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3549 Background: Strategies to detect and prevent young-onset colorectal cancer (YOCRC, diagnosed under age 50) are critical. Established high-risk screening guidelines (SGs) aim to detect/prevent YOCRCs arising from hereditary syndromes. For non-hereditary YOCRCs, average-risk screening is being considered at an earlier age, but family history (FH)-based increased-risk screening has been poorly studied. We aimed to define the proportion of non-hereditary YOCRC with a FH, and to determine whether existing SGs could have detected/prevented these cases. Methods: 394 consecutive YOCRC patients presenting for surgical resection were reviewed for tumor MMR status, pedigree and genetic testing. Those with known/suspected hereditary syndrome (by phenotype, MMR status, and/or germline mutation) were excluded (N = 65). Pedigrees (N = 329) were analyzed for first- or second-degree relatives (FDR, SDR) with CRC and the ages of diagnosis. The gap between the recommended age for FH-based CRC screening and the age of YOCRC diagnosis was calculated. Results: 89 (27%) non-hereditary YOCRC patients had a FH of CRC. The median age of diagnosis was 45; the tumors were mostly from the distal colon (22%) and rectum (60%), and stage III (48%) and IV (27%). Twenty-one (24%) patients had 22 FDRs with CRCs diagnosed at age 64 (median); and 71 (80%) patients had 92 SDRs with CRCs diagnosed at age 65 (median). Thirteen (15%) had a FH of YOCRC. The existing SGs consider 39 patients (44%) at increased-risk, and the remaining, average-risk (Table). Screening would have begun prior to the YOCRC diagnoses in 28 (31% [or 46, 52%]) patients. But YOCRC diagnosis preceded the recommended screening age in the remaining 61(69% [or 43, 48%]) patients by a median of 5.3 [or 3.9] years (Table). Conclusions: FH is found in 27% of the non-hereditary YOCRC patients; 15% has a FH of YOCRC. In nearly half of the patients, YOCRC was diagnosed several years earlier than the recommended age for FH-based screening, even assuming perfect SG adoption and starting average risk screening at age 45. Refining existing FH-based SGs can potentially be impactful.[Table: see text]

1515 Background: Self-reported family cancer history (FCH) is one of the key indicators of hereditary cancer risk. Studies have shown that accurate FCH documentation by healthcare providers is suboptimal, but data regarding patient-provided FCH are limited. We evaluated the quality of FCH as entered by the patient into the electronic health record (EHR) to determine its adequacy for Lynch syndrome (LS) risk assessment. Methods: At our tertiary referral cancer center, FCH is self-reported via an online questionnaire sent prior to appointment, which is reviewed/updated by clinic nurse during initial visit and then imported into EHR review of systems. Records of all new patients from September 2016 to August 2017 were retrospectively reviewed and analyzed. FCH quality was estimated by calculating rates of reporting of 3 FCH variables required for PREMM5, a risk-prediction model for LS. Parameters required for the model were sex, age, personal history of cancer, and for FCH, degree of kinship (first/second degree), cancer site/type, and age at diagnosis. Results: Of 47,647 unique patients, 47.5% reported FCH for 1 or more relative (46.1% were first degree, 64.8% second degree, 3.0% other, and 2.4% missing). A cancer type/site was specified for 88.8% reporting FCH. Age at diagnosis was listed for 21.7% of the relatives’ cancers. Overall, only 20.9% provided all 3 FCH data elements required for running PREMM5 (9.9% of the total sample, n=4738). Fewer men (9.5%) than women (28.1%) provided all 3 FCH elements. Furthermore, 46.7% of breast cancer patients, 21.9% of gastrointestinal cancer patients, 47.2% and 23.1% of patients seen for cancer prevention screening and endoscopy respectively, reported 3 FCH elements. Lower rates were observed for other cancers. Conclusions: Patient self-reported FCH is suboptimal for estimation of LS risk and genetic counseling referral. Future steps to optimize online patient-facing FCH collection to enable routine automated risk-assessment in an essentially provider-free setting may include, patient education regarding importance of FCH, EHR prompts for FCH completion, and implementation of algorithms in EHRs using FCH to identify patients at risk for hereditary cancer predisposition syndromes.

3592 Background: Lynch-like syndrome (LLS) is characterized by a diagnosis of mismatch repair deficient (dMMR) malignancy where somatic bi-allelic mutations in canonical MMR pathway genes ( MLH1, MSH2, MSH6, PMS2) have been identified as the main cause. Yet, a substantial proportion of cases remain unexplained by MMR somatic bi-allelic events or germline mutations. We hypothesize that LLS cases with young-onset cancers carry cryptic germline alterations in other pathways. To explore this contribution, we performed analyses of the germline and tumor mutation landscapes in LLS patients diagnosed with dMMR cancers. Methods: 18 probands with young-onset (age

Genetic testing is being adopted increasingly to identify individuals with germline mutations that predispose to hereditary colorectal cancer syndromes. Deciding who to test and for which syndrome is of concern to members of the GI oncology community, molecular geneticists, and genetic counselors. The purpose of this review is to help provide guidelines for testing, given that the results influence syndrome diagnosis and clinical management. Although family history may determine whether testing is appropriate and may direct testing to the most informative family member, evolving clinicopathologic features can identify individual patients who warrant testing. Thus, although the usual absence of clinical premonitory signs in hereditary nonpolyposis colorectal cancer (or Lynch syndrome) adds difficulty to its diagnosis, use of the Amsterdam Criteria and Bethesda Guidelines can prove helpful. In contrast, premonitory stigmata such as pigmentations in Peutz-Jeghers syndrome and the phenotypic features of familial adenomatous polyposis aid significantly in syndrome diagnosis. We conclude that the physician's role in advising DNA testing is no small matter, given that a hereditary cancer syndrome's sequelae may be far reaching. Genetic counselors may be extremely helpful to the practicing gastroenterologist, oncologist, or surgeon; when more specialized knowledge is called for, referral can be made to a medical geneticist and/or a medical genetics clinic.

1555 Background: Physical activity, diet, and healthy weight may reduce cancer risk in hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) families. Evidence-based programs to help affected families make these behavioral changes are lacking. We evaluated data from a 16-week family-centered lifestyle intervention trial for individuals with HBOC or LS germline gene mutations and their relatives. Methods: Index cases with HBOC- or LS-associated mutations were recruited from an institutional registry and advocacy organizations, and identified relatives to participate with them in the study. Those eligible had BMI>25 and/or did not meet recommendations for exercise or fruit/vegetable consumption. Participants were randomized to multiple conditions including text messaging, online weight/diet monitoring, an online social network, and E-mail or telephone coaching. All monitored activity using Fitbits. Behavioral outcomes were assessed online at baseline and 8 weeks. Results: 65 HBOC index cases with 63 family members, and 35 LS index cases with 36 family members participated in the study. At 8 weeks, participants lost 3.2 pounds on average (p

PURPOSE To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.

1525 Background: Universal testing of resected CRC for Microsatellite Instability (MSI) status has been widely advocated. While PCR-based MSI analysis is the current gold standard test, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is more commonly performed. At present, it remains un-established whether PCR-based MSI analysis remains reliable when performed on post-neoadjuvant treated specimens. Our goal was to examine the effect of neoadjuvant therapy on MSI analysis using both in vitro and clinical data. Methods: MSI analysis was performed using the standard panel of 7 markers. In vitro, MMR deficient (HCT116) and proficient (HCT116+Ch3) isogenic cell lines were exposed to 3 cycles of single agent 5-Fluorouracil, Oxaliplatin and Irinotecan and MSI analysis was tested after each cycle. To evaluate the induction of genomic instability, 3 additional coding microsatellite tracts in ATR, BLM and CHK1 were assessed by fragment analysis. In parallel, clinical data from 238 CRCs that were resected after neoadjuvant chemoradiation (n=191) or chemotherapy (n=47) between 9/2009 and 8/2011 were queried for MSI results. MSI analysis performed on paired pre-treatment and post-treatment resection tissues was compared. Results: No changes in MSI status were detected and there was no increase in genomic instability post-treatment in cell line models. In the clinical setting, pre-neoadjuvant MSI testing was limited by the availability of pre-treatment biopsy tissue. 3 patients found to be MMR proficient based on MSI analysis performed on pre-treatment biopsy remained microsatellite stable when analyzed on post-treatment resection tissue. 7 patients were MMR deficient based on MSI analysis performed on post-treatment resection tissue but most had strong clinical evidence to expect MMR deficiency. Conclusions: Based on both preclinical in vitro and clinical data, results of the MSI analysis does not appear to be affected by neoadjuvant therapy for both MMR proficient and deficient cases. In addition, preclinical results do not suggest that neoadjuvant chemoradiation induces an increase in genomic instability. Therefore, MSI analysis remains a reliable gold standard test on post-treatment specimens.

1573 Background: A mismatch repair (MMR) pathogenic mutation in an index patient provides a basis for predictive mutation testing in at-risk members of Lynch syndrome (LS) families. Mutation carriers warrant aggressive surveillance. As importantly, non-carriers can safely follow general population screening guidelines. However, penetration of predictive testing has been disappointing in first-degree relatives (FDR), and has been even more limited in second- and more distant-degree relatives, even though the benefits can be as great as in FDRs. Family Information Services (FISs), involve an in-person session in which expert providers and counselors meet with multiple family members in a convenient geographical location. Education and counseling are intended to lead to testing for the family MMR mutation, followed by appropriate surveillance. Methods: LS families with a known MMR mutation (n=97) were targeted for this study. Selection for FIS was based on family size and convenient geographic location. Twenty-eight were offered an FIS and 69 received standard care (mailed educational material and invitation for testing). Data were collected on testing rates. Results: In at-risk patients that did receive FIS, 20.4% (std dev = 11.4%, 95% CI: 16.0 to 24.8%, range: 3 to 57.5%) were DNA tested, whereas in families that did not receive FIS, 12.9% (std dev = 10.8%, 95% CI: 10.2 to 15.5%, range: 0 to 43.5%) were DNA tested. The difference in proportions tested between the FIS and non-FIS families was statistically significant (p=0.003) and was more pronounced in family members whose relationship to the proband was beyond first-degree (p

396 Background: The optimal strategy to detect HNPCC in CRC pts remains controversial, and may include testing tumors for microsatellite (MSI) status and/or pts for mutations in DNA mismatch repair (MMR) genes. Costs of 6 testing strategies were compared against their risks of missing pt managed as HNPCC. Methods: 185 consecutive CRCs were prospectively tested by both immunohistochemistry (IHC, for protein expressions of MLH1, MSH2, MSH6, PMS2) and PCR-based MSI. Secondary tests included MLH1 promoter methylation, BRAF mutation, and germline mutation, as appropriate. A decision tree compared the strategy of performing both IHC and MSI in all (Strategy 1) to five alternatives (Strategies 2-6, Table ). Costs were obtained from commercial list prices, Medicare reimbursement, and literature; probabilities were calculated from pt data. Incremental cost-effectiveness ratios (ICERs) were reported for each additional pt managed as HNPCC Results: 20 (10.8%) pts were identified as being managed as HNPCC. Performing IHC and MSI in all (Strategy 1) or IHC first in all followed by MSI when IHC was normal (Strategy 4) detected all 20 cases. When compared to performing IHC only (Strategy 2), Strategy 4 demonstrated an ICER of $31,821 per additional case detected, while other strategies were more costly and/or less effective (Table). Between the two strategies that detected all cases of HNPCC, Strategy 4 was less costly ($1,049 vs $1,098 per patient, Table). Conclusions: When combined with appropriate secondary and confirmatory testing, performing IHC and MSI in all or IHC in all followed by MSI when IHC were normal, both showed a zero miss rate, while the latter was slightly more cost-effective. [Table: see text]

1500 Background: Germline mutations in the mismatch repair (MMR) genes MLH1 and MSH2 cannot be identified in about 30% of families fulfilling Amsterdam I criteria for Lynch syndrome (LS). Recently,...

1563 Background: Endometrial and colorectal cancers are the most common cancers in Lynch syndrome. Consensus guidelines recommend both annual endometrial biopsy (EMB) and colonoscopy. While an EMB is traditionally performed in the office without sedation, it can be a painful procedure. Because colonoscopy is routinely performed with sedation, we assessed the feasibility of performing concurrently an EMB with a colonoscopy and evaluated women's perception of pain, satisfaction and acceptability. Methods: From July 2002 to December 2009 women with a gene mutation for Lynch syndrome, met the Amsterdam II criteria, or had a high risk situation that required screening were prospectively enrolled. After conscious sedation, the procedures were sequentially performed. Patients completed pre- and post-procedure questionnaires assessing pain, level of satisfaction and acceptability. Pain scores for colonoscopies were used as an internal control. The Wilcoxon rank test and Mann-Whitney test were used to compare pain...

e14028 Background: Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for 2–3% of all colorectal cancers (CRC) and is characterized by mutations in DNA mismatch repair (MMR) genes. Colon ca...

1023 Background: Hereditary non-polyposis colon cancer (HNPCC) syndrome confers 60% and 12% lifetime risks of endometrial cancer (EC) and ovarian cancer (OC), respectively, and EC is the second mos...

PURPOSE: Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. PATIENTS AND METHODS: All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m2/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m2/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed. RESULTS: All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma (≥ 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity. CONCLUSION: It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.