Antwi, Samuel O

Abstract Background: Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL. Methods: A case–control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). Results: Shorter peripheral blood LTL was associated with a higher risk of PDAC (ORT1vsT3 = 1.26, 95% CI = 1.03–1.54, Ptrend = 0.02; ORcontinuous = 1.14, 95% CI = 1.02–1.28), but the association was restricted to cases with treatment-naïve blood samples (ORT1vsT3 = 1.51, 95% CI = 1.16–1.96, Ptrend = 0.002; ORcontinuous = 1.25, 95% CI = 1.08–1.45) and not cases whose blood samples were collected after initiation of cancer therapy (ORT1vsT3 = 1.10, 95% CI = 0.87–1.39, Ptrend = 0.42; ORcontinuous = 1.08, 95% CI = 0.94–1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs. Conclusions: Treatment-naïve short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined. Impact: Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.

AbstractDeficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend < .0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend = .001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend = .04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk.

Background and Aims Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). Approach and Results A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06‐61.87; P < 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24‐7.36; P < 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16‐0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21‐0.41) and dCCA (OR, 0.06; CI, 0.03‐0.14), all P < 0.0001. Moderate‐intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34‐0.67; P < 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29‐0.97; P = 0.04). Conclusions This case‐control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.

Abstract Direct-acting antivirals (DAA) are now the mainstay of treatment for patients with chronic hepatitis C virus (HCV); however, there is some controversy over whether use of DAAs for HCV, as compared with IFN-based regimens, leads to an increased risk for hepatocellular carcinoma (HCC) development. We investigated the association between use of DAAs and subsequent development of HCC in longitudinal data from patients with HCV from diverse backgrounds (various ages, ethnicities, and geographic regions) across the United States. The design was a retrospective study performed using medical and pharmacy claims from OptumLabs. HCV treatment exposure was categorized as DAA-only, DAA + IFN, any-DAA, or IFN-only. To account for confounding by indication, inverse probability of treatment weighting was performed. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). We identified 5,781 patients with HCV with no history of HCC at baseline. Compared with IFN-only regimen, no significant increase in HCC risk was found for use of DAA-only (HR, 1.53; 95% CI, 0.73–3.23), DAA + IFN (HR, 1.02; 95% CI, 0.51–2.06), or any-DAA (HR, 1.04; 95% CI, 0.65–1.65). When stratified by sustained virological response (SVR), we noted a higher HCC risk for DAA-only among patients who achieved SVR post-treatment (HR, 7.53; 95% CI, 1.48–38.34), but the CIs were wide, which might be due to the small sample size of the subgroups. Among those who did not achieve SVR, no association was found for use of DAA-only (HR, 0.59; 95% CI, 0.19–1.91). These findings do not provide compelling evidence for the conception that use of DAAs for HCV is associated with increased risk of HCC development.

Goal: To investigate associations of prediagnosis and postdiagnosis use of statins and metformin on overall survival of patients with diabetes who later developed HCC. Background: Statins and metformin have received considerable interest as potential chemopreventive agents against hepatocellular carcinoma (HCC) development in individuals with type 2 diabetes mellitus (T2DM); however, their impact on overall survival of patients with T2DM who later develop HCC (diabetic HCC patients) is unclear. Study: Data on 2499 elderly diabetic HCC patients obtained from the SEER-Medicare program (2009 to 2013) were analyzed. Patients were categorized based on use of statins only, metformin only, both, or neither (reference for all comparisons). The patients were further categorized based on: (1) metformin dose: ≤1500 or >1500 mg/d; (2) statins functional form: hydrophilic (pravastatin and rosuvastatin) or lipophilic (atorvastatin, fluvastatin, lovastatin, and simvastatin); (3) statins potency: high (atorvastatin, rosuvastatin, and simvastatin) or low (fluvastatin, lovastatin, and pravastatin); and (4) individual statins type. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. Results: Prediagnosis use of metformin dose ≤1500 mg/d was associated with lower risk of death after HCC diagnosis in patients with T2DM (HR, 0.72; 95% CI, 0.58-0.91), adjusting for postdiagnosis metformin dose, diabetes severity, Charlson comorbidity index, tumor characteristics, and other relevant factors. No association was found for prediagnosis metformin dose >1500 mg/d or postdiagnosis metformin use. Further, no association was found for either prediagnosis or postdiagnosis statins use. Conclusions: Prediagnosis use of metformin dose ≤1500 mg/d is associated with longer overall survival of elderly diabetic HCC patients.

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: Pancreatic cancer (PC) ranks among the top causes of cancer mortality. Risk stratification is an important step toward prevention and early detection. Prior work has shown that ABO blood type (non-O) and first-degree family history of PC are associated with increased PC risk. Individuals with first-degree family history of PC have a 2- to 3-fold increased risk, but it is unclear if ABO blood type plays a role in the familial aggregation of PC. We investigated PC risk among first-degree relatives (FDRs) of PC probands based on the probands' serologic blood type (O vs non-O). Methods: A total of 702 probands sequentially enrolled in the Mayo Clinic Pancreas Research Registry from 2000-2016 with serologic ABO blood type provided information on family history of cancer for 5,178 FDRs. FDRs were grouped based on their related probands' blood type as type O (n=242; 1,768 FDRs) vs non-O (n=460; 3,410 FDRs). Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the number of PC cases observed among FDRs to those expected using data from the Surveillance, Epidemiology and End Results (SEER) Program as the reference population. SIRs for PC risk were calculated separately for FDRs of probands with type O vs FDRs of probands with non-O blood, and stratified by sex of FDRs and relationship to proband (parent, sibling, or offspring). Results: Compared to the SEER reference, PC risk was nearly 2-fold higher among FDRs of PC probands (SIR=1.76; 95%CI: 1.35-2.26). When stratified by probands' ABO type, risk for PC was higher among FDRs of probands with non-O blood (SIR=1.94; 95%CI: 1.41-2.60), compared to FDRs of probands with O blood (SIR=1.42; 95%CI: 0.83-2.28). Parents of probands with non-O blood had increased PC risk (SIR=3.28; 95%CI: 2.18-4.74, n=920), but not parents of probands with O blood (SIR=1.75; 95%CI: 0.75-3.45, n=484), p-value for between-group difference=0.10. Among FDRs of probands with O blood, female FDRs had increased PC risk (SIR=2.12; 95%CI: 1.06-3.79), but male FDRs did not (SIR=0.86; 95%CI: 0.31-1.88). Higher PC risk was observed among female FDRs of probands with non-O blood (SIR=2.28; 95%CI: 1.44-3.41) than male FDRs of probands with non-O blood (SIR=1.62; 95%CI: 1.00-2.48). Mothers of probands with O blood had increased PC risk (SIR=2.89; 95%CI: 1.05-6.28) compared to fathers (SIR=0.79; 95%CI: 0.09-2.84). Both mothers (SIR=3.60; 95%CI: 1.96-6.03) and fathers (SIR=2.95; 95%CI: 1.61-4.95) of probands with non-O blood had increased PC risk. No major findings were observed among probands' siblings or offspring. Conclusions: PC risk is greater among FDRs of PC probands with non-O blood than among FDRs of probands with type O. PC risk is higher among parents of probands with non-O blood, and female FDRs and mothers of probands with non-O blood. Possible clustering of non-O blood type in families may contribute to increased PC risk. Citation Format: Aarti Kolluri, Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, Brendan T. Broderick, William R. Bamlet, Ann L. Oberg, Robert R. McWilliams, Gloria M. Petersen. Risk of pancreatic cancer is increased among first-degree relatives of pancreatic cancer probands who have non-O ABO blood type [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 1239.

Abstract Background: Hepatocellular carcinoma (HCC) is a lethal malignancy that currently ranks fourth in cancer-related deaths in the US and is projected to become the third leading cause of cancer death in the US by 2030. Thus, there is a pressing need to identify modifying risk factors to improve survival after diagnosis of HCC. Statins and metformin are among the most commonly prescribed medications in the elderly in the US and there are experimental data suggesting that these medications may improve overall survival after cancer diagnosis; however, results from observational studies have been equivocal. We therefore investigated the potential benefits of pre- and post-diagnosis use of statins and metformin both independently and jointly on overall survival after diagnosis of HCC. Methods: The study was performed using data from the Surveillance, Epidemiology, and End Results (SEER-18) registry linked to Medicare claims data and included 8,922 elderly (≥65 years) patients diagnosed with HCC between 2009-2013. Data on metformin and statins use were extracted from the Medicare Part D Claims file and the patients were grouped as statins only users, metformin only users, both statins and metformin users, or neither (i.e., non-users, referent group). We assessed association of both pre-diagnosis (≥2 years) and post-diagnosis statins and metformin use on risk of death after diagnosis of HCC. Statins users were further categorized into high potency statins users (simvastatin, atorvastatin, and rosuvastatin) or low potency statins users (pravastatin, lovastatin, and fluvastatin) and compared with non-users. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for multiple risk factors, including age sex, race, cancer stage at diagnosis, cancer grade, first course therapy, neighborhood level education and income, Charlson comorbidity index, and diabetes severity index. Results: Compared with non-users, post-diagnosis statins use was independently associated with 27% lower risk of death after diagnosis of HCC (HR=0.73, 95% CI: 0.60-0.88; p-value = 0.002), adjusting for pre-diagnosis statins use and other risk factors. Further analysis showed that the association for post-diagnosis statins use is evident only among high potency statins users (HR=0.72, 95% CI: 0.60-0.88; users versus non-users) but not low potency statins users (HR=0.83, 95% CI: 0.55-1.25; users versus non-users). No association was found for pre-diagnosis statins use or for pre- or post-diagnosis metformin use. Conclusions: This study suggests that post-diagnosis statins use, particularly high potency statins use, may improve overall survival after diagnosis of HCC. Metformin use, both before and after diagnosis of HCC, is not associated with overall survival. Citation Format: Samuel O. Antwi, Zhuo Li, Kabir Mody, Tushar C. Patel. Independent and joint use of statins and metformin on overall survival after diagnosis of hepatocellular carcinoma: A SEER-Medicare matched study [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 1192.

Introduction and aim: Combined hepatocellular-cholangiocarcinoma (HCC-CCA) is a rare liver malignancy distinct from either hepatocellular carcinoma (HCC) or cholangiocarcinoma. Liver transplantation (LT) is not recommended for HCC-CCA because of suboptimal outcomes. Because non-invasive diagnosis of HCC-CCA is extremely challenging, some HCC-CCAs are presumed as HCC on imaging and listed for LT with the correct diagnosis ultimately made on explant pathology. We compared HCC-CCA with HCC to determine the utility of response to pre-transplant loco-regional therapy (LRT) in predicting outcomes for HCC-CCA after LT as a potential means of identifying appropriate HCC-CCA patients for LT. Materials and methods: Retrospective review of 19 patients with pathologically confirmed HCC-CCA individually matched to 38 HCC patients based on age, sex, and Milan criteria at listing was performed. The modified response evaluation criteria in solid tumors was used to categorize patients as responders or non-responders to pre-transplant LRT based on imaging performed before and after LRT. Overall survival (OS) and recurrence-free survival (RFS) were examined. Results: OS at 3 years post-transplant was 74% for HCC-CCA and 87% for HCC. RFS at 3 years was 74% for HCC-CCA, and 87% for HCC. Among responders to LRT, the 3-year OS was 92% for HCC-CCA and 88% for HCC; among non-responders, 3-year OS was 43% for HCC-CCA and 83% for HCC. Higher 3-year OS was observed among HCC-CCA responders (77%) compared with HCC-CCA non-responders (23%). Conclusions: OS was similarly high among responders to pre-transplant LRT irrespective of tumor type. Radiologic response to LRT could potentially be used to select appropriate HCC-CCA patients for LT if the findings are validated in independent studies.