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Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A*02:01, HLA-DRB1*15:01 and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS).Transcriptome-wide association (TWAS) and genome-wide association (GWAS) analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n=133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared to 1358 and 403 non-AC-DILI cases.TWAS revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7x10We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B*15:18. GRS based on the five risk variants may assist AC-DILI causality assessment and risk management.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

Can strategic information acquisition harm the provision of a public good? We investigate this question in an incentivized online experiment with a large sample of the German population. The marginal returns of the public good are uncertain: it is either socially efficient to contribute or not. In the information treatment, participants can choose between two information sources with opposite biases. One source is more likely to report low marginal returns, whereas the other is more likely to report high marginal returns. We find that information avoidance is a minor phenomenon. Most participants select the source biased towards reporting low marginal returns, independent of their prior beliefs. As a result, the information treatment reduces contributions and increases free-riding. When contributing is socially efficient, the information treatment reduces social welfare. We find that social preferences guide information acquisition: socially-oriented participants are more likely to acquire information and select the source that is biased towards reporting low marginal returns. JEL Classification: C99, D12, D61, D83, H41

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0-∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.

BACKGROUND: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal ancer (mCRC), nor how comorbidities impact treatment tolerance. METHODS: We utilized a cohort of 1,345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. RESULTS: In CALGB/SWOG 80405, 1,095 (81%) subjects were

Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (Pintx = 0.0167), VCAM-1 (Pintx = 0.0216), and PDGF-AA (Pintx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (Pintx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.

Figure S1, consort diagram. Table S1, pts characteristics. Table S2, baseline levels. Table S3, prognostic markers. Table S4, adjusted prognostic markers. Table S5, early changes. Table S6, late changes at disease progression.

Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

PDF file - 102K, Summary of KDR genetic variant found after resequencing of 72 healthy subjects of three different ethnicities.

Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC.Significance:Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734–44. ©2018 AACR.

PDF file - 46K, KDR regions containing dense clusters of transcription factor binding motifs identified by Cluster-Buster.

Genotyped genes.

Purpose:Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer.Experimental Design:We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders.Results:At study entry, 63% of patients were vitamin D deficient (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics.Conclusions:In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53.Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies.Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies.Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. (Clin Cancer Res 2009;15(18):5714–23)

PDF file - 26K, Correlation of VEGFR-2 and KDR mRNA levels.

Purpose: UGT1A1*28 confers a higher risk of toxicity in patients treated with irinotecan. Patients with *1/*1 and *1/*28 genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with *1/*1 and *1/*28 genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics.Experimental Design: Previously untreated patients with mCRC (25 *1/*1; 23 *1/*28) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m2. The MTD was the highest dose at which Results: For *1/*1 patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2 was not tolerated (2 DLTs in 4 patients). For *1/*28 patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2 was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal.Conclusions: The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m2 for UGT1A1 *1/*1 patients and 260 mg/m2 for *1/*28 patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab. Clin Cancer Res; 23(4); 918–24. ©2016 AACR.

Supplementary Table 1. Toxicities during the first cycle of FOLFIRI plus bevacizumab. Number of patients (%) is indicated. Toxicities were included if they occurred in at least 10% of patients or if they were grade 3 or greater, and if they were at least possibly related to treatment.

Expression of WT and T494A VEGFR-3 in HUVECs (A) and replication of phosphorylation experiments testing the effect of FLT4 rs307826 (A>G, T494A) on VEGFR-3 phosphorylation (B).

PDF file - 60K, KDR conserved regions determined using comparative genomics analysis in the UCSC Genome Browser.

Background and Aims: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint.Experimental Design: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis.Results: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10−7). Median OS was significantly shorter (P = 2.61 × 10−8) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3–4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8–7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10−7.Conclusions: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer. Clin Cancer Res; 18(2); 577–84. ©2011 AACR.

Supplemental Methods, Tables and Figures Table S1. Analyzed candidate genes Table S2. Gene sets and pathways used for candidate gene selection Table S3. Quality of sequencing reads per sample Table S4. Post-QC quality per sample Table S5. Replication cohorts Table S6. Gene-based analysis of rare and low frequency variants (MAF < 0.03) in candidate genes Table S7. Characteristics of replication patient subgroups Figure S1. Candidate gene analysis workflow. Figure S2. Associations with bevacizumab-induced hypertension in the SLC29A1-HSP90AB1 region. Figure S3. Top SLC29A1-HSP90AB1 SNPs are in predicted transcriptionally active regions in human umbilical vein endothelial cells. Figure S4. Proportion of high-grade hypertension in replication cohorts stratified by variant allele carrier status. Figure S5. Dose-dependent effects of adenosine on cyclic AMP and nitric oxide levels. Figure S6. Effects of adenosine receptor blockade on cyclic AMP and nitric oxide levels in HUVEC. Figure S7. Effect of ENT1 inhibition on cyclic AMP levels. Figure S8. Effect of SLC29A1-overexpression on cyclic AMP levels in HUVEC. Figure S9. Linkage disequilibrium plot of SLC29A1-HSP90AB1 intergenic region.

Supplementary Table from Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)

Supplementary Data from Tumor Immunogenomic Features Determine Outcomes in Patients with Metastatic Colorectal Cancer Treated with Standard-of-Care Combinations of Bevacizumab and Cetuximab

SNP selection criteria, imputation and bioinformatic analyses

Supplementary Data from Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer

PDF file - 94K, Bioinformatic analyses of the putative functional effects of KDR genetic variants.

PDF file - 155K

Supplementary Figures 1-5 and Supplementary Tables 1-5

Purpose:Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405.Experimental Design:Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models.Results:The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10−6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10−6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced.Conclusions:This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.

Individualized drug dosing is a longstanding goal of clinical pharmacologists. Given the narrow therapeutic index of most anticancer agents, it is plausible that this approach would be of particular value in oncology. Irinotecan is an interesting agent for individualized dosing, given its complex metabolism and increasing knowledge of its pharmacokinetics predictors. Clin Cancer Res; 16(2); 371–2

Purpose: VEGF receptor 2 (VEGFR-2) plays a crucial role in mediating angiogenic endothelial cell responses via the VEGF pathway, and angiogenesis inhibitors targeting VEGFR-2 are in clinical use. As angiogenesis is a host-driven process, functional heritable variation in KDR, the gene encoding VEGFR-2, may affect VEGFR-2 function and, ultimately, the extent of tumor angiogenesis.Experimental Design: We resequenced KDR using 24 DNAs each from healthy Caucasian, African American, and Asian groups. Nonsynonymous genetic variants were assessed for function by phosphorylation assays. Luciferase reporter gene assays were used to examine effects of variants on gene expression. KDR mRNA and protein expression and microvessel density (MVD) were measured in non–small cell lung cancer (NSCLC) tumor samples, and matching patient DNA samples were genotyped to test for associations with variants of interest.Results: KDR resequencing led to the discovery of 120 genetic variants, of which 25 had not been previously reported. Q472H had increased VEGFR-2 protein phosphorylation and associated with increased MVD in NSCLC tumor samples. −2854C and −2455A increased luciferase expression and associated with higher KDR mRNA levels in NSCLC samples. −271A reduced luciferase expression and associated with lower VEGFR-2 levels in NSCLC samples. −906C and 23408G associated with higher KDR mRNA levels in NSCLC samples.Conclusions: This study has defined KDR genetic variation in 3 populations and identified common variants that impact on tumoral KDR expression and vascularization. These findings may have important implications for understanding the molecular basis of genetic associations between KDR variation and clinical phenotypes related to VEGFR-2 function. Clin Cancer Res; 17(16); 5257–67. ©2011 AACR.

Supplementary Figure and Table

PDF file - 30K, MVD and tumor histology. Panel A shows the log2-transformed MVD percentage of NSCLC samples from different tumor histologies (SCC = squamous cell carcinoma; AC = adenocarcinoma; LCC = large cell carcinoma; NOS = not otherwise specified). In panel B, Group 1 is composed of squamous cell carcinomas and NSCLCs not otherwise specified/mixed; Group 2 is composed of adenocarcinomas and large cell carcinomas. The result of a t-test examining the differences between the two groups is shown.

PDF file - .97MB, Select analysis for KDR SNPs within three ethnic groups (MAF>5%, r2�0.8). The top colored panels shows the genotype of each individual from the different ethnic groups using the SNP ID labels from Table S4. Haplotype tagging SNPs (tSNPs) are denoted with an asterisk and haplotype blocks with the line above. The bottom panels show the pair-wise LD pattern with r2�0.8.

PDF file - 31K, Correlation of VEGFR-2 and MVD levels.

Supplementary Figure 1. Progression-free survival (PFS) overall (A), by UGT1A1 genotype (B), and by irinotecan dose (C).

Purpose:CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.Patients and Methods:In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment.Results:In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097).Conclusions:In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725

PDF file - 7.40MB, Pairwised LDPlotter analysis for KDR SNPs within three ethnic groups (MAF>5%). The panels show the pair-wise LD pattern using for the three ethnic groups using the SNP ID labels from Table S4.

Supplementary Figure from Tumor Immunogenomic Features Determine Outcomes in Patients with Metastatic Colorectal Cancer Treated with Standard-of-Care Combinations of Bevacizumab and Cetuximab

PDF file - 57K, KDR re-sequencing primers.