What, how, when and who of trial results summaries for trial participants : Stakeholder informed guidance from the RECAP project.

Funding RECAP was funded by the Academy of Medical Sciences (SBF002\1014) and KG was funded by a Medical Research Council Strategic Skills Methodology Fellowship (MR/L01193X/1). The Health Services Research Unit, Institute of Applied Health Sciences (University of Aberdeen), is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates (CZU/3/3).Peer reviewedPublisher PD

Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab

Background Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesized that common germline variants within these pathways may also play similar roles. Methods We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy +cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. Results We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab - in patients with KRAS wild type CRCs, 36.4% of patients with one allele encoding proline responded, as compared to 71.2% of patients homozygous for alleles encoding serine (OR 0.23, 95% CI 0.09-0.56, P=0.0014) and this association was predictive for cetuximab (Pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. Conclusions Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity

Pharmacogenetic analyses of 2,183 patients with advanced colorectal cancer; Potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy.

BACKGROUND: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). METHODS: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. RESULTS: Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2-2.9, P = 0.004, and OR 0.7, 95% CI 0.5-0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7-1.0, P = 0.008, and OR 1.6, 95% CI 1.1-2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1-1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. CONCLUSIONS: DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy

Applications of a novel assay to investigate variation in DNA repair in human populations

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background

A Bloom’s deficient mouse model (Blmm3/m3) has been shown to induce colorectal tumorigenesis when crossed with Apc+/Min mice. Here, we investigated whether the Blmm3/m3 genotype could induce tumorigenesis in extracolonic tissues in tuberous sclerosis 1–deficient (Tsc1+/) mice that are predisposed to renal cystadenomas and carcinomas. Genotyping of offspring from Tsc1+/ Blm+/m3 intercrosses showed that a f24% excess of Tsc1+/ over Tsc1+/+ mice died before weaning (P = 0.016), although Blm deficiency had no cumulative effect on Tsc1+/ survival. Tsc1+/ Blmm3/m3 mice had significantly more macroscopic and microscopic renal lesions at 3 to 6 months compared with Tsc1+/ Blm+/m3 mice (P =0.0003 and 0.0203, respectively), and their tumors showed significantly increased levels of somatic loss of heterozygosity (LOH) of the wild-type Tsc1 (Tsc1wt) allele compared with those from Tsc1+/ Blm+/+ mice (P < 0.0001). Tsc1+/ Blm+/m3 mice did not show significantly more renal lesions compared with Tsc1+/ Blm+/+ animals; however, their lesions still showed significantly increased levels of somatic LOH of the Tsc1wt allele (P = 0.03). Ninety-five percent (19 of 20) of lesions from Tsc1+/ Blm+/m3 mice retained the wild-type Blm (Blmwt) allele, indicating that the increased somatic LOH at Tsc1 was mediated by Blm haploinsufficiency. Renal lesions from a Blm-deficient background stained positively with anti-phospho-S6 ribosomal protein (Ser240/244), suggesting that these lesions develop through the normal pathway of Tsc-associated tumorigenesis. This work shows the use of the Blmm3/m3 mice for inducing renal tumorigenesis, and the high levels (f87%) of LOH in the resultant tumors will help facilitate mapping of loci involved in tumor progression. (Cancer Res 2005; 65(22): 10179-82

Tsc1 Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation in Tsc1+/- Mice

Tuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 gene. Both genes are generally considered to act as tumor suppressors that fulfill Knudson’s ‘‘two-hit hypothesis’’ and that function within the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (mTOR) pathway. We previously generated Tsc1+/� mice that are predisposed to renal cysts, which develop into cystadenomas and renal cell carcinomas. Here, we identified somatic Tsc1 mutations (second hits) in f80% of cystadenomas and renal cell carcinomas, but only 31.6% of cysts from Tsc1+/� mice (P < 0.0003), raising the possibility that haploinsufficiency for Tsc1 plays a role in cyst formation. Consistent with this proposal, many cysts showed little or no staining for phosphorylated mTOR (53%) and phosphorylated S6 ribosomal protein (37%), whereas >90% of cystadenomas and renal cell carcinomas showed strong staining for both markers (P < 0.0005). We also sought somatic mutations in renal lesions from Tsc1+/� Blm �/� mice that have a high frequency of somatic loss of heterozygosity, thereby facilitating the detection of second hits. We also found significantly less somatic mutations in cysts as compared with cystadenomas and renal cell carcinomas from these mice (P = 0.017). Our data indicate that although activation of the mTOR pathway is an important step in Tsc-associated renal tumorigenesis, it may not be the key initiating event in this process. (Cancer Res 2006; 66(16): 7934-8

Providing trial results to participants in Phase III pragmatic effectiveness RCTs : a scoping review

RECAP was funded by the Academy of Medical Sciences (SBF002\1014), and KG was funded by the Medical Research Council (MR/L01193X/1). AS was funded by the Medical Research Council (grant number: MC_UU_12023/24). The Health Services Research Unit is core-funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates (CZU/3/3). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the funders.Peer reviewedPublisher PD