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sSa1929

A Novel, Multi-Analyte Assay With the Potential to Predict Responses toNeoadjuvant Chemoradiation in Rectal Adenocarcinoma PatientsRobert W. Cook, Natalie Lassen, Yaeli Bierman-Harrar, Clare E. Johnson, KristenOelschlager, Derek Maetzold, Romil Saxena, Weiwei Shan, Daniel G. Rosen

Background: Rectal cancer is the third most commonly diagnosed cancer worldwide. Neoad-juvant chemotherapy and radiotherapy (CTRT) followed by total mesorectal excision (TME)represent the standard of care for patients with locally-advanced rectal cancer in the US. Aproprietary, multi-analyte test that accurately predicts extreme resistance to pre-operativeCTRT has been developed and validated in more than 300 esophageal adenocarcinoma (EC)patients. Recent evidence has indicated that the tumor biomarkers used for the predictionof EC patient response to therapy could predict the extent of response to neoadjuvanttreatment by rectal adenocarcinoma (RC) patients. Here we report preliminary results of themulti-analyte test in rectal cancer specimens. Methods: Formalin-fixed, paraffin-embedded(FFPE) pre-treatment biopsied tissue was collected from ten RC patients with loco-regionaldisease. Pathologic review identified five of these cases as extremely resistant to neoadjuvanttreatment (exCTRT) and five cases as partial or complete responders (non-exCTRT). Immuno-histochemistry was performed to assess the cellular localization of three tumor biomarkers(NF-kB, SHH, and Gli1) and a labeling index score was generated for each analyte by twoclinical scientists blinded to the patient outcome. The labeling index scores were subsequentlyanalyzed by logistic regression modeling (SAS® software) to generate a binary predictionoutcome of exCTRT or non-exCTRT for each patient. Data from the predictive algorithmwere then compared to the tumor regression grades as assigned by an independent clinicalpathologist using surgically-resected tumor tissue (TRG grading system). Results: Comparingthe labeling index scores of the ten RC cases to a previously established training set, theprediction outcome for the rectal cancer set reached an area under the receiver operatorcharacteristic curve (AUC) of 0.92, and an accuracy of 80% (8/10). Specificity and positivepredictive value (PPV) both achieved 100% in the RC specimens tested, suggesting that theassay was able to identify 100% of those patients who would be likely to experience exCTRT.Conclusions: The current study was limited by a small sample size. However, it suggestedthat the test shows promise for predicting response to neoCTRT in rectal cancer patientsand supports further development. A second study with a significantly larger cohort ofspecimens is currently underway to validate the test in rectal adenocarcinoma patients.

Sa1930

Correlation Between Cotinine - 'A Smoker's Signature' and Erlotinib Exposureand Clinical Outcomes in Pancreatic CancerRavi Chhatrala, Graham Warren, Wei Tan, Renuka Iyer

Purpose: Elevated serum cotinine level suggests active nicotine exposure. Smokers havehigher clearance of erlotinib (tyrosine kinase inhibitor) contributing to lower drug exposure.Accuracy of self reported smoking status in patients receiving erlotinib has never beenobjectively evaluated. Higher cotinine level may correlate with poor clinical outcomes inpatients receiving erlotinib. Methods and Materials: Blood samples of eighteen patientstreated with erlotinib 150mg PO daily until progression for advanced pancreatic cancerwere collected in a phase II trial. Participants' self reported smoking status, plasma erlotiniblevel and serum cotinine level were assessed using published methods. Subjects whosecotinine level exceeded 10ng/mL were categorized as active smokers. The association ofcotinine level and smoking status, response to therapy, as well as development of rash wereanalyzed using Fisher's exact test. The Wilcoxon rank sum test was used to compare cotininelevel in regards to numeric variables. Kaplan-Meier method and log-rank tests were usedfor survival analyses. Results: All current smokers (n=6) had cotinine level >10ng/mL andall never smokers (n=2) had level <10ng/mL. Seven of 10 past smokers had cotinine level<10ng/mL. Cotinine level could not predict the drug response (P=0.6579). The associationbetween cotinine level and smoking status was significant (P=0.009). The median progressionfree survival (PFS) and overall survival (OS) were respectively 1.3 (95% CI:1.1-1.6) and 3.4(95% CI:1.4-19.9) months for those with cotinine level >10ng/mL, and 1.4 (95% CI:0.9-2.4) and 3.1 (95% CI:1.2-6.7) months for those with cotinine level <10ng/mL. The associationbetween serum cotinine level and PFS (P=0.3223) or OS (P=0.3343) was insignificant. Meanserum erlotinib and its metabolite OSI-420 level were higher in subjects with cotinine level<10 ng/mL [1443.9ng/mL (SD 598.3) for erlotinib and 180.4ng/mL (SD 124.2) for OSI-420] compared to those with cotinine level >10ng/mL [782.2ng/mL (SD 450.7) for erlotiniband 95.4ng/mL (SD 65.5) for OSI-420] but the difference was not significant (P=0.0693for erlotinib and P=0.1464 for OSI-420). The incidence of skin rash was higher in subjectswith cotinine level <10 ng/mL (62.5% vs. 37.5%, P=0.6372). Conclusion: Cotinine, a validbiochemical marker of tobacco smoke exposure can be used to determine accurate smokingstatus of patients receiving erlotinib and correlates with lower drug exposure as expected.Observed trend towards positive correlation between cotinine and erlotinib level as well asskin rash merits further study to define its utility in clinical practice to titrate dose to optimizeclinical benefit and counsel patients about smoking cessation.

Sa1931

Association Between Common Genetic Variants in Pre-MicroRNAs andPrognosis of Advanced Gastric Cancer Treated ChemotherapyTomomitsu Tahara, Masaaki Okubo, Tomoyuki Shibata, Kazuya Sumi, TakamitsuIshizuka, Yuichiro Ichikawa, Tomohiko Kawamura, Masakatsu Nakamura, MitsuoNagasaka, Yoshihito Nakagawa, Naoki Ohmiya, Tomiyasu Arisawa, Ichiro Hirata

Background: Common single-nucleotide polymorphisms (SNPs) in pre-miRNAs have beenassociated with various malignancies and their prognosis. We evaluated the associations ofselected three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (hsa-mir196a2, hsa-mir146a and hsa-mir499) with the prognosis of advanced gastric cancers(AGCs) treated by chemotherapy. Methods: The rs11614913 (T>C), rs2910164 (C>T), andrs3746444 (A>G) SNPs were genotyped in 130 AGCs performing chemotherapy. Survivaland response evaluation was based on overall survival (OS) and progression-free survival

S-332AGA Abstracts

(PFS). Response rate (RR) was also evaluated according to the RECIST. Results: 63 patientsperformed gastrectomy after chemotherapy (neoadjuvant chemotherapy) and the remainingcases performed chemotherapy alone for the treatment (chemotherapy alone). Majority ofAGCs performed S-1 based chemotherapy as the first line treatment (n=119, 92%). rs3746444(A>G) SNP was significantly associated with OS by the log-rank test (p=0.018), while otherSNPs were not associated with OS. The rs3746444 (A>G) SNP was also associated with OSand PFS among cases performing neoadjuvant chemotherapy (p=0.038, 0.024, respectively).Multivariate survival analysis using Cox's regression model revealed that non-responder bythe RESIST (HR: 2.14 95%CI 1.06-4.19), upper third cancer (HR: 2.48 95%CI 1.12-5.49)and more advanced stage (HR: 4.12 95%CI 1.06-16.02) were predictive factors for worseOS, while rs3746444 A allele carrier was the predictive factors for better OS (HR: 0.3395%CI 0.18-0.75). Conclusion: rs3746444 A allele carrier in the hsa-mir499 is associatedwith better prognosis in AGCs performing chemotherapy.

Sa1932

The Effect of Adjuvant Pre-Operative Therapy (APT) on Patients WithColorectal Cancer Awaiting Surgical ResectionSamir Rahmani, Dermot Burke, Simon J. Howell

Introduction The modern treatment of colorectal cancer consists of surgery, with or withoutadjuvant pre-operative radiotherapy, chemotherapy or chemoradiotherapy (APT) for selectedcases. In the United Kingdom, therapy may be given prior to surgery in an attempt tofacilitate surgical excision and improve survival. However, there is some evidence that APTin other cancers may adversely affect the patient's health and increase the risk of operativemorbidity. This study examined the affect of APT on the cardiopulmonary status, bodycomposition, cytokines assay, nutritional status and quality of life in patients with colorectalcancer. Methods Cardiopulmonary function was measured with exercise bicycle to achieveAnaerobic Threshold (AT) and Maximum Oxygen consumption (VO2-max) after 10 minutesof Cardiopulmonary exercise (CPX) testing. Anthropometric parameters (mid-arm circumfer-ence, Triceps skin fold, grip strength measurements, Body weight, height and body massindex) as well as body fluid composition (Extracellular and Intracellular water, total bodywater, fat free mass) were measured using a tetrapolar, single frequency Holtain BC Bio-impedance analyser. CRP and 9 cytokines were measured using a Luminex assay. Nutritionalstatus and quality of life were assessed using two validated questionnaires (EORTC QLQ-C30and PG-SGA). These assessments were made before and two weeks after the administration ofAPT. Shapiro-Wilk test and normality plots were used to verify a normally distributed data.Wilcoxon rank sum test represented in median and interquartile range was used to compareresults before and after the exposure to APT. Results Between February 2010 and July 2011,36 patients with colorectal cancer were recruited (mean age 63.7 years, range 41-80 years,28 male, 32 rectal cancers). There was a significant decline in VO2-max with p=0.028, anincrease in the ventilatory equivalent ratio for CO2 (VE/VCO2) with p= 0.006, a decreasein the extracellular water (ECW) with p= 0.014 as well as a decrease in mid arm circumference(MAC) with p= 0.006 and a reduction in triceps skin fold (TSF) with p= 0.011 followingexposure to APT. There is an overall reduction in the quality of life following APT. ConclusionsThese preliminary data suggest that APT has a significant effect upon the cardiopulmonarycapacity with reduced VO2max and anaerobic threshold (AT) as well as an increased VE/VO2 & VE/VCO2. There were also signs of fluid depletion with a significant reduction inthe extra and intracellular water. Fat free mass (FFM), MAC and TSF were also reducedwhich indicate a loss in the lean body mass. These changes may increase the risk of peri-and post-operative morbidity. In view of this, a period of optimisation following APT andprior to surgery may serve to minimise the risk of such complications.

Sa1933

PLCE1 mRNA and Protein Expression and Survival of Patients WithEsophageal Squamous Cell Carcinoma and Gastric AdenocarcinomaWenqing Li, Nan Hu, Victoria Burton, Howard H. Yang, Hua Su, Catherine M. Conway,Lemin Wang, Chaoyu Wang, Ti Ding, Yi Xu, Carol Giffen, Christian C. Abnet, AlisaGoldstein, Stephen M. Hewitt, Philip R. Taylor

Background and objective Germline genetic variants at 10q23 in PLCE1 have demonstratedconsistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastriccancer (GC) among Chinese in prior genome-wide association studies. We evaluated PLCE1mRNA and protein expression in paired tumor-normal tissue specimens, and their relation-ship with survival. Methods PLCE1 mRNA was profiled using three probes in the AffymetrixGeneChip U133 for paired tumor-normal tissues of ESCC (n=132), gastric cardia adenocarci-noma (GCA, n=62) and gastric noncardia adenocarcinoma (GNCA, n=72). We used immuno-histochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n=525 with tumor and n=303 with paired tumor-normal tissues),and tumor tissues of GCA (n=298) and GNCA (n=124). Results Compared with normaltissues, PLCE1 mRNA expression was significantly reduced in tumors of ESCC (P=0.03 forprobe 205112_at), as well as in GCA and GNCA tumors (P<0.0001 for each of the threeprobes in both cancers). Protein expression was non-significantly reduced in ESCC tumors(P=0.51). Increased tumor-normal mRNA fold change (probe 205112_at) was associatedwith longer survival in ESCC cases (P-trend=0.02 in Cox regression analysis). In GC,increased mRNA tumor-normal fold change (probe 205111_at) was also associated withlonger survival of GCA (P-trend=0.04), but not with GNCA (P=0.72). Similar to mRNAexpression, elevated tumor-normal fold change for protein expression in ESCC was alsoassociated with improved survival (P-trend=0.04). Conclusions Both ESCC and GCA tumorsshow dysregulated PLCE1 expression, and the altered PLCE1 expression appears to beassociated with cancer prognosis.