Citations

Abstract Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13–1.63; P = 9.29 × 10−4; 7p13, rs17688601: OR = 0.76; 95% CI, 0.63–0.93; P = 6.59 × 10−3). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P < 5 × 10−5) to pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185–91. ©2016 AACR.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

BACKGROUNDPatients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality‐related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms.METHODSA total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN‐SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC‐QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age‐matched, healthy control population.RESULTSOverall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN‐SAF score of 3.6 vs 2.0; P<.001), with 64% of patients with MPN describing some degree of sexual dysfunction and 43% experiencing severe symptoms. The presence of sexual symptoms correlated closely with all domains of patient functionality (physical, social, cognitive, emotional, and role functioning) and were associated with a reduced quality of life. Sexual problems also were found to be associated with other MPN symptoms, particularly depression and nocturnal and microvascular‐related symptoms. Sexual dysfunction was more severe in patients aged >65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids.ConclusionsThe results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management. Cancer 2016;122:1888–96. © 2016 American Cancer Society.

Purpose The inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC). Patients and Methods Of newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis. Results Median survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naïve to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis. Conclusion Our findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.

Monocyte‐derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell‐cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte‐derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk‐stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte‐derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte‐derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687–691, 2016. © 2016 Wiley Periodicals, Inc.

The impact of race on outcomes of patients with chronic lymphocytic leukemia (CLL), the most common leukemia in the west, is not well studied. We aimed to understand racial variations in clinical and disease characteristics, treatment patterns, and outcomes in patients with CLL. We utilized the Mayo Clinic CLL database to perform an analysis of these characteristics and natural history of non‐white (NW) compared to white (W) CLL patients. Differences by race in median overall survival (OS) and time‐to‐first‐treatment (TTFT) were investigated. Of the 4215 CLL patients, 4114 (97.6%) were W and 101 (2.4%) were NW. NW patients were younger (median age at diagnosis 59.4 vs. 63.4; P = 0.003) and more likely to have an elevated LDH (28.0% vs. 16.2%; P = 0.02). No differences in prognostic parameters were noted. No major differences were observed in treatment selection. OS and TTFT were similar between both groups. In the largest analysis of NW‐CLL patients in North America, and contrary to historical retrospective reports, W and NW patients appear to have comparable outcomes when treated similarly. These findings suggest previously noted outcome differences may be due to disparities in access to care and management rather than differences in disease biology. Am. J. Hematol. 91:677–680, 2016. © 2016 Wiley Periodicals, Inc.

ObjectivesPerformance measurement is used by health care providers, payers, and patients. Historically accomplished using administrative data, registries are used increasingly to track and improve care. We assess how measured diabetes care quality differs when calculated using claims versus registry.Data Sources/Study SettingCross‐sectional analysis of administrative claims and electronic health records (EHRs) of patients in a multispecialty integrated health system in 2012 (n = 368,883).Study DesignWe calculated percent of patients attaining glycohemoglobin <8.0 percent, LDL cholesterol <100 mg/dL, blood pressure <140/90 mmHg, and nonsmoking (D4) in cohorts, identified by Medicare Accountable Care Organization/Minnesota Community Measures (ACO‐MNCM; claims‐based), Healthcare Effectiveness Data and Information Set (HEDIS; claims‐based), and registry (EHR‐based).Data Collection/Extraction MethodsClaims were linked to EHR to create a dataset of performance‐eligible patients.Principal FindingsACO‐MNCM, HEDIS, and registry identified 6,475, 6,989, and 6,425 measurement‐eligible patients. Half were common among the methods; discrepancies were due to attribution, age restriction, and encounter requirements. D4 attainment was lower in ACO‐MNCM (36.09 percent) and HEDIS (37.51 percent) compared to registry (43.74 percent) cohorts.ConclusionsRegistry‐ and claims‐based performance measurement methods identify different patients, resulting in different rates of quality metric attainment with implications for innovative population health management.

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

ObjectiveTo prospectively analyze quality‐of‐life outcomes following transoral diverticulotomy with cricopharyngeal myotomy (DCPM) for Zenker’s diverticulum (ZD).Study DesignProspective single‐group study.SettingsTertiary academic institution.Subjects and MethodsA prospective multicenter study performed from January 1, 2012, to July 1, 2014, included 18 patients presenting with ZD undergoing DCPM. Standardized questionnaires—including the 10‐item Eating Assessment Tool (EAT‐10), Functional Outcome of Swallowing Scale (FOSS), and the Reflux Symptom Index (RSI)—were completed preoperatively and at 3 and 6 months postoperatively. Videofluoroscopic studies were obtained and analyzed by our senior speech‐language pathologist, who was blinded to the clinical outcomes.ResultsEighteen patients were included (11 women; mean age, 72.6 years; range, 53‐86 years). All patients had ZD on preoperative videofluoroscopic swallowing studies. The most common comorbidities included hypertension (10 of 18, 55.6%), dyslipidemia (8 of 18, 44.4%), hiatal hernia (6 of 18, 33.3%), and gastroesophageal reflux disease (5 of 18, 27.8%). Median preoperative RSI was 27 (interquartile range [IQR], 22.5‐31.5); FOSS, 2 (IQR, 2‐3); and EAT‐10, 21.5 (IQR, 13.5‐27.5). The 3‐month questionnaire (88.9% completion) demonstrated an improved median RSI of 5 (IQR, 1‐7.5; P <. 001), FOSS of 0 (IQR, 0; P <. 001), and EAT‐10 of 0 (IQR, 0‐3; P <. 001). Fourteen patients (77.8%) completed the 6‐month questionnaire, demonstrating a median RSI of 4 (IQR, 0‐8), FOSS of 0 (IQR, 0‐0.5), and EAT‐10 of 1 (IQR, 0‐3). While regurgitation decreased following surgery (P =. 007), nighttime cough did not (P =. 25).ConclusionThis study supports an improvement in functional outcome and quality of life in patients with ZD undergoing DCPM.

Abstract Background: Epidemiologic studies have suggested that metformin use is associated with cancer death reduction. The results for pancreatic ductal adenocarcinoma (PDAC) are inconsistent. Retrospective studies of cancer survival may potentially have unintended biases; due to complexities of diabetes management, metformin use exposure is commonly categorized as simply “yes/no.” Nevertheless, in part based on epidemiologic studies, there are at least 20 open cancer clinical trials that include metformin in a treatment arm. We aimed to study metformin use and survival of patients with PDAC, addressing potential inherent biases. Methods: A retrospective cohort study for the years 2000-2011 was conducted using the patient database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. 1,360 PDAC patients (59% male; mean age 67) with diabetes were studied; overall survival was the primary outcome. Initiation and duration of metformin use was carefully abstracted from medical records. Patients were categorized into 5 groups based on metformin initiation: (A) Never used, n = 908 (reference group); (B) Metformin started &gt;1 year prior to PDAC diagnosis, n = 84; (C) Metformin started within 1 year prior to PDAC diagnosis, n = 212; (D) Metformin started &lt;30 days post-PDAC diagnosis, n = 104; (E) Metformin started &gt;30 days post PDAC diagnosis, n = 34. Hazard ratios (HR) and 95% confidence intervals (C.I.) for survival differences between groups were computed using Cox proportional hazards models, adjusting for age, sex, disease stage, body mass index, and diagnosis year group. Results: Median survival of patients in Groups B-E was 292 days compared to 308 for Group A; this was not significantly different. However, among 413 resectable patients, metformin users appeared to survive longer than non-users (782 vs. 612 days, p = 0.07). Survival in each group was 308, 245, 249, 243 and 818 days, respectively. Because Group E had already survived &gt;30 days, a bias existed. With Group E excluded, there was no survival difference among the other 4 groups (p = 0.18). Compared to Group A, HR and 95% C.I. for metformin use were 1.08 (0.85-1.37), 0.99 (0.85-1.17), 1.04 (0.83-1.31) and 0.49 (0.33-0.74), for Group B-E, respectively. Conclusions: Our thorough analysis suggests that metformin use does not improve survival of patients with PDAC. The benefit of metformin was observed only in patients who started metformin post-PDAC diagnosis; however, there is an inherent survival bias in this group of patients. Studies of medication exposure and cancer survival warrant very careful and detailed data collection. Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies. Citation Format: Roongruedee Chaiteerakij, David B. Zhen, Patrick A. Burch, Kari G. Chaffee, William R. Bamlet, Ann L. Oberg, Lewis R. Roberts, Gloria M. Petersen. Metformin use does not increase survival of pancreatic cancer patients: A cautionary lesson. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-183. doi:10.1158/1538-7445.AM2015-LB-183