Citations

Comorbidity was associated with shorter overall survival but not toxicity or relapse among older women with breast cancer with good functional status.

Abstract Background: Hormone therapy (HT) may prevent colorectal cancer (CRC), but the molecular mechanisms have not been fully defined. Expression of estrogen receptor beta (ERβ) has been associated with CRC stage and survival and may influence HT-related prevention pathways. In this prospective cohort study, we examined HT-associated CRC risk by ERβ protein expression levels in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). Exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases, diagnosed through 12/31/2002, for molecular epidemiology studies. HT was categorized as never, former, and current and with durations of <=5 years or >5 years. ERβ protein expression was determined by immunohistochemistry on tissue microarrays. For each tumor core, both staining intensity (0-3) and proportion of cells stained (0-5) were scored. These two scores were added to determine negative (0), low (1-5) or high (6-8) ERβ protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Complete HT and ERβ data were available from 484 CRC cases. Associations between HT and CRC subtypes defined by ERβ expression level are shown in the Table. Conclusions: Data from the IWHS cohort suggest that current and longer-duration HT exposure favorably influence the risk for ERβ-neg or ERβ-low CRC cases to a greater degree than ERβ-high CRC cases. Further investigation is required to confirm these observations, and to clarify the underlying mechanisms. ERβ Neg or Low ERβ High Hormone Therapy Person years Events, N RR* (95% CI) Events, N RR* (95% CI) Never 341377 128 1.00 (Ref.) 196 1.00 (Ref.) Ever 212696 62 0.74 (0.54,1.03) 98 0.82 (0.63,1.07) Former 151535 48 0.79 (0.56,1.12) 67 0.73 (0.54,0.99) Current 61161 14 0.60 (0.33,1.09) 31 1.11 (0.74,1.64) P-trend 0.05 0.52 Duration < = 5yrs 148704 47 0.84 (0.59,1.19) 68 0.80 (0.60,1.08) >5yrs 60064 14 0.5 (0.26,0.93) 28 0.89 (0.59,1.34) P-trend 0.03 0.25 Citation Format: Lori S. Tillmans, Robert A. Vierkant, Alice H. Wang, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, John D. Potter, Susan L. Slager, Thomas C. Smyrk, Stephen N. Thibodeau, James R. Cerhan, Paul J. Limburg. Hormone therapy and incident colorectal cancer risk by ER beta protein expression level in a population-based cohort of older women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3652. doi:10.1158/1538-7445.AM2013-3652

Abstract Background: Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are collectively classified as myeloproliferative neoplasms (MPN). Given that little is known about their etiology, we investigated the role of anthropometric, medical and lifestyle factors in the development of MPNs and the common subtypes (ET & PV) in a population-based cohort of women. Methods: The IWHS is a prospective cohort of Iowa women aged 55-69 years at enrollment in 1986. Participants completed 6 self-administered questionnaires between 1986-2004. This analysis includes 27370 women who completed the 1993 questionnaire, had no history of cancer, and were enrolled in Medicare at least 1 year. MPN cases through 2004 were identified by linkage to Medicare. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression, with age as the underlying time variable. Results: After >250,000 person-years of follow-up, 257 cases of MPNs were identified (172 ET, 64 PV and 21 MF). Height, body mass index (BMI) and waist-to-hip ratio were not associated with risk of MPN. In subtype analysis, BMI was positively associated with risk of ET (RR=1.52 for >29.3 vs <23.5 kg/m2; p-trend=0.042) but not PV. Physical activity (PA) showed a suggestive association with MPN (RR=0.74 for high vs low activity; p-trend=0.063), specific only to ET (RR=0.66; p-trend=0.04). Diabetes (DM) was positively associated with risk of MPN (RR=1.51; 95% CI 1.02-2.24), also specific only to ET (RR=1.82; 95% CI 1.16-2.84). Regular use of aspirin, but not other non-steroidal anti-inflammatory agents, was associated with a lower risk of MPN (RR=0.71; 95% CI 0.55-0.92); slightly stronger for ET (RR=0.68; 95% CI 0.50-0.93) than for PV (RR=0.84; 95% CI 0.50-1.43). There was no dose-response with frequency of use. Cigarette smoking was associated with risk of MPN, which was stronger for PV (RR=0.94 for former and RR=2.83 for current; p-trend=0.016) than for ET (RR=1.28 for former and RR=1.32 for current; p-trend=0.15). There were no associations with alcohol use. In a multivariate model for ET, the associations for BMI (RR=1.28; p-trend=0.21) and DM (RR=1.51; 95% CI 0.92-2.46) attenuated, while there was little change for PA (RR=0.66; p-trend=0.062) or aspirin use (RR=0.70; 95% CI 0.51-0.96). In PV, there was little impact on the association with smoking (RR=0.92 for former and RR=2.67 for current; p-trend=0.028) after adjustment for BMI, PA, DM and aspirin use. Conclusions: Risk factors were unique to the 2 most common types of MPN. ET was associated with obesity-related factors (PV was not), and PV was associated with current smoking (ET was not). Aspirin use had a stronger inverse association for ET. Our results suggest distinct etiologies of these PMN subtypes, and raises mechanistic hypotheses related to inflammation for ET and smoking-related carcinogenic pathways for PV. Citation Format: Alexis D. Leal, Carrie A. Thompson, Alice Wang, Robert A. Vierkant, Thomas M. Habermann, Julie A. Ross, Beth A. Virnig, James R. Cerhan. Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in the Iowa Women's Health Study (IWHS) cohort. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2013-2536

Abstract Background: Cognitive changes for older women who receive chemotherapy are poorly understood. Methods: Cancer and Leukemia Group B (CALGB) 49907 enrolled 633 women ≥65 years with early stage breast cancer and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). Patients enrolled on the Quality of Life companion study (N = 350) included women who had cognitive and psychological functioning sufficient for providing informed consent and participation in the trial (J Clin Oncol 29:1022, 2011). Participants completed an 18 item questionnaire focusing on their subjective report of cognitive function (attention, problem-solving, speed, new learning, and remote memory) at 6 time points (baseline, mid-treatment, within 1 month post treatment, and at 12, 18, and 24 months post treatment). Possible scores for each item ranged from 1–7 (‘above average’ - ‘severe problem’). Cognitive function score (CFS) was defined as the mean score of items 1–18. Cognitive impairment was defined as CFS 1.5 standard deviations above the overall average baseline. Univariate associations were tested between baseline CFS and patient characteristics (treatment, race, education, number of positive nodes, hormone receptor status, HER2 status, performance status, number of comorbidities, fatigue and depression) using Kruskal-Wallis testing. Frequency distributions were used to describe cognitive impairment. Multivariate analyses were not completed because few women reported subjective cognitive impairment during the study period. Results: 297 assessments were received at baseline, 280 at both mid-treatment and within 1 month post-treatment, 259 at 12 months, 245 at 18 months and 240 at 24 months post-treatment. The median age was 72 (65–85); 32% received AC, 21% CMF, and 47% capecitabine. Most women were white (87%) and had a performance status of 0 (73%). Approximately half of women had a high school degree or less and the majority had stage I-II (78%), hormone-receptor positive (68%) cancers and most did not experience depression or fatigue at baseline. At baseline, the overall mean CFS was 2.1 (‘normal ability’) and 19 women (6%) had mild to severe impairment. Baseline scores did not differ by treatment (p = 0.35). Worse cognitive function at baseline was associated with less education (p < 0.01), increased number of positive nodes (p = 0.02), 4+ comorbid conditions (p < 0.01) and fatigue (p = 0.02), although differences for these groups were small. During the study period, overall mean cognitive function scores remained at ‘normal ability’. At mid-treatment, within 1 month post treatment, 12, 18 and 24 months, cognitive impairment was present in 19 (6%), 19 (6%), 29 (10%), 31 (12%), 18 (7%), and 22 (9%), respectively. Conclusions: Our data suggest that in a healthy group of women without baseline cognitive impairments on objective screening, chemotherapy does not seem to be associated with changes in self-reported cognitive function over time. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-08-05.

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Abstract Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites. Aims Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. Methods Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. Results Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5·5%) were randomized during the first five years and 1387(55·5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model. Conclusions Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity.