IV infusion on Days 1, 8 and 15 of a 21-day cycle. Tumor response was assessed according to the revised Cheson criteria (2007). Results: To date a total of 7 patients have been enrolled and were evaluable at the time of data cutoff (24NOV2020). The patients were mostly men (6/7 pts, 86%) with a median (range) age of 70 (58-84) years. All patients received ≥2 prior therapies, including 2 patients with bone marrow transplant. Three of 7 patients (29%) had ≥3 prior therapies. The median time on treatment was 22 days (range 8-1361 days). The most common adverse events of any grade were: constipation, fatigue, nausea (each 3/7 pts, 43%) and abdominal pain, diarrhea, lymphocyte count decrease, neutrophil count decrease, skin infection, tumor pain, and vomiting (each 2/7 pts, 29%). Most were Grade 1 and Grade 2. The Grade 3 adverse events were fatigue, lymphocyte count decrease, neutrophil count decrease (each 1/7 pts, 14%) and tumor pain (2/7 pts, 29%). One Grade 4 lymphocyte count decrease was reported. Two patients had a serious adverse event (Grade 3 syncope and Grade 3 tumor pain). Two patients had dosing held for an adverse event; however, no patient withdrew from treatment due to any adverse events. One death occurred due to disease progression. Pharmacodynamic biomarker analysis showed significant reduction of MYC, PCNA, and MCL-1 mRNA in all patients across multiple timepoints. Antitumor activity consisted of 2 complete metabolic responses in 7 patients (29%) based on investigator-assessed FDG-PET scans. Due to the COVID pandemic, the patients withdrew consent after 3.7 and 2.3 years, respectively, of treatment. Both patients were in complete metabolic response. Conclusions: VIP152 had a manageable safety profile, on-target pharmacodynamic activity and signs of durable monotherapy antitumor activity in patients with DHL. These encouraging results warrant further evaluation of VIP152 in patients with MYC-driven lymphoma and solid tumors. Clinical trial information: NCT02635672.

Abstract Background Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04). Conclusion In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.

Abstract Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively). Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

320 Background: Genomic profiling studies have reported somatic HER2 mutations in ~2–5% of biliary tract cancers (BTC). Clinical data from the SUMMIT study demonstrate that neratinib, a pan-HER irreversible tyrosine kinase inhibitor, has encouraging clinical activity in multiple types of HER2-mutant solid tumor malignancies. Methods: SUMMIT is a multi-histology, open-label, phase II ‘basket’ study of neratinib in patients with somatic HER2 mutations (ClinicalTrials.gov NCT01953926). Patients with activating somatic HER2 mutations with different histologies, including BTC, received neratinib monotherapy (240 mg oral daily). Loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints: objective response rate (ORR, RECIST v1.1); clinical benefit rate (CBR); duration of response; progression-free survival (PFS). Adverse events (AEs) were assessed by CTCAE v4.0. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 3-Sep-2020, 25 patients with HER2-mutant BTC were enrolled: gallbladder (40%); intrahepatic (24%); extrahepatic (20%); ampulla of Vater (16%). 68% of patients received ≥2 systemic regimens (96% received prior gemcitabine-based regimens). The S310F/Y variant accounted for nearly half of HER2 mutations (n=11). Other HER2 mutations: V777L (n=5); L755S (n=2); V842I (n=2); R678Q (n=2). Confirmed ORR in 25 evaluable patients was 12% (95% CI 3–31%) and CBR was 20% (95% CI 7–41%), including 3 confirmed PRs and 2 patients with SD for ≥16 weeks. Tumor shrinkage was observed in multiple HER2-activating mutations and enriched in gallbladder and extrahepatic subtypes of BTC. Median PFS was 2.8 (95% CI 1.1–3.7) months; median overall survival (OS) was 5.4 (95% CI 3.7–11.7) months. Nine (36%) patients (3 of whom with ECOG PS 2) came off study within 28 (range 6–47) days of treatment due to clinical deterioration (unrelated to study drug) followed by death. The most common treatment-related AEs (any grade) were diarrhea (56%) and vomiting (48%). Diarrhea was the most common Grade 3 event (24%); 4 patients (16%) required a neratinib dose reduction; no patients discontinued treatment due to diarrhea. Conclusions: Neratinib is safe and tolerable in patients with advanced BTC patients and somatic HER2 mutations. The antitumor activity of neratinib appears comparable to current standards of care, with similar PFS and OS in heavily pretreated patients. Analysis of co-occurring oncogenic mutations and response is ongoing, and consideration is being given to neratinib-based combination regimens to further improve outcomes in this setting. Clinical trial information: NCT01953926.

Abstract Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. Significance: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

Abstract Background: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. Methods: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. Results: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10−4), KRT16 (PG×E = 2.3 × 10−4), CD14 (PG×E = 9.38 × 10−4), and CYP27A1 (PG×E = 1.44 × 10−3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10−5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. Conclusions: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. Impact: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

AbstractBackgroundPostmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.MethodsWe pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided.ResultsAmong postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors.ConclusionsWe observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.