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Background Extensive extracellular matrix (ECM) remodeling is a hallmark of metastatic pancreatic ductal adenocarcinoma (mPDA). We investigated fragments of collagen types III (C3M, PRO-C3), VI (PRO-C6), and VIII (C8-C), and versican (VCANM) in plasma as biomarkers for predicting progression-free survival (PFS) and overall survival (OS) in patients with mPDA treated with pegvorhyaluronidase alfa, a biologic that degrades the ECM component hyaluronan (HA), in a randomized phase 2 study (HALO109-202). Methods HALO109-202 comprised a discovery cohort (Stage 1, n = 94) and a validation cohort (Stage 2, n = 95). Plasma ECM biomarkers were analyzed by ELISAs. Univariate Cox regression analysis and Kaplan–Meier plots evaluated predictive associations between biomarkers, PFS and OS in patients treated with pegvorhyaluronidase alfa plus nab-paclitaxel/gemcitabine (PAG) versus nab-paclitaxel/gemcitabine (AG) alone. Results PFS was improved with PAG vs. AG in Stage 1 patients with high C3M/PRO-C3 ratio (median cut-off): median PFS (mPFS) 8.0 vs. 5.3 months, P = 0.031; HR = 0.40; 95% CI 0.17–0.92). High C3M/PRO-C3 ratio was validated in Stage 2 patients by predicting a PFS benefit of PAG vs. AG (mPFS: 8.8 vs. 3.4 months, P = 0.046; HR = 0.46; 95% CI 0.21–0.98). OS was also improved in patients with high C3M/PRO-C3 ratio treated with PAG vs. AG (mOS 13.8 vs 8.5 months, P = 0.009; HR = 0.35; 95% CI 0.16–0.77). Interestingly, high C3M/PRO-C3 ratio predicted for a PFS benefit to PAG vs. AG both in patients with HA-low tumors (HR = 0.36; 95% CI 0.17–0.79) and HA-high tumors (HR = 0.20; 95% CI 0.06–0.69). Conclusions The C3M/PRO-C3 ratio measuring type III collagen turnover in plasma has potential as a blood-based predictive biomarker in patients with mPDA and provides additional value to a HA biopsy when applied for patient selection. Trial registration: NCT01839487. Registered 25 April 2016

Introduction Subcutaneous (SC) formulations of therapeutics with recombinant human hyaluronidase PH20 (rHuPH20) are currently approved across various disease indications. The rHuPH20-mediated enzymatic degradation of SC hyaluronan (HA) facilitates bulk fluid flow and dispersion of co-administered therapeutics. However, current methods of quantifying dispersion in the SC space are limited. Here, a novel method is outlined to quantify and follow rapid SC volumetric dispersion of a representative therapeutic fluid in the presence of rHuPH20 using computed tomography (CT). Methods Ten Yucatan miniature swine were randomized to three groups. Animals received simultaneous infusions of contrast agent (CA) alone (left side of the animal) or in combination with rHuPH20 (right side) at infusion rates of 2.5, 5, or 10 mL/min. Spiral CT scans (1.5 mm thickness) were conducted before and after the infusion and at regular time intervals throughout. Scans were used to create three-dimensional (3D) reconstructions of the fluid pockets and analyze surface area, volume, and sphericity. Results 3D reconstruction showed increased dispersion of CA with rHuPH20 compared with CA alone, with fenestration and increased dispersion in the craniocaudal and lateromedial directions. The CA with rHuPH20 fluid pockets showed an average increase of 46% in surface area (p = 0.001), a 35% increase in volume (p = 0.001) and a 17% decrease in sphericity post-infusion compared with CA alone at 30 min post-infusion. Discussion This exploratory study confirms the value of CT imaging as a non-invasive method of assessing real-time spatial and temporal behavior of SC-administered fluids. This technique could help to assess the dispersion pattern of novel rHuPH20 SC co-formulations.

Genetic variation at insulin-like growth factor 1 (IGF1) has been linked to prostate cancer risk. However, the specific predisposing variants have not been identified. In this study, we fine-mapped the IGF1 locus for prostate cancer risk in African Americans. We conducted targeted Roche GS-Junior 454 resequencing of a 156-kb region of IGF1 in 80 African American aggressive prostate cancer cases. Three hundred and thirty-four IGF1 SNPs were examined for their association with prostate cancer risk in 1,000 African American prostate cancer cases and 991 controls. The top associated SNP in African Americans, rs148371593, was examined in an additional 3,465 prostate cancer cases and 3,425 controls of non-African American ancestry—European Americans, Japanese Americans, Latinos, and Native Hawaiians. The overall association of 334 IGF1 SNPs and prostate cancer risk was assessed using logistic kernel-machine methods. The association between each SNP and prostate cancer risk was evaluated through unconditional logistic regression. A false discovery rate threshold of q < 0.1 was used to determine statistical significance of associations. We identified 8 novel IGF1 SNPs. The cumulative effect of the 334 IGF1 SNPs was not associated with prostate cancer risk (P = 0.13) in African Americans. Twenty SNPs were nominally associated with prostate cancer at P < 0.05. The top associated SNP among African Americans, rs148371593 [minor allele frequency (MAF) = 0.03; P = 0.0014; q > 0.1], did not reach our criterion of statistical significance. This polymorphism was rare in non-African Americans (MAF < 0.003) and was not associated with prostate cancer risk (P = 0.98). Our findings do not support the role of IGF1 variants and prostate cancer risk among African Americans. Cancer Epidemiol Biomarkers Prev; 23(9); 1928–32. ©2014 AACR.

404 Background: Hyaluronan (HA) can be a constituent of the tumor microenvironment (TME). Accumulation of HA in the TME may result in elevated interstitial pressure, vascular compression, hypoxia, and reduced drug delivery and immune cell access. Pegvorhyaluronidase alfa (PEGPH20; PVHA) enzymatically degrades HA, potentially increasing access and antitumor efficacy of cytotoxic and immuno-therapies. Liquid biopsies may provide a non-invasive approach to predict therapeutic efficacy of PVHA. Methods: Total plasma HA was analyzed as a pharmacodynamic biomarker for PVHA activity in HALO 109-202 (NCT01839487), a Phase 2, open-label, two-stage randomized study of PVHA + nab-paclitaxel + gemcitabine (PAG) vs AG only, in previously untreated patients with Stage IV metastatic PDAC. HA was measured with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) disaccharide assay using baseline plasma samples from Stage 1 (n = 132) and Stage 2 (n = 128) of the study. Results: Lower baseline plasma HA values were significantly correlated with survival outcomes, predicting progression-free survival (PFS) benefit in PVHA-treated patients in Stages 1 and 2, and overall survival (OS) benefit in PVHA-treated patients in Stage 2 (Table). Conclusions: These results support further exploration of a liquid biopsy-based companion diagnostic (CDx) for predicting the therapeutic efficacy of PVHA. [Table: see text]

Colorectal cancer is the third most common cancer, and the third most common cause of cancer-related death, among both men and women in the United States. To address this unmet clinical need, ongoing efforts have focused on classifying different subtypes of colorectal cancer, with the goal of identifying therapies with the highest likelihood of success for a given tumor subtype. One marker that has been associated with poor clinical outcome in multiple solid tumor types, including colorectal cancer, is the accumulation of the glycosaminoglycan hyaluronan (HA), which, in preclinical tumor models, increases interstitial fluid pressure, compresses tumor vasculature, and restricts the access of therapeutics. PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20), which enzymatically degrades HA, is currently being evaluated in combination with existing therapies in clinical trials for HA-accumulating pancreatic, gastric, non-small cell lung, and bile duct cancers. Here, we review the available data for PEGPH20 as published by the authors to evaluate the potential utility of PEGPH20 in treating colorectal cancer. We first studied PEGPH20 in two HA-accumulating murine colon tumor models: CT26 transduced with hyaluronan synthase-3 (HAS3) and MC38 (Charles River Laboratories). In CT26-HAS3 tumors, PEGPH20 monotherapy induced 43% tumor growth inhibition and was associated with tumor blood vessel decompression. In combination with anti-CTLA4 treatment, PEGPH20 further enhanced tumor growth inhibition (79%, p≤0.002 vs anti-CTLA4 alone and PEGPH20 alone). In MC38 tumors, combination of PEGPH20 with anti-PD-L1 treatment significantly increased infiltration of CD8+ T cells (2.8-fold, p Citation Format: Renee Clift, Benjamin J. Thompson, Darin Taverna, Barbara Blouw, Jisook Lee, Curtis B. Thompson, Daniel C. Maneval. Rationale for evaluating PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20) in patients with hyaluronan (HA)-accumulating colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1743.

12030Background: Hyaluronan (HA) and collagens are major constituents of the ECM. HA accumulation in the tumor microenvironment may result in elevated interstitial fluid pressure, vascular compress...

e24270Background: Hyaluronan (HA), a primary component of the extracellular matrix (ECM), can accumulate in a variety of solid malignancies. Analyses of patient tumor tissues demonstrated that incr...

Background— Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts. Methods and Results— The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P =4.7×10 −41 ), 16q23.1 (rs2549513; P =0.0004), 6p24.1 (rs499818; P =0.0002), 2q36.3 (rs2943634; P =6.7×10 −6 ), MTHFD1L (rs6922269, P =5.1×10 −10 ), APOE (rs429358; P =2.7×10 −18 ), ZNF627 (rs4804611; P =5.0×10 −8 ), CXCL12 (rs501120; P =1.4×10 −6 ) and LPL (rs268; P =2.7×10 −17 ). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities. Conclusions— Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

Genome-wide association studies (GWAS), in which thousands of single-nucleotide polymorphisms (SNPs) spanning the genome are genotyped in individuals who are phenotypically well characterized, -currently represent the most popular strategy for identifying gene regions associated with common -diseases and related quantitative traits. Improvements in technology and throughput capability, development of powerful statistical tools, and more widespread acceptance of pooling-based genotyping approaches have led to greater utilization of GWAS in human genetics research. However, important considerations for optimal experimental design, including selection of the most appropriate genotyping platform, can enhance the utility of the approach even further. This chapter reviews experimental and technological issues that may affect the success of GWAS findings and proposes strategies for developing the most comprehensive, logical, and cost-effective approaches for genotyping given the population of interest.

senting 54 different chromosome regions, were suggestively associated with knee OA at a threshold of P < 10 -4 . We then tested these SNPs for association with knee OA in cases and controls from the JoCo Study. Of the 87 SNPs available for replication in JoCo, none were significantly associated with knee OA at a nominal P < 0.01. At our tested levels of significance (i.e., P < 10

Introduction: 5-Lipoxygenase-activating protein (FLAP) binds to arachidonic acid (AA) and activates arachidonate 5-lipoxygenase (ALOX5). ALOX5 is upregulated in colon cancer and is involved in the synthesis of leukotriene A4, which plays an important role in immunity and inflammation. ALOX5 also competes with the prostaglandin H synthases PTGS1 and PTGS2, which convert AA into prostaglandins. NSAIDs reduce the risk of colorectal neoplasia and inhibit PTGS1 and PTGS2. We investigated associations between ALOX5 and FLAP and risk of colorectal neoplasia, as well as potential NSAID interactions in three independent study populations that capture the range of colorectal carcinogenesis by including both adenoma and cancer cases. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 32 tagSNPs in FLAP, representing common genetic variation in Europeans. ALOX5 lacked resequencing data, and we were only able to look at candidate polymorphisms. We used an identical Illumina platform to investigate FLAP SNPs and 1 ALOX5 candidate SNP in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). VNTR polymorphisms in both genes were also genotyped. Multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study participants). A p value < 0.05 without multiple comparison adjustment was considered statistically significant. Results: The variant ALOX5 allele of rs4986832 G>A showed a significant trend towards decreased risk of rectal cancer (ORhzv=0.65; 95% CI 0.43-0.98; p-trend=0.04). For FLAP, several SNPs showed increased risk of colorectal neoplasia across all three studies, with the strongest associations for: rs12429692 A>T ORhzv=2.05, 95% CI 1.20-3.53 in adenoma (global p=0.01); rs17239025 G>C ORhet/hzv=1.43, 95% CI 1.01-2.04 in rectal cancer (global p=0.05, p-trend=0.04); rs17222919 A>C ORhzv=1.55, 95% CI 1.00-2.42 in rectal cancer (p-trend=0.05). The inverse association with NSAID use was stronger among those with the wildtype genotype for rs9551960 A>G (rectal cancer p-interaction=0.05) and rs17239025 G>C (colon cancer p-int=0.02), whereas those with variant genotypes had greater NSAID risk reduction of rectal cancer for rs9315053 A>C (p-int=0.03), rs9508832 G>A (p-int=0.02), and rs9506352 G>A (p-int=0.04). Conclusion: We show evidence that genetic variability in ALOX5 and FLAP may affect risk of colorectal neoplasia. These results suggest that, in ALOX5, rs4986832 is associated with a decreased risk of rectal cancer, whereas FLAP SNPs rs12429692, rs17239025 and rs17222919 increase colorectal neoplasia risk. Additionally, we provide evidence that genetic variability in FLAP may modify the protective association of NSAID use against colorectal neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3761. doi:10.1158/1538-7445.AM2011-3761

Introduction: Arachidonate lipoxygenase (ALOX) enzymes generate potent inflammatory mediators via the metabolism of arachidonic acid. Genetic polymorphisms in the lipoxygenase gene family have been implicated in cancer and inflammatory diseases such as asthma, bone loss, and atherosclerosis. NSAIDs, which reduce colorectal cancer risk, induce apoptosis in colon cancer cells via upregulation of ALOX15. We hypothesize that polymorphisms in lipoxygenases ALOX12 and ALOX15 may influence colorectal neoplasia risk and protective NSAIDs effects. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in ALOX12 and ALOX15 representing common genetic variation in Europeans. We genotyped 17 SNPs in ALOX12 and 21 SNPs in ALOX15 in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma, colon, and rectal cancer cases. We investigated these SNPs in relation to colorectal neoplasia risk and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424/1780 cases/controls), rectal cancer (n=583/775), and colorectal adenoma (n=485/578). Multiple logistic regression analysis was used, adjusting for age, sex, and study site, and restricted to Caucasians (>90% of all study participants). A p value < 0.05 without multiple comparison adjustment was considered statistically significant. Results: In ALOX12, rs11571364 was associated with a modestly increased risk of colon cancer among variant allele carriers (OR: 1.23, 95% CI: 1.01-1.51). A risk increase was also seen in rectal cancer, but was not statistically significant (OR: 1.26, 95% CI: 0.92-1.71). The homozygous variant genotype of another SNP in ALOX12 showed a possible reduced risk of rectal cancer (rs2073438, OR: 0.66, 95% CI: 0.42-1.04), but not colon cancer or adenomas. No significant interactions between SNPs in ALOX12 and NSAID use were observed in any of the three studies. In ALOX15, rs2619112 showed a suggested increase in rectal cancer risk. However, the risk was more elevated among those with a heterozygous genotype (OR: 1.37; 95% CI: 1.06-1.77) than among those with a homozygous variant genotype (OR: 1.13, 95% CI: 0.83-1.55). We detected a significant interaction between this SNP and NSAID use. Among NSAID non-users, the homozygous genotype was associated with increased rectal cancer risk (OR: 1.24). Among NSAID users, the homozygous wildtype and homozygous variant genotypes were associated with decreased risk, but there was no association among heterozygous NSAID users (p-interaction=0.04). Conclusion: Polymorphisms in ALOX12 and ALOX15 are associated with risk of rectal and colon cancer, but not colorectal adenomas. An ALOX15 SNP previously associated with bone mineral density levels and coronary artery disease risk was associated with rectal cancer risk and showed possible interaction with NSAID use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2011-3756

Introduction: Glutathione peroxidases (GPXs) are selenium-dependent enzymes that scavenge hydroperoxides linked to oxidative stress, prostaglandin synthesis, inflammation and proliferation. Because these processes are important in carcinogenesis, we hypothesized that genetic variability in the GPXs may influence colorectal neoplasia risk. We investigated candidate polymorphisms and tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 24 tagSNPs, including the candidates (GPX1 P200L and GPX4 2573 C>T), representing common genetic variation in Europeans. We used an identical Illumina platform to investigate GPX SNPs in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal components analysis (PCA). Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: In PCA, GPX3 was significant for rectal cancer at p=0.03. Without correction for multiple testing, five polymorphisms in GPX2 and GPX3 were associated with significant differences in rectal cancer risk at α=0.05 (see Table). GPX3 rs8177406 also reduced risk in rectal polyps. The candidate GPX1 P200L showed a marginally increased risk for LP/LL vs. PP (1.22, 0.98-1.52, p=0.06). No other SNPs in GPX1-4 showed significant associations for rectal cancer or adenomas. No associations were observed for colon cancer. Conclusion: These data provide evidence that genetic variability in GPX2 and GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for unique etiological mechanisms for colon and rectal cancer.Table.Selected tagSNPs in GPX1, GPX2 and GPX3 and risk of rectal cancer, adjusted for age, sex, and study center*SNPGenotypeCasesControlsOR95%CIp (2df)p-trendGPX1rs105045**CC252367 2834 C>T, P200LCT or TT3013601.220.981.520.06NAGPX2rs2277502**GG4595741.00.. 2834 G>AGA or AA1141890.770.600.990.04NA rs4902347**GG4565741.00.. 1756 G>AGA or AA1141880.780.601.000.05NAGPX3rs3828599CC3404091.00.. 1580 C->TCT2142980.850.681.07 TT29660.520.330.830.010.01 rs736775CC2372821.00 9133 C->TCT2753540.910.721.15 TT701380.590.420.830.010.01 rs8177447CC4135001.00 7241 C->TCT1552350.790.621.01 TT14350.480.260.910.020.01* r2 < 0.70, except rs2277502 and rs4902347 (r2 > 0.90)** Dominant model is shown because there were 10 or fewer subjects with the homozygous variant model Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 933.

Introduction: Pancreatic phospholipase A2 (also known as PLA2G1B or PLA2A) catalyzes the release of fatty acids from dietary phospholipids for adsorption in the small intestine. Some of the polyunsaturated fatty acids removed from the intestinal lumen are precursors to eicosanoids, which are linked to inflammation, cell proliferation and colorectal carcinogenesis. We suspect that genetic variation at the PLA2A locus might affect colorectal neoplasia and thus we evaluated the association of PLA2A tagSNPs with colorectal neoplasia risk in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 3 tagSNPs in PLA2A. We genotyped these SNPs on the same Illumina platform in 3 US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). LD was calculated among Caucasian controls for each study. For gene-level associations, we conducted principal components analysis (PCA) and haplotype analysis. Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: Two PLA2A variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702G>A Ser98Ser, p-trend = 0.03 and rs9657930, 1593C>T p-trend = 0.01, see table). Linkage disequilibrium between the SNPs was modest (r2 Conclusion: The results suggest that genetic variability in PLA2A affects susceptibility to rectal but not colon cancer. Additional observational and functional follow-up studies are needed.Table.Selected tagSNPs in PLA2A and risk of rectal cancer, adjusted for age, sex, and study centerSNPGenotypeCasesControlsOR95%CIp (2df)p-trendrs56373702 G>AGG4285361.00.. Ser98SerGA1472150.850.661.08 AA8230.430.190.980.060.03 rs9657930CC4886141.00.. 1593 C>TCT891480.750.561.00 TT3100.390.111.430.050.01 rs2070873GG4365741.00.. 3027 G>TGT1391811.000.781.29 TT6190.420.171.060.150.36Principal component analysis p= 0.02 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 934.

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk of colorectal adenomas and cancer. NSAIDs, including aspirin, target the prostaglandin H synthases, COX-1 and COX-2, which convert arachidonic acid into prostaglandins. We examined tagSNPs and candidate polymorphisms in COX-1 and COX-2 in relation to colorectal neoplasia risk and potential interactions with NSAID use. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in PTGS1 (COX-1) and PTGS2 (COX-2) representative of common genetic variation in Europeans. Including candidate polymorphisms, we genotyped 18 SNPs in PTGS1 and 17 SNPs in PTGS2. SNPs were genotyped on the same Illumina platform in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma and cancer cases. We investigated these SNPs in relation to the risk of colorectal neoplasia and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424) vs. controls (n=1780), rectal cancer (n=583) vs. controls (n=775), and colorectal adenoma (n=485) vs. controls (n=578). For single SNP associations, multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study populations). No correction was made for multiple testing. Results: There were no main associations with PTGS1 tagSNPs or candidate polymorphisms (R8W, P17L and L237M) and colorectal neoplasia risk. Although not statistically significant, the L15-L16 deletion allele showed a trend towards increased risk for both colon and rectal cancer, consistent with the previously reported increased adenoma risk. In PTGS2, a rare 5′ tagSNP (rs4648250, −1877A>G, MAF=1%) was associated with a marginally decreased risk of both rectal (OR: 0.24, 95% CI: 0.05-1.08) and colon cancer (OR: 0.63, 95% CI: 0.36-1.10). NSAID use is known to reduce the risk of colorectal neoplasia and all three studies have shown the same protective effect in previous analyses. Interactions between genotypes and NSAID use essentially fell into one of two general categories: a) Individuals with the variant allele lost the protective effect of NSAID use (PTGS1 rs10306110-G, rectal p-interaction=0.02, adenoma p-int=0.08; PTGS2 [rs689466][1]-G, rectal p-int=0.03, colon p-int=0.18; rs20424-G, colon p-int=0.05; [rs689469][2]-A, colon p-int=0.03, rectal p-int=0.09).); and b) Individuals with the variant allele showed stronger protection with by NSAIDs than individuals with the wildtype genotype (PTGS1 rs6478565-G, rs10306135-T, rs10306164-G, rectal p-int=0.01-0.02). Conclusion: These data suggest that a rare 5′ SNP in PTGS2 may predict risk of colorectal cancer and provide further evidence that genetic variability in PTGS1 and PTGS2 may modify the protective association between NSAID and colorectal neoplasia risk, especially for rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5710. [1]: /lookup/external-ref?link_type=GEN&access_num=rs689466&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs689469&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom

3071 An important question that arises when caring for patients referred for phase I clinical trials is, if one studied the patients’ tumors carefully enough, would there be targets in those patients’ tumors for which a therapeutic agent might already be available. Perhaps treating the patient with that therapeutic agent would be better than trying the phase I agent. To address that issue we have performed IHC assays for up to 13 targets (e.g. Her2/neu, ER, c-kit, etc.) as well as a two color Agilent oligonucleotide microarray with 17, 085 unique probes, on tumors from patients with advanced cancer who have exhausted conventional therapy and who were undergoing a procedure for a cancer related matter (e.g. obstruction, ascites, etc.). Ninety-one patients had excess tissue submitted from the procedure, immediately frozen and subjected to microarray analysis and had IHC performed on sections obtained from the paraffin blocks prepared as part of their standard surgical workup. IHC was considered positive if ≥ 30% of tumor cells were scored as +1 or greater staining. For microarray studies the gene expressions were called significantly increased or decreased if the fold change in expression relative to the nominal tissue of origin reference was significant at p≤0.001. For the 91 patients where frozen tumor was submitted 89 (98%) of them had RNA that was of excellent quality. The findings were a surprise in that IHC identified an average of 1.2 targets (for which a conventional therapeutic agent is available) per patient (range 0 - 4 targets). The DMA identified an average of 3.3 targets per patient (range 0 - 8 targets). Overall, a target was found for 89 (98%) of the patients. This data indicates that using IHC and DMA one can consistently find a potential target for which we have a therapeutic agent in patients’ tumors even thought they have progressed on prior therapies. This has implications for patients’ planning on participating in phase I clinical trials. It is important to conduct a prospective clinical trial to determine whether the targets discovered using IHC and DMA can be used to select therapy which will further benefit the patient who would otherwise be participating in a phase I clinical trial. [Table: see text]