Citations

AbstractHigher ratios of the pre‐treatment peripheral blood absolute lymphocyte (ALC) to absolute monocyte counts (AMC) are associated with improved outcomes in lymphoma. Conversely, elevated pre‐treatment serum cytokines are associated with inferior outcomes. The relationship between pre‐treatment serum cytokines and ALC/AMC ratios remains unknown. We studied twelve serum cytokines and the ALC/AMC ratios in 390 patients with untreated diffuse large B‐cell, follicular, mantle cell, T‐cell, and Hodgkin lymphoma. Different pre‐treatment serum cytokine concentrations correlated with ALC, AMC, and ALC/AMC ratios depending on the lymphoma type. In the entire cohort (n = 390) lower ALC/AMC ratios modestly correlated with higher IL‐2R (r = −0.36), IL‐12 (r = −0.17), IP‐10 (r = −0.23), and MIG (r = −0.32) concentrations (p < 0.001). Elevated IL‐2R was independently associated with suppressed ALC (OR 2.69, 95% CI 1.77–4.07,p < 0.001), elevated AMC (OR 2.05, 95% CI 1.34–3.14,p < 0.001), and suppressed ALC/AMC ratios (OR 3.51, 95% CI 2.31–5.34,p < 0.001). Both elevated IL‐2R (HR 2.27, 95% CI 1.48–3.49,p < 0.001) and suppressed ALC/AMC ratios (HR 1.53, 95% CI 1.03–2.28,p = 0.037) were independently associated with inferior overall survival. These data support the notion that elevated serum cytokines are immunosuppressive and provide further rationale to target the tumor microenvironment for therapeutic benefit.

193 Background: National standards recommend distress screening as part of cancer care. While many patients report improved quality of life after cancer treatment concludes there remains a population who experience ongoing anxiety and depressive symptoms. We sought to describe psychosocial distress in lymphoma survivors and frequency of visits to mental health providers (MHP). Methods: Lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource and systematically followed. Brief Profile of Mood States (POMS) and State Trait Anxiety Inventory (STAI) were administered 3 yrs after diagnosis. Lower scores on POMS indicated more distress. A higher score on STAI indicated more anxiety, and a score ≥ 40 was considered clinically significant. Pts were asked if they ever saw a MHP due to their lymphoma. Results: Between 2002-2012, 2465 lymphoma pts age 18-91 (10% 18-40, 54% 41-65, and 36% > 65) were enrolled, met survivor definition, and completed 3-yr POMS and STAI questionnaires. 57% were male. 40% had aggressive and 60% had indolent lymphoma. The median score on STAI 1 (state) was 32 (range 20-76) and on STAI 2 (trait) was 31 (range 20-77). Median POMS total mood disturbance (TMD) score was 88 (range 1-100). 8% of pts reported seeing a MHP. 609 pts (25%) had clinically significant anxiety by STAI 1, 73 (12%) of whom saw a MHP. Those who reported clinically significant anxiety on STAI were more likely to be younger, unemployed, unmarried, and less likely to have seen a MHP. Anxiety levels were similar between those with aggressive lymphoma and indolent lymphoma regardless of treatment. Higher distress levels, measured by TMD, were more often reported by those who were unemployed or over age 65 while there was no association with lymphoma subtype, marital status, or choice of therapy. Conclusions: Clinically significant anxiety was reported in 25% of 3-yr survivors of lymphoma and was associated with younger age, unmarried status, and unemployment. Higher distress levels were associated with older age, and unemployment. However, only 8% of our cohort was seen by a MHP. Identifying distress and appropriately referring to a MHP is important for the optimal care of lymphoma survivors.

75 Background: We investigated the association of germline variation in ten candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with overall survival (OS) in a cohort of metastatic CRPC stage patients. Methods: Patients (N=497) were enrolled at the time of androgen deprivation therapy failure for D2 stage prostate cancer. Candidate genes were selected from the literature and pilot studies. Genes were tagged using SNPs from HapMap with minor allele frequency (MAF) of >5% and r2≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was OS, defined as time from development of CRPC to death. Principle components analysis was used for gene-levels tests. To account for multiple testing we calculated the false discovery rate (FDR). For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and adjusted for age and Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 497 Caucasian subjects. The median age of the CRPC cohort was 71 years (range 43,93). The GS distribution was 51% subjects with GS≥8; 32% with GS7 and 17% with GS<7. After a median follow up of 2.1 years (IQ range: 1.2-3.6), 297 subjects had died. In unadjusted gene level analyses, NKX3-1 (p=0.04; FDR=0.03) was associated with OS. After adjusting for age and GS the result remained significant (p=0.03). Two of the 5 genotyped SNPs in this gene were associated with OS after adjustment for age and GS: rs10503733 (dominant model p=0.03, HR=0.77; 95 CI=0.60-0.98; A>C; MAF = 0.22) and rs7005368 (dominant model p=0.05, HR=1.38, 95CI=1.0-1.92; G>A; MAF=0.07). Both SNPs are in Hardy Weinberg Equilibrium and in complete LD (D'=1), although r2 is low (r2=0.025) due to different allele frequencies. Conclusions: Variation in the homeobox NKX-1 gene, a prostate specific tumor suppressor gene involved in prostate development and carcinogenesis is significantly associated with OS in CRPC after accounting for age and GS. Further validation is needed to develop these as prognostic biomarkers.

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]

209 Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]

12 Background: Cholesterol is needed in prostate cancer cells for cell proliferation and for androgen biosynthesis. Cholesterol-lowering statin drug use is associated with a lower risk of total and advanced prostate cancer and lower prostate cancer-specific mortality (PCSM). We hypothesized that tumor expression of cholesterol synthesis enzymes, transporters and regulators is associated with PCSM. Methods: We studied mRNA expression of 43 cholesterol metabolism genes in surgical specimens from 249 participants in the Health Professionals' Follow-up Study diagnosed with prostate cancer between 1986 and 2004. We included 81 cases of lethal prostate cancer and 168 indolent cases who survived >8 years without metastases. After multivariate dimensionality reduction for the synthesis, transport and regulator pathways using principal components analysis, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We adjusted for age, year of diagnosis, body mass index, smoking status, family history, multivitamin use, high serum cholesterol and cholesterol-lowering drug use. Results: Reflecting the impact of the synthesis pathway and of the regulator pathway, respectively, the expression of squalene epoxidase (SQLE) and low-density lipoprotein receptor (LDLR) were significantly associated with lethal cancer in opposing directions. Compared to men with the mean level of SQLE expression, men with SQLE expression >1 standard deviation (SD) above the mean were 15.4 times more likely to have lethal cancer (95% CI: 3.31–71.53). For LDLR, expression >1 SD above the mean was associated with 96% lower odds of lethal cancer (95% CI: 0.01–0.70). Higher SQLE expression and lower LDLR expression were associated with higher Gleason grades (Fisher's test, p < 0.001 and p = 0.036, respectively) and were also predictive of PCSM independently from grade and tumor stage. Conclusions: These results suggest that the local cholesterol metabolism of the prostate tumor is tightly linked with mortality. Lethal cancers have higher activity of the second rate-controlling enzyme of cholesterol synthesis and are less dependent on cholesterol uptake.

77 Background: Prostate cancer cells rely on cholesterol for proliferation and androgen production. We recently demonstrated that increased expression of the second key enzyme of cholesterol synthesis, squalene monooxygenase (SQLE), is associated with higher prostate cancer-specific mortality (PCSM). We here validate findings in two additional prospective studies and investigate putative mechanisms. Methods: We analyzed the prospective prostatectomy cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS) as well as initially expectantly managed patients in the Swedish Watchful Waiting Study (SWWS). 258 lethal cancer cases and 469 patients who survived > 8 years without metastases were included. SQLE mRNA was measured in tumor specimens at diagnosis of all patients and in benign prostate tissue of 197 patients. Markers of tumor angiogenesis were assessed via immunohistochemistry in 169 HPFS patients. We estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. Results: Higher SQLE expression was confirmed to be predictive of higher PCSM in the validation prostatectomy cohort PHS. Combining the two prostatectomy cohorts, men with high SQLE expression ( > 1 standard deviation above the mean) were 6.7 times (95% CI, 2.9 to 15.8; p < 0.001) more likely to die from their cancer compared to men with the mean level of SQLE expression. A 10% higher ratio of SQLE mRNA expression in tumor vs. benign prostate tissue of the same patient was predictive of 42% higher PCSM (95% CI, 15% to 74%). Higher SQLE expression was strongly associated with increased angiogenesis markers (all p ≤ 0.001). This increased risk associated with high SQLE expression was not modified by statin use (p ≥ 0.52). In initially untreated patients in SWWS, a more modest association of tumor SQLE expression with PCSM was observed (p = 0.047). Conclusions: SQLE, the second rate-limiting enzyme of cholesterol synthesis, is associated with prostate cancer progression. Its expression at cancer diagnosis is predictive of lethal disease both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.

313 Background: We evaluated variation in candidate genes implicated in either initiation or progression of prostate cancer with survival in CRPC stage. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of > 5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model using Cox regression adjusted for age at CRCP and Gleason score (GS) were used. Results: Two hundred and forty five CRPC patients who met the criteria of having adequate DNA were genotyped (14 genes, 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS = 7 and 13% with GS < 7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level JAK2 was detected to be associated with OS. Six of 18 JAK2 SNPs were associated with OS after adjustment for age and GS as well as pruning of SNPs in high linkage disequilibrium with each other (see table). In our multivariate model including age, GS, rs2149556, and rs4372063, the adjusted HRs for rs2149556 and rs4372063 were 0.67 (95% CI 0.38-1.18) and 2.17 (95% CI 1.25-3.76), respectively. The protective effect of rs2149556 appears after adjusting for the presence of minor alleles for rs4372063 in this dataset. Conclusions: Germline variation in the JAK2gene is associated with survival in CRPC stage and warrants further validation as a potential prognostic biomarker. [Table: see text]

236 Background: Patients (pts) with aggressive lymphoma are generally treated with curative intent and many become long-term survivors. There is little data on health behaviors after lymphoma diagnosis and their effect on QOL and long-term outcomes. Methods: Lymphoma pts were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and systematically followed. We measured QOL (FACT-G) and health behaviors (tobacco/alcohol use; diet/exercise habits) 3 years after diagnosis. For this study, “survivor” was defined as alive at 3 years from diagnosis with no active disease or treatment within the previous year. Results: From 2002-2012, 671 patients with aggressive lymphoma were enrolled, met survivor definition, and completed 3-year QOL and health behavior questionnaires. At 3-years, 31% of female (F) and 48% of male (M) reported a history of tobacco use for 6+ months. Of these, 13% of F and 7% of M were still smoking; 52% reported decreased use from baseline. 66% reported no change in alcohol intake at 3-years while 25% of F and 34% of M reported decreased intake. 60% often chose whole grains and 65% get 2+ servings of vegetables daily. 42% of F and 38% of M “somewhat” believed diet could change the course of their lymphoma. Most pts endorsed no significant change in diet as a result of diagnosis. Those who made changes did so primarily out of concern for “health problems other than cancer”. Overweight/obese responders were 72% pre- and 66% post-treatment. A desire to lose weight was reported by 55% of pts. 14% of F and 23% of M often engaged in regular physical activity (PA). Nearly 50% reported a decrease in PA. Pts with advanced stage (p = 0.006), age > 60 (p = 0.001), ECOG PS > 2 (p = 0.04), and worse prognostic score (p = 0.006) were more likely to report decreased PA since diagnosis. 68% of F and 61% of M intend to become more active in the next months. Regular PA (p = < 0.0001) was associated with higher QOL, while increased alcohol intake was associated with lower QOL (p = 0.009) at 3 years. Conclusions: Many survivors of aggressive NHL strive to adopt healthy behaviors and these behaviors are associated with higher QOL. Interventions aimed at emphasizing these behaviors may have potential to improve long-term outcomes and QOL.