Roberts, Lewis R.

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as > 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.

452 Background: Surgical resection is the only curative treatment for patients with gallbladder cancer, despite surgical advances many patients ultimately develop recurrent disease. Management of resected gallbladder cancer mostly relies on single-arm trials and retrospective observations. The purpose of our study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer patients who have undergone surgical resection. Methods: Clinical data were collected on 251 patients who underwent surgical resection for stage I-III gallbladder cancer and presented to Mayo clinic from January 2000-December 2015. Patients were then classified into adjuvant treatment group and surveillance only group. Overall survival and recurrence were compared between the two groups. Results: 78 (31.1%) patients received adjuvant therapy while 173 patients were observed only. Patients who received adjuvant tended to be younger (63.0[SD 11] vs 66.2 [SD 13.1]), have higher stage, and underwent extended surgery. Most patients received chemoradiotherapy (55) with 5-Fluorouracil (67.3%) and capecitabine (25.5%) as radiosensitizing agents. 21 patients received additional adjuvant chemotherapy. 27% of patients received chemotherapy as the sole adjuvant treatment. The most common chemo regimens included gemcitabine (52.3%) and gemcitabine plus cisplatin combination (23.8%). On multivariate analysis patients > 65 years(HR 1.53 [1.07-2.19], p = 0.02), males (HR 1.7 [1.2-2.4], p = 0.003), positive margins (2.77 [1.69-4.38], p < 0.01), and stage III (HR 1.91 [1.35-2.70], p < 0.01) had worse overall survival. Patients who underwent extended radical resection (HR 0.73 [0.51-1.05], p = 0.09) had better overall survival. Adjuvant therapy had no statistical significant effect on overall survival (HR 1.10 [0.75-1.59], p = 0.63 or disease free survival (HR 1.05 [0.69-1.59], p = 0.81) on overall population. However, in stage IIIB, patients receiving adjuvant therapy had better overall survival (HR 0.51 [0.25-1.01], p = 0.05) and disease free survival (HR 0.45 [0.19-1.09], p = 0.06). Conclusions: In our study, adjuvant treatment, especially chemoradiation therapy, was only beneficial in patients with stage IIIb gallbladder cancer patients.

450 Background: The standard treatment for patients with gallbladder cancer is a combination of gemcitabine and cisplatin based on ABC-02 trial. However, there are no guidelines regarding treatment after first-line therapy. We retrospectively analyzed the efficacy and overall survival of different second-line regimens. Methods: We identified 203 patients with advanced gallbladder cancer who received palliative treatment between January 2000 and December 2015 at Mayo Clinic, Rochester. RECIST criteria was used to assess response. Results: 68 patients received second-line chemotherapy. Median age was 63 years (range: 32-86) and majority were males (60.6%). The median time from the diagnosis to the start of the second line chemotherapy was 8 (1-120) months. The most common used second-line chemotherapy were FOLFOX (14), gemcitabine alone (10), single agent fluoropyrimidine (11), gemcitabine with capecitabine (5), and capecitabine with oxaliplatin (4). There were 30 patients that received 5-fluorouracil based regimens, 20 patients received gemcitabine-based regimen, 3 patients received taxane-based regimen, and 15 patients received other types of chemotherapy. Median progression free survival and overall survival was 2.1 (1.8-2.7) and 16.7 (13.2-21.3) months respectively. There were 10 (52%), 11 (37%), 2 (67%), 5 (33%) with partial response and stable disease in 5-fluorouracil-based, gemcitabine-based, taxane-based, and others, respectively. There were no difference in PFS, with median PFS of 2.5, 2.0, 2.8 and 2.3 months, respectively (p=0.43). The overall survival were 15.7 (8.9-40.2), 15.0 (10.7-21.3), 40.3 (22.0-47.0), and 20.4 (9.2-30.7) months, respectively (p=0.83). There were 27 patients that received single agent chemotherapy and 41 patients that received combined regimen. There were 17 (42%) patients and 13 (48%) patients with partial response or stable disease in single and combined regimen. There were no differences in progression free survival and overall survival between single and multi agent chemotherapy. Conclusions: In this largest single institution study, second-line chemotherapy regimens for gallbladder cancer provided benefit in select patients and there is an urgent need to develop more active therapeutic regimens.

448 Background: Cholangiocarcinoma (CCA) is a rare, lethal cancer with five-year survival of less than 10%. Although incidence rates have been increasing in the United States, ethnic variations in survival have not been investigated. We examined multi-ethnic variation in overall survival (OS) and CCA-specific survival (CSS) using data from the population-based Surveillance Epidemiology and End Results (SEER) program in the four year periods before and after introduction of gemcitabine/cisplatin as treatment for CCA. Methods: The study included data from 9,975 CCA cases reported in SEER between 2006 and 2013. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated to examine overall and cholangiocarcinoma-specific survival by ethnicity, age, gender and in the pre- and post- gemcitabine/cisplatin era (2006-2009 vs. 2010-2013). Results: Compared to non-Hispanic Whites, Hispanics had poorer 3-year OS (HR = 1.18, 95% CI = 1.10-1.26) and 3-year CCA-specific survival (HR = 1.25, 95% CI = 1.16-1.35). Similarly, non-Hispanic Blacks had 3-year OS (HR = 1.22, 95% CI = 1.12-1.30) and 3-year CCA-specific survival (HR = 1.24, 95% CI = 1.13-1.37). Males and older patients also were found to have shorter survival compared to females and younger patients. Also noted was an increase in CCA incidence rate over time (2006-2013) of 5.93%. Among those < 50 versus ≥50 years old, a 23% higher rate of incidence in those < 50 was noted. Overall survival and CSS were both significantly improved for patients post-advent of Gemcitabine/Cisplatin. Statistically significant improvement in CSS pre- and post-advent of Gemcitabine/Cisplatin was noted in non-hispanic whites (p < 0.001) and Hispanics (p = 0.02). Conclusions: Hispanics and non-Hispanic Blacks have worse survival after diagnosis with CCA. Further studies are needed to determine the determinants of poor survival among these groups toward targeted intervention. Significant improvements in OS and CSS have been seen after the advent of Gemcitabine/Cisplatin. The incidence of CCA is rising faster in young persons, under the age of 50, compared with older patients.

Abstract Background: The GALAD score is a serum biomarker–based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93–97], which was higher than the AUC of ultrasound (0.82, P &lt;0.01). At a cutoff of −0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88–0.96; cutoff −1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85–0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96–0.99; cutoff −0.18, sensitivity 95%, specificity 91%). Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. Impact: The GALAD score was validated in the United States.

AbstractBackground/AimsHypothyroidism has been associated with hepatocellular carcinoma (HCC) incidence; however, the relationship between hypothyroidism and HCC patient outcomes is unclear. We investigated the impact of hypothyroidism on outcomes after liver transplantation for HCC.Materials and MethodsWe retrospectively studied HCC patients transplanted between January 2000 and December 2015. Hypothyroidism was defined as a thyroid‐stimulating hormone (TSH) level continuously greater than 5 mIU/L, a documented history of hypothyroidism, or treatment with thyroid hormone replacement therapy. Multivariate Cox regression was used to assess the impact of hypothyroidism on overall survival (OS) and recurrence‐free survival (RFS) adjusting for potential confounders. Subgroup analyses and interaction tests were conducted to compare the impact of hypothyroidism in different subgroups and assess for possible synergistic effects. Sensitivity analyses were performed among different cohorts to verify the stability of the results.ResultsA total of 343 HCC patients who underwent liver transplantation were included in the analysis. The primary analysis was conducted among 288 patients diagnosed with HCC prior to transplantation. Hypothyroidism was independently associated with worse OS and RFS, as was elevated TSH. The adjusted hazard ratio (AHR) of hypothyroidism was 2.45 (95% confidence interval [CI], 1.44‐4.18) for OS and 5.54 (2.36, 13.01) for RFS. The AHR of TSH for OS was 1.05 (1.02, 1.09) and 1.08 (1.03, 1.13) for RFS. No interaction was found among different subgroups categorized by etiology and comorbidity. The results were stable to sensitivity analyses.ConclusionHypothyroidism is associated with poorer overall and recurrence‐free survival of HCC patients receiving liver transplantation. These results require validation.

BACKGROUND: African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades. METHODS: HCC patients from three US medical centers were matched by year of diagnosis (1991–2016): AA ( n = 578)/Caucasian ( n = 578) and placed in one of two groups—HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted. RESULTS: Prior to 2010, there was no difference in survival between Caucasians and AA ( p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26–2.43, p = 0.001) and child’s class C (aHR 2.05, 95% CI: 1.23–3.41, p = 0.006) were the strongest predictors of mortality, while race was not. CONCLUSIONS: African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Abstract Infection is a common cause of death in patients with advanced cirrhosis. We aimed to develop a predictive model in Child–Turcotte–Pugh (CTP) class C cirrhotics hospitalized with infection for optimizing treatment and improving outcomes. Clinical information was retrospectively abstracted from 244 patients at Tianjin Third Central Hospital, China (cohort 1). Factors associated with mortality were determined using logistic regression. The model for predicting 90-day mortality was then constructed by decision tree analysis. The model was further validated in 91 patients at Mayo Clinic, Rochester, MN (cohort 2) and 82 patients at Seoul St. Mary's Hospital, Korea (cohort 3). The predictive performance of the model was compared with that of the CTP, model for end-stage liver disease (MELD), MELD-Na, Chronic Liver Failure–Sequential Organ Failure Assessment, and the North American consortium for the Study of End-stage Liver Disease (NACSELD) models. The 3-month mortality was 58%, 58%, and 54% in cohort 1, 2, and 3, respectively. In cohort 1, respiratory failure, renal failure, international normalized ratio, total bilirubin, and neutrophil percentage were determinants of 3-month mortality, with odds ratios of 16.6, 3.3, 2.0, 1.1, and 1.03, respectively (P < .05). These parameters were incorporated into the decision tree model, yielding area under receiver operating characteristic (AUROC) of 0.804. The model had excellent reproducibility in the U.S. (AUROC 0.808) and Korea cohort (AUROC 0.809). The proposed model has the highest AUROC and best Youden index of 0.488 and greatest overall correctness of 75%, compared with other models evaluated. The proposed model reliably predicts survival of advanced cirrhotics with infection in both Asian and U.S. populations.

e15641 Background: CC pts with biliary stents or catheters are prone to have obstruction/infection and studies show 20-40% present with fever/or jaundice requiring urgent treatment for which there is no uniform guideline. We aimed to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: We recruited 13 physician experts from relevant specialty, geography, and practice settings. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a 1-9 scale and classified as appropriate, inappropriate, or uncertain. Scenarios with > 2 ratings of 1-3 (inappropriate) and > 2 ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions (92%) and the UK (8%); had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting, but re-rated only 288 clinical scenarios as they felt that ongoing treatment with chemotherapy did not influence decision-making. Disagreement decreased from 37.5% before the meeting to 10.4% after. Consensus statements are summarized in the table below. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in urgent management of ascending cholangitis in pts with CC. (Support: The Cholangiocarcinoma Foundation). [Table: see text]

Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation‐specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele‐specific real‐time target and signal amplification assays on independent plasma‐extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long‐probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross‐validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval [CI]) were reported after 500 iterations. In phase II, a six‐marker MDM panel (homeobox A1 [HOXA1], empty spiracles homeobox 1 [EMX1], AK055957 , endothelin‐converting enzyme 1 [ECE1], phosphofructokinase [PFKP], and C‐type lectin domain containing 11A [CLEC11A]) normalized by beta‐1,3‐galactosyltransferase 6 (B3GALT6) level yielded a best‐fit AUC of 0.96 (95% CI, 0.93‐0.99) with HCC sensitivity of 95% (88%‐98%) at specificity of 92% (86%‐96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha‐fetoprotein (AFP) was 0.80 (0.74‐0.87) compared to 0.94 (0.9‐0.97) for the cross‐validated MDM panel (P < 0.0001). Conclusion : MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.