Review of genetic and pharmacogenetic differences in cytotoxic and targeted therapies for pancreatic cancer in African Americans.

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality and the incidence is projected to increase by 2030. Despite recent advances in its treatment, African Americans have a 50-60% higher incidence and 30% higher mortality rate when compared to European Americans possibly resulting from differences in socioeconomic status, access to healthcare, and genetics. Genetics plays a role in cancer predisposition, response to cancer therapeutics (pharmacogenetics), and in tumor behavior, making some genes targets for oncologic therapeutics. We hypothesize that the germline genetic differences in predisposition, drug response, and targeted therapies also impact PDAC disparities. To demonstrate the impact of genetics and pharmacogenetics on PDAC disparities, a review of the literature was performed using PubMed with variations of the following keywords: pharmacogenetics, pancreatic cancer, race, ethnicity, African, Black, toxicity, and the FDA-approved drug names: Fluoropyrimidines, Topoisomerase inhibitors, Gemcitabine, Nab-Paclitaxel, Platinum agents, Pembrolizumab, PARP-inhibitors, and NTRK fusion inhibitors. Our findings suggest that the genetic profiles of African Americans may contribute to disparities related to FDA approved chemotherapeutic response for patients with PDAC. We recommend a strong focus on improving genetic testing and participation in biobank sample donations for African Americans. In this way, we can improve our current understanding of genes that influence drug response for patients with PDAC.

Racial Disparity in Pathologic Response following Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: A Multi-Institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Major pathologic response (MPR) following neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) patients undergoing resection is associated with improved survival. We sought to determine whether racial disparities exist in MPR rates following NAT in patients with PDAC undergoing resection. METHODS: Patients with potentially operable PDAC receiving at least 2 cycles of neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ± radiation followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Self-reported race was dichotomized as Black and non-Black, and multivariable models evaluated the association between race and MPR (i.e., pathologic complete response [pCR] or near-pCR). Cox regression evaluated the association between race and disease-free (DFS) and overall survival (OS). RESULTS: Results of 486 patients who underwent resection following NAT (mFOLFIRINOX 56%, gemcitabine/nab-paclitaxel 25%, radiation 29%), 67 (13.8%) patients were Black. Black patients had lower CA19-9 at diagnosis (median 67 vs. 204 U/mL; P = 0.003) and were more likely to undergo mild/moderate chemotherapy dose modification (40 vs. 20%; P = 0.005) versus non-Black patients. Black patients had significantly lower rates of MPR compared with non-Black patients (13.4 vs. 25.8%; P = 0.039). Black race was independently associated with worse MPR (OR 0.26, 95% confidence interval [CI] 0.10-0.69) while controlling for NAT duration, CA19-9 dynamics, and chemotherapy modifications. There was no significant difference in DFS or OS between Black and non-Black cohorts. CONCLUSIONS: Black patients undergoing pancreatectomy appear less likely to experience MPR following NAT. The contribution of biologic and nonbiologic factors to reduced chemosensitivity in Black patients warrants further investigation.

Eligibility Criteria Perpetuate Disparities in Enrollment and Participation of Black Patients in Pancreatic Cancer Clinical Trials.

PURPOSE: Clinical trials determine safety and efficacy of cancer therapeutics and establish standards of care. Minority patient participation in cancer clinical trials is dismal. We aimed to determine the impact of eligibility criteria on disparities in pancreatic ductal adenocarcinoma (PDAC) clinical trial candidacy. METHODS: Traditional PDAC trial eligibility criteria were obtained from ClinicalTrials.gov. Patients with PDAC who sought care at Virginia Commonwealth University Health from 2010 to 2019 were included. Clinical data were obtained from billing codes and discrete values in the electronic medical record. Eligibility criteria differences between racial groups were determined using chi-squared tests and unconditional maximum likelihood-based odds ratios. RESULTS: Among 676 patients, most identified as Black or White race (42.5% and 51.6%, respectively). Using traditional criteria, Black patients were more likely to be ineligible for participation compared with White patients (42.4% v 33.2%, P = .023) secondary to hypoalbuminemia (14.1% v 7.9%, P = .023), HIV (3.1% v 0.3%, P = .010), hepatitis B (1.7% v 0%, P = .043), and hepatitis C (9.1% v 3.4%, P = .005). Black patients were also numerically more likely to be ineligible because of renal dysfunction, recent coronary stenting, and uncontrolled diabetes mellitus. Prior cancer treatment excluded fewer Black than White patients (9.1% v 14.0%, P = .072), most attributable to lower rates of neoadjuvant chemotherapy received. Strategic eligibility criteria revisions could equalize ineligibility rates between Black and White patients (26.8% v 24.8%, P = .581). CONCLUSION: Traditional eligibility criteria differentially exclude Black patients from participating in PDAC clinical trials. These criteria perpetuate disparities, limit generalizability, and are often not medically justifiable. Revised criteria may improve participant diversity, without compromising safety or study results.

The genetic landscape of pancreatic head ductal adenocarcinoma in China and prognosis stratification.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the major subtype of pancreatic cancer and head PDACs show distinct characteristics from body/tail PDACs. With limited studies based on Asian population, the mutational landscape of Asian PDAC remains unclear. METHODS: One hundred fifty-one Chinese patients with head PDAC were selected and underwent targeted 425-gene sequencing. Genomic alterations, tumor mutational burden, and microsatellite instability were analyzed and compared with a TCGA cohort. RESULTS: The genomic landscape of Chinese and Western head PDAC had identical frequently-mutated genes including KRAS, TP53, SMAD4, and CDKN2A. KRAS hotspot in both cohorts was codon 12 but Chinese PDACs containing more G12V but fewer G12R variants. Potentially pathogenic fusions, CHD2-BRAF and KANK1-MET were identified in two KRAS wild-type patients. Serum cancer antigens CA125 and CA19-9 were positively associated with SMAD4 alterations while high CEA was enriched in wild-type CDKN2A subgroup. The probability of vascular invasion was lower in patients with RNF43 alterations. The nomogram developed including histology grade, the mutation status of SMAD4, TGFBR2, and PREX2 could calculate the risk score of prognoses validated by Chinese and TCGA cohort. CONCLUSIONS: Chinese head PDAC contained more KRAS G12V mutation than Western population. The well-performed nomogram may improve post-operation care in real-world practice.

It's more than just cancer biology: Health disparities in patients with pancreatic neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) represent a rare form of pancreatic cancer. Racial/ethnic disparities have been documented in pancreatic ductal adenocarcinoma, but health disparities have not been well described in patients with PNETs. METHODS: A retrospective review of patients with PNETs in the National Cancer Database was performed for 2004-2014. Approximately 16 605 patients with PNETs and available vital status were identified. Survival was compared by race/ethnicity and socioeconomic status using Kaplan-Meier methods and Cox regression. RESULTS: There were no significant differences in survival between Non-Hispanic, White; Hispanic, White; or Non-Hispanic, Black patients on univariate analysis. Kaplan-Meier analysis showed that patients from communities with lower median household income and education level had worse survival (p < 0.001). Patients age less than 65 without insurance, similarly, had worse survival (p < 0.001). Multivariable modeling found no association between race/ethnicity and risk of mortality (p = 0.37). Lower median household income and lower education level were associated with increased mortality (p < 0.001). CONCLUSIONS: Unlike most other malignancies, race/ethnicity is not associated with survival differences in patients with PNETs. Patients with lower socioeconomic status had worse survival. The presence of identifiable health disparities in patients with PNETs represents a target for intervention and opportunity to improve survival in patients with this malignancy.

Thirty-day complication rates do not differ by race among patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: Black patients with pancreatic ductal adenocarcinoma (PDAC) are less likely to receive multimodality treatment and have worse survival compared to White patients. However, little is known regarding racial differences in postoperative outcomes. The primary aim of this study was to determine if 30-day complication rates following pancreaticoduodenectomy (PD) differ by race. METHODS: A retrospective cohort study of patients who underwent PD for PDAC from 2014 to 2016 within the ACS-NSQIP pancreatectomy-specific data set was performed. Primary outcomes were 30-day pancreas-specific and overall major complications. RESULTS: A total of 6936 patients were identified, including 91.4% (N = 6337) White and 8.6% (N = 599) Black. Pathologic stage and rates of neoadjuvant therapy were similar among Whites and Blacks. Rates of pancreas-specific (23.9% vs. 23.1%, p = .88) and major postoperative complications (39.2% vs. 39.9%, p = .55) were similar between Whites and Blacks. By multivariable regression analysis, there was no association between race and odds of pancreas-specific complications (odds ratio [OR] 1.10, 95% confidence interval [CI] 0.89-1.37) or overall major complications (OR 1.13, 95% CI 0.95-1.36). CONCLUSIONS: Among patients undergoing PD for PDAC, Black race is not associated with increased pancreas-specific or overall 30-day postoperative complications. Short-term postoperative outcomes do not appear to explain the increase in pancreatic cancer mortality among Black patients.

Association of Glycated Hemoglobin Levels With Risk of Pancreatic Cancer.

Importance: New-onset diabetes after the age of 50 years is a potential indicator of pancreatic cancer. Understanding the associations between hyperglycemia, diabetes, and pancreatic cancer, including pancreatic ductal adenocarcinoma, is key to developing an approach to early detection. Objective: To assess the association of elevation in glycated hemoglobin (HbA1c) with the risk of pancreatic cancer. Design, Setting, and Participants: This cohort study was conducted using data collected from an integrated health care system in California. A total of 851 402 patients aged 50 to 84 years who had HbA1c measurements taken between 2010 and 2014 were identified as the base cohort, with 12 contemporaneous cohorts created based on varying HbA1c thresholds (ie, 6.1%, 6.3%, 6.5%, and 6.7%) and prior diabetes status. Data analysis was conducted from August 2018 to September 2019. Main Outcomes and Measures: New cases of pancreatic cancer identified through cancer registry and California death files during a 3-year period. Three-year risk, incidence rate, sensitivity, number of patients needed to screen to detect 1 case, timing, and stage at diagnosis were determined. Results: Among 851 402 patients in the base cohort, 447 502 (52.5%) were women, 255 441 (30.0%) were Hispanic participants, 383 685 (45.1%) were non-Hispanic white participants, 100 477 (11.8%) were Asian participants, and 88 969 (10.4%) were non-Hispanic black participants, with a median (interquartile range) age of 62 (56-69) years and a median (interquartile range) HbA1c level of 6.0% (5.7%-6.6%). The incidence rate of pancreatic cancer was 0.45 (95% CI, 0.43-0.49) per 1000 person-years. After excluding prior diabetes as well as confirmation of new-onset hyperglycemia based on an HbA1c level of 6.5%, a total of 20 012 patients remained, with 74 of 1041 pancreatic ductal adenocarcinoma cases (7.1%) from the base cohort included. The rate of pancreatic cancer was 0.72 (95% CI, 0.32-1.42) per 1000 person-years among Asian patients, 0.83 (95% CI, 0.35-1.71) per 1000 person-years among non-Hispanic black patients, 0.84 (95% CI, 0.48-1.37) per 1000 person-years among Hispanic patients, and 2.37 (95% CI, 1.75-3.14) per 1000 person-years among non-Hispanic white patients. Overall, 42 of 74 cancers (56.8%) were diagnosed within 1 year of the index laboratory test. Among 1041 total cases, 708 (68.0%) had staging information available, of whom 465 (65.7%) had stage III or IV disease at diagnosis. In the base cohort, the number needed to undergo evaluation to identify a single case of pancreatic ductal adenocarcinoma was 818 (95% CI, 770-869), with estimates ranging from 206 (95% CI, 160-264) to 600 (95% CI, 540-666) in the subcohorts. Conclusions and Relevance: The findings of this study suggest that screening patients for pancreatic cancer based solely on elevation in HbA1c level is unlikely to represent an effective strategy. Future efforts to identify a high-risk population based on changes in glycemic parameters should account for racial/ethnic differences.

Disparities in Pancreatic Ductal Adenocarcinoma-The Significance of Hispanic Ethnicity, Subgroup Analysis, and Treatment Facility on Clinical Outcomes.

BACKGROUND: Disparities exist among patients with pancreatic ductal adenocarcinoma (PDAC). Non-White race is regarded as a negative predictor of expected treatment and overall survival. Data suggest that Academic Research Programs (ARP) provide better outcomes for minorities, but ethnic/minority outcomes are underreported. We hypothesize that outcomes among racially/ethnically diverse PDAC patients may be influenced by treatment facility. METHODS: The National Cancer Database was used to identify 170,327 patients diagnosed with PDAC between 2004 and 2015. Cox proportional-hazard regression was used to compare survival between race/ethnic groups across facilities. RESULTS: In unadjusted models, compared to non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB) had the worst overall survival (HR = 1.05, 95%CI: 1.03-1.06, P < .001) and Hispanics had the best overall survival (HR = 0.92, 95%CI: 0.90-0.94, P < .001). After controlling for socioeconomic and clinical covariates, NHB (HR = 0.95, 95%CI: 0.93-0.96, P < .001) had better overall survival compared to NHW, and Hispanics continued to have the best comparative outcomes (HR = 0.84, 95%CI: 0.82-0.86, P < .001). Among Hispanics, Dominicans and South/Central Americans lived the longest, at 10.25 and 9.82 months, respectively. The improved survival in Hispanics was most pronounced at ARP (HR = 0.80, 95%CI: 0.77-0.84, P < .001) and Integrated Network Cancer Programs (HR = 0.78, 95%CI: 0.73-0.84, P < .001). NHB had improved survival over NHW at Comprehensive Community Care Programs (HR = 0.96, 95%CI: 0.93-0.98, P = .002) and ARP (HR = 0.96, 95%CI: 0.94-0.98, P = .001), which was influenced by income, education, and surgical resection. CONCLUSION: Survival was improved at ARP for all populations. Hispanics had the best comparative overall survival. NHB had improved overall survival at higher volume centers, but this was dependent upon income, education, and surgical resection.

Association of Treatment Inequity and Ancestry With Pancreatic Ductal Adenocarcinoma Survival.

Importance: Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown. Objectives: To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity. Design, Setting, and Participants: This cohort study used data on 278 936 patients with PDAC with database-defined race from the National Cancer Database from January 1, 2004, to December 31, 2015. The median follow-up for censored patients was 24 months. The National Cancer Database, comprising academic and community facilities, includes about 70% of new cancer diagnoses in the United States. Race-stratified receipt of therapy was the primary variable of interest. Multivariable analyses included additional demographic and clinical parameters. Data analysis was initially completed on November 30, 2018, and revised data analysis was completed on June 27, 2019. Main Outcomes and Measures: Overall survival was the primary outcome, analyzed with Kaplan-Meier and multivariable Cox proportional hazards regression modeling. Results: The cohort included 278 936 patients (137 121 women and 141 815 men; mean [SD] age, 68.72 [11.57] years); after excluding patients from other racial categories, 243 820 of the 278 936 patients (87.4%) were white and 35 116 of the 278 936 patients (12.6%) were black. Unadjusted median overall survival was longer for white patients than for black patients (6.6 vs 6.0 months; P < .001). Black patients presented at younger ages than white patients (15 819 of 35 116 [45.0%] vs 83 846 of 243 820 [34.4%] younger than 65 years; P < .001) and with more advanced disease (20 853 of 31 600 [66.0%] vs 135 317 of 220 224 [61.4%] with stage III or IV disease; P < .001). Black patients received fewer surgical procedures than white patients for potentially resectable stage II disease (4226 of 8097 [52.2%] vs 39 214 of 65 124 [60.2%]; P < .001) and slightly less chemotherapy for advanced disease (2756 of 4067 [67.8%] vs 17 296 of 25 227 [68.6%] for stage III disease [P = .001]; 8208 of 16 104 [51.0%] vs 58 603 of 105 616 [55.5%] for stage IV disease [P < .001]). Decreased survival for black patients persisted in multivariable modeling controlled for sociodemographic parameters (hazard ratio, 1.04 [95% CI, 1.02-1.05]). Conversely, modeling that controlled specifically for clinical parameters such as disease stage and treatment revealed a modest survival advantage (hazard ratio, 0.94 [95% CI, 0.93-0.96]) among black patients. Resection was the factor most strongly associated with overall survival (hazard ratio, 0.39 [95% CI, 0.38-0.39]). Conclusions and Relevance: Black patients with PDAC present at younger ages and with more advanced disease than white patients, suggesting that differences in tumor biology may exist. Black patients receive less treatment stage for stage and fewer surgical procedures for resectable cancers than white patients; these findings may be only partly associated with socioeconomic differences. When disease stage and treatment were controlled for, black patients had no decrease in survival.

Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Quality of life (QOL) is impaired in pancreatic cancer patients. Our aim was to investigate the determinants and prognostic value of QOL after diagnosis in a hospital-based cohort of racially/ethnically diverse patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: QOL was prospectively assessed using the Short Form-12 in 2478 PDAC patients. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were categorised into tertiles based on their distribution. Ordered logistic regression was adopted to compare the risk of having lower PCS and MCS by patient sociodemographic and clinical characteristics. The association of PCS and MCS with mortality was assessed by Cox regression. RESULTS: Compared with non-Hispanic whites, Hispanics were at significantly higher risk of having lower PCS (odds ratio [95% CI], 1.69 [1.26-2.26]; P < 0.001) and lower MCS (1.66 [1.24-2.23]; P < 0.001). Patients diagnosed with stage III (1.80 [1.10-2.94]; P = 0.02) and stage IV (2.32 [1.50-3.59]; P < 0.001) PDAC were more likely to have lower PCS than stage I patients. Other determinants of QOL included sex, age, drinking, smoking, education level, comorbidities and time since diagnosis. The low tertile of PCS (hazard ratio [95% CI], 1.94 [1.72-2.18]; P < 0.001) and MCS (1.42 [1.26-1.59]; P < 0.001) were each related to poor prognosis. Similar results were found for non-Hispanic whites as compared with African-Americans/Hispanics/others. CONCLUSION: QOL after diagnosis is a significant prognostic indicator for patients with PDAC. Multiple factors determine QOL, suggesting possible means of intervention to improve QOL and outcomes of PDAC patients.

African Americans with pancreatic ductal adenocarcinoma exhibit gender differences in Kaiso expression.

Kaiso, a bi-modal transcription factor, regulates gene expression, and is elevated in breast, prostate, and colon cancers. Depletion of Kaiso in other cancer types leads to a reduction in markers for the epithelial-mesenchymal transition (EMT) (Jones et al., 2014), however its clinical implications in pancreatic ductal adenocarcinoma (PDCA) have not been widely explored. PDCA is rarely detected at an early stage but is characterized by rapid progression and invasiveness. We now report the significance of the subcellular localization of Kaiso in PDCAs from African Americans. Kaiso expression is higher in the cytoplasm of invasive and metastatic pancreatic cancers. In males, cytoplasmic expression of Kaiso correlates with cancer grade and lymph node positivity. In male and female patients, cytoplasmic Kaiso expression correlates with invasiveness. Also, nuclear expression of Kaiso increases with increased invasiveness and lymph node positivity. Further, analysis of the largest PDCA dataset available on ONCOMINE shows that as Kaiso increases, there is an overall increase in Zeb1, which is the inverse for E-cadherin. Hence, these findings suggest a role for Kaiso in the progression of PDCAs, involving the EMT markers, E-cadherin and Zeb1.

Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.

PURPOSE: The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. PATIENTS AND METHODS: Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. RESULTS: Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P=.02, P<.001, and P=.05, respectively). However, the majority of the BRCA mutation-positive patients did not actually meet these genetic testing criteria. CONCLUSION: Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.

Low frequency of KRAS mutation in pancreatic ductal adenocarcinomas in Korean patients and its prognostic value.

OBJECTIVES: Low prevalence and prognostic relevance of KRAS mutations in Korean pancreatic ductal adenocarcinomas (PDACs) need to be validated with sensitive detection method. METHODS: Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping was used to precisely detect KRAS mutation in 72 paraffinized tumor samples and was validated by pancreatic cell lines to compare the efficiency of direct sequencing. RESULTS: The PNA-mediated PCR clamping detected mutant allele proportions of as low as 0.5% against a background of wild-type DNA and was 20-fold more sensitive than direct sequencing through the validation of pancreatic cell lines. Peptide nucleic acid-mediated PCR clamping detected KRAS mutations in 47.2% of 72 PDACs. Low tumor cellularity and low PCR amplification efficiency led to be undetected or failed by direct sequencing in pancreatic paraffinized samples.KRAS mutations were an independent worse prognostic factor predicting a reduced progression-free survival rate in the postoperative chemotherapy group. CONCLUSIONS: Peptide nucleic acid clamp real-time PCR was a sensitive method for detecting KRAS status in paraffinized PDAC samples. We identified a low KRAS mutation rate among the Korean PDAC patients using PNA clamp real-time PCR, potentially implicating epidemiological characteristics. The low KRAS mutation rate and its prognostic role may suggest the further survival benefit in Korean PDAC patients.

Case-control study of diabetes-related genetic variants and pancreatic cancer risk in Japan.

AIM: To examine whether diabetes-related genetic variants are associated with pancreatic cancer risk. METHODS: We genotyped 7 single-nucleotide polymorphisms (SNPs) in PPARG2 (rs1801282), ADIPOQ (rs1501299), ADRB3 (rs4994), KCNQ1 (rs2237895), KCNJ11 (rs5219), TCF7L2 (rs7903146), and CDKAL1 (rs2206734), and examined their associations with pancreatic cancer risk in a multi-institute case-control study including 360 cases and 400 controls in Japan. A self-administered questionnaire was used to collect detailed information on lifestyle factors. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these diabetes-associated variants and pancreatic cancer risk. RESULTS: With the exception of rs1501299 in the ADIPOQ gene (P = 0.09), no apparent differences in genotype frequencies were observed between cases and controls. Rs1501299 in the ADPIOQ gene was positively associated with pancreatic cancer risk; compared with individuals with the AA genotype, the age- and sex-adjusted OR was 1.79 (95%CI: 0.98-3.25) among those with the AC genotype and 1.86 (95%CI: 1.03-3.38) among those with the CC genotype. The ORs remained similar after additional adjustment for body mass index and cigarette smoking. In contrast, rs2237895 in the KCNQ1 gene was inversely related to pancreatic cancer risk, with a multivariable-adjusted OR of 0.62 (0.37-1.04) among individuals with the CC genotype compared with the AA genotype. No significant associations were noted for other 5 SNPs. CONCLUSION: Our case-control study indicates that rs1501299 in the ADIPOQ gene may be associated with pancreatic cancer risk. These findings should be replicated in additional studies.

Pancreatic cancer susceptibility loci and their role in survival.

Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.

Familial pancreatic carcinoma in Jews.

Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80-90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1-3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5-10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1 . Other hereditary disorders predisposing to PC include Peutz-Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32-34 mutation, hereditary breast-ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1 , familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis, as well as screening and control, may take place.

Clinicopathologic analysis of pancreatic adenocarcinoma in African Americans and Caucasians.

INTRODUCTION: African Americans have a higher incidence of pancreatic adenocarcinoma than do Caucasians for unknown reasons. Whether other clinicopathologic differences exist between these two groups is not known. This study was undertaken to compare the clinical, pathologic, and biologic findings for a group of patients with a histologic diagnosis of pancreatic ductal adenocarcinoma of the usual type in a single institution. METHODOLOGY: We studied 410 patients (166 African Americans and 244 Caucasians) with a histologic diagnosis of pancreatic ductal adenocarcinoma of the usual type and analyzed (a) the clinicopathologic characteristics of the tumors, (b) the immunohistochemical expression of biomarkers implicated in pancreatic carcinogenesis (Fas, Fas ligand, HER2, p21/waf-1, p27, and p53), and (c) the presence and types of K- mutations at codon 12 as determined by polymerase chain reaction-mediated amplification. All elements of data were not available for all patients. RESULTS: African Americans had significantly higher rates of K-ras mutations to valine than did Caucasians (58% versus 22%, respectively; p = 0.015) and were less likely to have received chemotherapy (45% versus 70%, respectively; p = 0.001) or radiation therapy (34% versus 57%, respectively; p = 0.003). African Americans also had more frequent positive surgical margins than did Caucasians (56% versus 25%, respectively; p = 0.001), although mean tumor size was similar between the two groups (African Americans, 3.4 cm; Caucasians, 3.5 cm). Other clinicopathologic variables were similar between the two groups, including median survival (African Americans, 8.5 months; Caucasians, 10.1 months), 5-year survival (African Americans, 3%; Caucasians, 6%), and stage at presentation. Differences in biomarker immunoreactivity included less frequent Fas expression (4% versus 24%, respectively; p = 0.048) and a trend toward more frequent strong HER2 expression (39% versus 18%, respectively p = 0.11) in African Americans than in Caucasians. CONCLUSION: Although African American and Caucasian patients had similar survival rates associated with usual type pancreatic ductal adenocarcinoma, there were differences in management and expression of biologic markers between these two groups. African Americans were significantly less likely to receive radiation therapy or chemotherapy than were Caucasians, which may assume more importance as treatment improves. At the molecular level, African Americans had more frequent K- mutations to valine than did Caucasians.