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1556 Background: In ~15% of CRC tumors mismatch repair deficiency (dMMR) is observed and is usually caused by LS (germline mutations in MLH1, MSH2, MSH6 or PMS2) or sporadic inactivation of MLH1 (hypermethylation [HM] of MLH1 gene promoter). The objective of this study was to retrospectively compare clinical factors and outcomes in pts with dMMR with LS to those without LS. Methods: This cohort includes pts with CRC diagnosed between 5/98 and 5/12 with dMMR on immunohistochemistry (IHC) staining. Prior to 2006 pts came from the Columbus area HNPCC study. After 2006, we included all CRC pts at OSU as universal IHC was initiated. Chi-square was used to compare nominal parameters and log-rank to compare overall survival (OS). Results: A total of 189 pts had dMMR per IHC staining (see characteristics in table). In 36 pts (19.0%) a diagnosis of LS was made after germline testing, in 59 pts (31.2%) a diagnosis of MLH1 HM was made with methylation or BRAF testing, in 65 pts (34.4%) a LS or MLH1 HM diagnosis was assumed based on clinical criteria. Median OS was 159 mos in the LS group and 49 mos in the MLH1MH group (p=0.003) and OS was significantly longer in the LS group across all 4 stages (p=0.002) (see Table). Conclusions: Pts with LS-associated CRC had longer OS than pts with MLH1 HM-associated CRC, even in the setting of a higher incidence of other cancers (44.1% vs. 28%). This is likely related to younger age in the LS group. The MLH1HM group was older at diagnosis and more often female. There are a number of limitations to our study including the potential for survivorship bias and lack of a definitive diagnosis in ~50% of patients despite using clinical criteria to define these pts. [Table: see text]

4014 Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n = 46. Study treatment consisted of erlotinib 100 mg + selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1st-line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) > 6 weeks, 10 with SD > 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline > 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no study-related deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.

Purpose Liver abnormalities have prognostic impact on the outcome of patients with advanced heart failure.We evaluated the Model of End-stage Liver Disease (MELD) score and its modified versions, established measures of liver dysfunction, as a tool to evaluate HTx urgency in ambulatory HF patients. Methods and Materials We retrospectively evaluated 343 patients undergoing HTx evaluation between 2005 and 2009. The prognostic effectiveness of MELD/MELDNa/MELD-XI for endpoint events defined as death/HTx/ventricular assist device (VAD) requirement was evaluated in our cohort and in subgroups of patients on and off oral anticoagulation. Results The MELD and MELDNa score were excellent predictors for 1 year endpoint events (AUC: 0.71 and 0.73, respectively). High scores (>12) were strongly associated with poor survival at one year (MELD: 69.3% vs. 90.4%, p Conclusions Assessment of liver dysfunction using the MELD scoring system provides additional risk information in patients with ambulatory heart failure.

518 Background: Pts with stage II/III rectal cancers are treated with neoadjuvant chemoradiation and surgical resection followed by adjuvant CT per practice guidelines. It is unclear whether adjuvant CT provides survival benefit, and the purpose of this study was to measure outcome in pts who did and did not receive adjuvant CT. Methods: We used a prospectively collected database for pts treated at The Ohio State University, and analyzed overall survival (OS), time to recurrence (TTR), pt characteristics, tumor features, and treatments. Survival curves were estimated using Kaplan-Meier method and compared by the log-rank test. Age was compared using the Wilcoxon test, and other categorical variables were compared using Chi-square test or Fisher’s exact test. Results: Between August 2005 to July 2011, 110 pts were identified and 71 pts had received adjuvant CT. There was no significant difference in sex, race, pathologic tumor (T) stage, and pathologic complete response between the two pt groups. Pts receiving adjuvant CT were significantly younger (median age 54.3 vs. 62 years, p=0.01) and had more advanced pathologic nodal (N) stage (43 vs. 19%, p=0.02). Median OS was 72.6 months with CT vs. 36.4 months without CT (p=0.0003). Median TTR has not yet been reached. Conclusions: In this retrospective analysis, adjuvant CT was associated with a longer OS despite more advanced pathologic nodal staging. Prospective randomized studies are warranted to determine whether adjuvant CT provides a survival benefit for pts across the spectrum of stage II and III rectal cancer. [Table: see text]

366 Background: Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and increases the risk of colon and several other cancers. Prostate cancer is not currently considered part of the LS-tumor spectrum. The objective of this retrospective study was to assess whether the incidence of prostate cancer is increased above that of the general population in MMR mutation carriers. Methods: Patients who were identified as MMR mutation carriers and included in previous LS studies or evaluated at the genetics clinic at The Ohio State University were contacted and their cancer history documented. Follow-up time was defined as the time between their first index cancer or their entry onto the LS studies until the last date of follow-up or date of death, whichever came first. The prostate cancer incidence was adjusted for age and race and compared to that of the SEER registry of 1999-2009. A standardized rate ratio (SRR) was obtained by comparing the observed rate to the expected rate. Results: 186 males (median age 49 years, range 17-83) were identified as MMR mutation carriers either by testing (95%) or as obligate carriers (5%) in 94 families. Their mean follow-up time was 5.1 years (SD+/-6.0 years) with a total of 938 person-years (p-ys). Caucasians comprised 95.1% of the cohort, African-Americans 3.8% and Asians 1.1%. Of the patients who were tested for mutations, MSH2 was most commonly mutated (49.2%), followed by MLH1 (23.7%), PMS2 (14.7%) and MSH6 (12.4%). Ten patients (5.4%), all Caucasian, were diagnosed with prostate cancer at a median age of 59 years (range 52-82). 7 patients were identified as MSH2 carriers, 2 as MSH6 carriers and 1 as a PMS2 carrier. The observed incidence rate was 102.8 cases per 100,000 p-ys versus the expected number of 158.2 cases per 100,000 p-ys, the standardized rate ratio was 0.65 (95% CI 0.53-0.79). Conclusions: Prostate cancer incidence was not increased in this relatively large cohort of LS patients.

609 Background: T is the mainstay of adjuvant therapy in pts with HER2+ breast cancer. CNS disease as the site of first relapse after exposure to adjuvant T has been reported, although the overall incidence and relative risk (RR) of this remains unclear. We performed an up-to-date meta-analysis to determine the risk of CNS metastases as the first site of recurrence in pts with HER2+ breast cancer who received adjuvant T. Methods: Pubmed databases were searched for articles from 1966 to 2011. Abstracts presented at the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were also searched for relevant clinical trials. Eligible studies include randomized trials with adjuvant T administered for 1 year in pts with HER2+ breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the summary incidence, RR, and 95% CIs using fixed effects inverse variance models. Results: A total of 9,020 pts were included. The incidence of CNS metastases as first site of disease recurrence in HER2+ pts receiving adjuvant T was 2.56% (95% CI 2.07% to 3.01%) compared to 1.94% (95% CI: 1.54% to 2.38%) in HER2+ pts who did not receive adjuvant T. The RR of CNS as first site of relapse in T-treated pts was 1.35 (95% CI 1.02 to 1.78, p=0.038) compared with control arms without T therapy. In subgroup analyses, there was no significant difference in CNS incidence or risk between pts treated with concurrent versus sequential T (p=0.29), weekly versus every 3 week T (p=0.56), and no difference in the T groups between studies due to median follow up time in years (p=0.68). No evidence of publication bias was observed (Q=1.78; P=0.62; I2 = 0.0%). Conclusions: This is the largest report to date demonstrating that adjuvant T is associated with an increased risk of CNS metastases as a site of first recurrence in HER2+ breast cancer pts.

e14658 Background: The 5-year survival of PAC with surgery alone is below 10%, and with adjuvant chemotherapy increases to about 20%. The original GITSG adjuvant study demonstrating a survival benefit compared to surgery could be attributed to the use of 2-years of weekly IV bolus 5FU, and not only chemoradiation. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that may remain in G0 arrest, by attacking them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated our pts who were treated with or without maintenance Cape. Methods: Pts in the Georgetown/Lombardi Cancer Center EMR since Oct 2007 were sought for PAC that was resected with curative intent, received standard adjuvant chemotherapy with or without chemoradiation. The study group received maintenance cape for at least 2 months, and the control group was monitored until disease recurrence. Only pts with complete follow-up survival data were analyzed. Results: 20 pts met the criteria as study group, and 58 pts as the control group. In the study group, cape was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, up to 2 years. Pts received cape for median duration of 12.5 months (2 to 24 months), and the median follow-up duration was 33 months (16 to 78 months). The median overall survival (OS) for the study group was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. 4 pts discontinued cape due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea. The control group was of comparable staging, and the median OS was 22 months, 5 year OS rate was 16%, median RFS was 13 months, 2 year RFS was 19%. Conclusions: In this single institute retrospective controlled cohort study, Cape maintenance therapy following adjuvant therapy in resected PAC is associated with a significantly (p

e14178 Background: Panitumumab (Pmab) is a fully humanized monoclonal IgG-2 antibody against epidermal growth factor receptor (EGFR). It was approved by the FDA in September 2006 as 3rd line therapy in metastatic colorectal cancer with disease progression on or following fluoropyrimidine (5-FU), oxaliplatin, and irinotecan chemotherapy regimens. Cetuximab (Cmab) is a chimeric monoclonal IgG-1 antibody and has been on the market since February 2004. It is unclear whether patients who have previously progressed on Cmab will benefit from therapy with Pmab. Methods: This is a retrospective analysis of 13 patients previously treated at OSUMC. The primary aim was to assess clinical benefit rate of Pmab in patients who failed Cmab. Patients were identified through our database from Sep 2006 until Dec 2011. Patient characteristics, length of treatment duration, response rate, and time elapsed from Cmab to Pmab were recorded. Clinical benefit (CR, PR, SD) was assessed by RECIST criteria. CEA was recorded. Results: Median age was 61 years (range 29-80), 8 males and 5 females. One patient had one FU-based line of chemotherapy while 12 patients had two FU-based lines of chemotherapy before starting Pmab. Five patients were KRAS wild-type, 8 were unknown. Five patients got Pmab as a single agent, 6 with FOLFIRI, 1 with irinotecan and 1 with capecitabine. Median time elapsed from stopping Cmab to starting Pmab was 4 months (range 0-25 months). One patient had a partial response to Pmab, 6 had stable disease, 2 had progressive disease and 4 patients did not have imaging studies. CEA decreased in 7 patients with mean decrease of 55% (SD +/- 34%). Median time to progression on Pmab was 5 months (range 1-13 months). Of 3 patients without clinical benefit to Cmab, 2 (67%) had clinical benefit from Pmab. Of 8 with clinical benefit to Cmab, 5 (63%) had clinical benefit from Pmab. Median duration of time from stopping Cmab to starting Pmab was similar for responders (3.5 months) and nonresponders (2.5 months). Conclusions: Our data suggest that Pmab can be given to patients previously treated on Cmab with clinical benefit seen in 2/3 of cases. Of interest, patients who did not have clinical benefit from Cmab did so with Pmab in 2/3 of cases.

judged as signs of possible LVAD indication. Lastly, in-hospital and 1-year outcome was analyzed and compared with outcome of LVAD implanted from 2007 to 2010 (C-LVAD). Results: 1244 pts were hospitalized for HF in one year. 191 were excluded due to age and 270 for other causes. 59 out of the remaining 783 pts had LVEF 0.35 and received inotropes, but only 38 (3%) were considered appropriate potential LVAD candidates after hospital chart review. Inhospital mortality was 5/38 (13%). Within 1-year, 8 pts underwent to heart transplant and 3 to LVAD with 10 surviving; 8/16 (50%) of medically managed pts died. In-hospital mortality after 2007-2010 C-LVAD implantation was 5/27 (18.5%). In 1-year, 3 pts were transplanted and only 1/20 pts remaining on LVAD died. Conclusions: Pts with HF characterized by low LVEF and the need for inotropes have a poor 1-year prognosis on medical therapy and would probably benefit from LVAD. The proportion of pts potentially candidates for LVAD is low with respect to the total population of HF, but the absolute number is high due to the prevalence of this syndrome.

333 Background: The 5-year disease free survival of pancreatic adenocarcinoma (PAC) with surgery alone is below 10%, and adjuvant chemotherapy increases that to about 20%. The original GITSG adjuvant study demonstrating a survival benefit compared to surgery could be attributed to the use of 2-years of weekly IV bolus 5FU, and not chemoradiation. This hypothesis has not been tested since that trial. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that may remain in G0 arrest, by attacking them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated our patient (pts) who were treated with maintenance capecitabine (cape). Methods: Pts in the Georgetown University Hospital/Lombardi Cancer Center electronic medical record database since Oct 2007 were sought for PAC that were resected with curative intent, received standard adjuvant chemotherapy with or without chemoradiation, and received maintenance cape for at least 2 months. Results: Among 214 PAC pts that have been treated at our institution in this time, 21 pts met these criteria. Among the 21 pts, 1 was lost to follow up after moving overseas, and 20 pts were eligible for this analysis. 13 of the 20 pts had lymph node involvement at resection. Cape was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, most often two years. Pts received cape for median duration of 12.5 months (2 to 24 months), and the median followup duration was 33 months (16 to 78 months). The median overall survival (OS) for the 20 analyzed patients was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. 4 pts discontinued cape due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea respectively. Conclusions: Cape maintenance therapy following adjuvant chemotherapy in resected PAC is associated with a promising higher overall survival and PFS compared to historical data, and this approach should be further studied in a randomized controlled study.

4130^ Introduction: Pmab is a fully human antibody targeting the epidermal growth factor receptor that is approved as monotherapy for mCRC in the US, EU, and Canada. AMG 655 is an investigational, fully human agonistic antibody against death receptor 5. This is the first study to evaluate the safety, tolerability, and efficacy of AMG 655 and pmab for the tx of mCRC. Methods: Eligible patients (pts) were ≥ 18 years old, had ECOG status 0–1, radiographic disease progression (PD) during or after tx with fluoropyrimidine, irinotecan, and/or oxaliplatin chemotherapy for mCRC. This is a 2-part study: in part 1 (n∼6–27 pts), the primary endpoint is the incidence of dose-limiting toxicities (DLTs); in part 2 (n∼38–41 pts), the primary endpoint is objective response rate per modified RECIST. Secondary endpoints for both parts include efficacy, pharmacokinetics (PK), and antibody formation. In part 1, pts received pmab 6 mg/kg Q2W plus AMG 655 at a starting dose of 10 mg/kg (evaluation of subsequent doses of 3 mg/kg or 1 mg/kg if needed; 6–9 pts at each dose) by sequential intravenous infusion at week 1 and Q2W thereafter until PD or intolerability. The tolerable dose in part 1 was selected for part 2. Results: We describe here the safety of the first 15 pts (n=5 part 1; n=10 part 2) after ≥ 8 weeks on study. Eight (53%) pts were women, 14 (93%) pts were white, and 9 (60%) pts had ECOG 1. Median (range) age was 61 (38–77) years. All pts received pmab 6 mg/kg and AMG 655 10 mg/kg Q2W. Median (range) follow-up time was 15.4 (9–31) weeks. There were no DLTs in part 1, thus AMG 655 10 mg/kg Q2W was selected for part 2. One (7%) pt had a tx-related adverse event (AE) ≥ grade (gr) 3: gr 3 hypomagnesemia. Tx-emergent Aes ≥ 25% are shown ( Table ). Laboratory values ≥ gr 3: one gr 3 AST and ALT; one gr 3 lipase. From intensive PK samples from the first 6 pts, pmab had no apparent impact on the PK of AMG 655. Conclusions: AMG 655 and pmab can be safely combined in later lines of tx for mCRC. The study is ongoing. Safety results for additional pts will be presented. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

Single-point intensity scaling and time-intensity methods were used to record oral irritation from solutions of 2 ppm capsaicin, capsaicin with added sucrose (0.04M), NaCl (0.3M), citric acid (0.01M) or xanthan gum (0.2%). Only sucrose depressed mouth-burn, both in magnitude and duration. The viscosity imparted by xanthan retarded perception of mouth-burn but did not effect its duration. While single-point scaling averaged perceived intensity across time, time-intensity provided much more information by displaying perception from onset to decay. Eaters and non-eaters of chili peppers did not differ in their perception of mouth-burn.

ObjectivesThis study evaluated the Model for End-Stage Liver Disease (MELD) score and its modified versions, which are established measures of liver dysfunction, as a tool to assess heart transplantation (HTx) urgency in ambulatory patients with heart failure.BackgroundLiver abnormalities have a prognostic impact on the outcome of patients with advanced heart failure.MethodsWe retrospectively evaluated 343 patients undergoing HTx evaluation between 2005 and 2009. The prognostic effectiveness of MELD and 2 modifications (MELDNa [includes serum sodium levels] and MELD-XI [does not include international normalized ratio]) for endpoint events, defined as death/HTx/ventricular assist device requirement, was evaluated in our cohort and in subgroups of patients on and off oral anticoagulation.ResultsThe MELD and MELDNa scores were excellent predictors for 1-year endpoint events (areas under the curve: 0.71 and 0.73, respectively). High scores (>12) were strongly associated with poor survival at 1 year (MELD 69.3% vs. 90.4% [p < 0.0001]; MELDNa 70.4% vs. 96.9% [p < 0.0001]). Increased scores were associated with increased risk for HTx (hazard ratio: 1.10 [95% confidence interval: 1.06 to 1.14]; p < 0.0001 for both scores), which was independent of other known risk factors (MELD p = 0.0055; MELDNa p = 0.0083). Anticoagulant use was associated with poor survival at 1 year (73.7% vs. 86.4%; p = 0.0118), and the statistical significance of MELD/MELDNa was higher in patients not receiving oral anticoagulation therapy. MELD-XI was a fair but limited predictor of the endpoint events in patients receiving oral anticoagulation therapy.ConclusionsAssessment of liver dysfunction according to the MELD scoring system provides additional risk information in ambulatory patients with heart failure.