No abstract

Chemotherapies administered at normal therapeutic dosages can cause significant side‐effects and may result in early treatment discontinuation. Inter‐individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome‐wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN‐B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome‐wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10−7) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10−7. rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0‐8.3, P = 9.8 × 10−10) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand‐foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10−6). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome‐wide analyses of large, well‐characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.

Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand‐foot syndrome (HFS) or palmar‐plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type‐2 diabetes (T2D), a disease also associated with HFS. We analysed genome‐wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN‐B trials. One thousand and fifty‐five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN‐B with grade 2‐3 HFS responded to treatment as compared to 58% with grade 0‐1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02‐1.2, P = 2.0 × 10−4). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84‐0.99, P = 4.6 × 10−2). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1‐4.6, P = 4.3 × 10−8) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42‐1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92‐0.96, P = 1.2 × 10−8) and the rs6783836‐T allele was associated with lowered HbA1c levels (P = 5.9 × 10−3) and lymphocyte count (P = 2.7 × 10−3), and psoriasis (P = 7.5 × 10−3) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

3028 Background: Fluoropyrimidine (FP) based adjuvant chemotherapy (5-Fluorouracil and Capecitabine) increases survival of patients with colorectal and breast cancers. However, 1-5 % of patients experience cardiovascular toxicity, which is not explained by variants in the gene encoding dihydropyrimidine dehydrogenase. Methods: We sought genetic determinants of FP-induced cardiovascular toxicity by performing a genome wide association study of NCI-CTCAE graded cardiovascular toxicity using samples from the QUASAR 2 trial (n=759 patients with colorectal cancer (CRC)). Validation studies (n= 5438 patients with CRC and 1478 patients with breast cancer) were performed in the SCOT, COIN and TACT2 trials. The most commonly reported symptoms were chest pain, angina and arrhythmias with 6 patients experiencing myocardial infarctions. Results: rs4904753, mapping to an intron of D-glutamate cyclase (DGLUCY) was genome wide significant in QUASAR 2 (P =4.38 x 10-16) and validated in SCOT, COIN and TACT2 (P<0.0002 in all studies. rs4904753 was associated with levels of expression of DGLUCY in multiple tissues including the atrial appendage. Under a recessive model, 45.3% (61/137) of patients with cardiac toxicity as compared to 10.2% (691/6786) of controls carried both minor alleles (meta-analysis: OR=7.72, 95% CI 5.31-11.22, P=1.03 x 10-26). Conclusions: The sensitivity, specificity, positive predictive value and negative predictive values of testing for two copies of the toxicity associated allele of rs4904753 were 48%, 90%, 8% and 99% respectively. Clinical implementation of testing for this variant has the potential to identify almost half of those at risk of FP-induced cardiovascular toxicity with high specificity, thereby enabling changes to their clinical management. [Table: see text]

Background: Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations.Methods: In total, 694 patients from the clinical trials COIN and COIN-B had MAPKactivated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2.Results: In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p = 2.0 Â 10 À5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (p Z-test = 2.1 Â 10 À3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio[HR] = 0.62, 95% confidence intervals [CI] = 0.5-0.8, p = 3.4 Â 10 À5 ) but not BRAF mutant (p = 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta = À0.037, standard error [SE] = 0.017, p = 3.2 Â 10 À2 ) and reduced RASAL2 expression in cultured fibroblasts (p = 1.6 Â 10 À11 ). Conclusion:Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.