Citations

Abstract Background: The standard treatment for epithelial ovarian cancer (EOC) patients with advanced disease is initial debulking surgery followed by carboplatin-paclitaxel combination therapy. Unfortunately, even with modern chemotherapy, most patients with advanced disease relapse and die of EOC. One of the biggest challenges in the treatment of EOC is the large inter-patient variation in clinical response and toxicity observed for taxane and platinum therapies. Purpose: To determine pharmacogenomic markers related to carboplatin-paclitaxel therapy with 33 Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines (LCLs) derived from EOC patients for which genome-wide genetic information exists. Methods: The 33 LCLs were treated with increasing concentrations of carboplatin and/or paclitaxel, followed by MTT cytotoxicity and Caspase3/7 assays. Using the measurements of MTT absorbance or Caspase3/7 fluorescence, dose response curves were fit to estimate the in vitro drug response (MTT or caspase3/7) for each LCL and treatment (paclitaxel, carboplatin, and combination) using the inflection point of the fitted curve (i.e.., the MTT IC50 or effective dose that kills 50% of the cells). The six in vitro phenotypes where then associated with genome-wide SNP data, imputed up to the markers in the 1000 Genomes Project. Results: Genetic association analysis of carboplatin, paclitaxel and combination therapy cell viability, as measured by MTT, found one SNP, rs202167095 within HS3ST4, in common with all three phenotypes (p < 0.0001). HS3ST4 is regulated by TRF2 and activates natural killer cells. Furthermore, TRF2 maintains telomere integrity and is involved in activating DNA damage response (DDR) pathway.. Similarly, three SNPs were found to be associated with the three Caspase3/7 activities: SNPs on chromosome 3 (rs13098237 and rs13098239), and a SNP on chromosome 10 (rs138004421 within LINC00858). Lastly, SNPs in the following genes were associated with carboplatin IC50 with p < 1x10-6 (i.e., the top associated SNPs with any drug response phenotype): JAKMIP3 (p=2.3x10-7), TSHZ3 (p = 4.9x10-7) and TGFA (p=3.6x10-7). JAKMIP3 has been implicated in some cancers and interacts with other janus kinases and JAK-STAT pathways, while TSHZ3 inhibits the expression of CASP4, thus limiting cell apoptosis. Lastly, TGFA codes for a growth factor that is a ligand for epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. Conclusions: Identifying genetic loci associated with response to platinum-taxane therapies will ultimately improve clinicians' ability to tailor therapy decisions for EOC patients. This research discovered novel candidate genes for which further research is needed to understand the mechanism by which they impact clinical response. Citation Format: Brooke L. Fridley, Taraswi M. Ghosh, Alice Wang, Ellen L. Goode, Jatinder Lamba. In vitro pharmacogenomic study of ovarian cancer finds novel genetic variants associated with response to platinum and taxane therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5565. doi:10.1158/1538-7445.AM2014-5565

Abstract Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor β (ESR2) has been associated with colorectal cancer stage and survival. Methods: In this prospective cohort study, we examined smoking, MHT, and folate-associated colorectal cancer risks by ESR2 protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded colorectal cancer tissue specimens were collected and evaluated for ESR2 protein expression by IHC. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between smoking, MHT, or folate and ESR2-defined colorectal cancer subtypes. Results: Informative environmental exposure and protein expression data were available for 491 incident colorectal cancer cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR, 4.24; 95% CI, 1.81–9.91 for ESR2-low and RR, 2.15; 95% CI, 1.05–4.41 for ESR2-high for ≥40 cigarettes compared with nonsmokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR, 0.54; 95% CI, 0.26–1.13 for >5 years compared with never use). No associations were found for folate. Conclusions: In this study, smoking and MHT were associated with ESR2 expression patterns. Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 24(4); 713–9. ©2015 AACR.

AbstractBACKGROUNDThe use of electrophoresis to monitor monoclonal immunoglobulins migrating in the β fraction may be difficult because of their comigration with transferrin and complement proteins.METHODSImmunoassays specific for IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ heavy/light chain (HLC) were validated for use in the clinical laboratory. We assessed sample stability, inter- and intraassay variability, linearity, accuracy, and reference intervals for all 6 assays. We tested accuracy by verifying that the sum of the concentrations for the HLC-pairs accounted for the total immunoglobulins in each of 129 healthy sera, and that the HLC-pair ratios (rHLCs) were outside the reference interval in 97% of 518 diagnostic multiple myeloma (MM) samples.RESULTSWe assessed diagnostic samples and posttreatment sera in 32 IgG and 30 IgA patients for HLC concentrations, rHLC, and total immunoglobulins and compared these nephelometry results with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). In sample sets from patients with IgG MM, the sensitivity of SPEP was almost the same as for rHLC, and no additional advantage was conferred by running HLC assays. In pre- and posttreatment samples from patients with IgA MM, the SPEP, rHLC, and IFE identified clonality in 28%, 56%, and 61%, respectively. In addition, when M-spikes were quantifiable, the concentration of the involved HLC was linearly related to that of the SPEP M-spike, with a slope near 1.CONCLUSIONSThe use of IgA HLC assays for monitoring β-migrating IgA monoclonal proteins can substitute for the combination of SPEP, IFE, and total IgA quantification.

Abstract Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer–specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. Clin Cancer Res; 21(3); 652–7. ©2014 AACR.

Background and Purpose— Evidence indicates that center volume of cases affects outcomes for both carotid endarterectomy and stenting. We evaluated the effect of enrollment volume by site on complication rates in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Methods— The primary composite end point was any stroke, myocardial infarction, or death within 30 days or ipsilateral stroke in follow-up. The 477 approved surgeons performed >12 procedures per year with complication rates <3% for asymptomatic patients and <5% for symptomatic patients; 224 interventionists were certified after a rigorous 2 step credentialing process. CREST centers were divided into tertiles based on the number of patients enrolled into the study, with Group 1 sites enrolling <25 patients, Group 2 sites enrolling 25 to 51 patients, and Group 3 sites enrolling >51 patients. Differences in periprocedural event rates for the primary composite end point and its components were compared using logistic regression adjusting for age, sex, and symptomatic status within site-volume level. Results— The safety of carotid angioplasty and stenting and carotid endarterectomy did not vary by site-volume during the periprocedural period as indicated by occurrence of the primary end point ( P =0.54) or by stroke and death ( P =0.87). A trend toward an inverse relationship between center enrollment volume and complications was mitigated by adjustment for known risk factors. Conclusions— Complication rates were low in CREST and were not associated with center enrollment volume. The data are consistent with the value of rigorous training and credentialing in trials evaluating endovascular devices and surgical procedures. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00004732.