tbuckley/cabot-search huggingface dataset:
<i> GPX3</i> as a predictive biomarker in gastrointestinal malignancies.
Authors: Lorraine Cheryl Pelosof, Sashidhar R. Yerram, Breann Yanagisawa, Nilofer Saba Azad, James Gordon Herman
Journal: Journal of Clinical Oncology (2014)

499 Background: Epigenetic heterogeneity within colorectal and pancreatic tumors influences their sensitivity to individual chemotherapy agents. Glutathione peroxidase 3 (GPX3), part of the cellular antioxidant system, is associated with platinum resistance in multiple tumor types. We explored the role of GPX3 methylation in colorectal (CRC) and pancreatic tumor cells’ sensitivity to platinum agents. Methods: Methylation-specific PCR (MSP) and quantitative real-time polymerase chain reaction (qPCR) were used to examine the promoter methylation status and expression level, respectively, of GPX3 in primary tumor xenografts and cell lines. Cell proliferation assays were used to measure cells’ sensitivity to cisplatin and oxaliplatin and short hairpin RNA (shRNA) was used to silence GPX3 in these cells. Results: We examined GPX3 promoter hypermethylation in colorectal and pancreatic primary tumor xenografts. GPX3 was methylated in 25% of colorectal cancer primary tumor xenografts tested and 50% of pancreatic cancer primary tumor xenografts tested; methylation correlated with decreased/absent expression in these samples. Additionally, GPX3 is methylated in 6 out of 9 colorectal cancer cell lines tested and cell lines with methylated GPX3 had significantly decreased GPX3 expression. Importantly, the cisplatin IC 50 for the cell lines with methylated GPX3 was 4-fold lower (median 4.5 mM) compared to those lines with unmethylated GPX3 (median 20 mM) and oxaliplatin demonstrates a similar trend with the IC 50 of the highly GPX3-expressing line CaCO2 being approximately two-fold that of the fully-methylated line HCT116. Underlying the importance of methylation, azacitidine treatment resulted in GPX3 re-expression in HCT116 cells with sensitivity to oxaliplatin decreasing as would be expected. Currently, we are using shRNA to silence GPX3 in CRC lines to directly test its role in platinum sensitivity; preliminary results demonstrate an approximately two-fold decrease in oxaliplatin IC 50 when GPX3 expression is decreased in GPX3-expressing cells. Conclusions: Epigenetically silenced GPX3 may serve as a predictive biomarker for platinum sensitivity in CRC and pancreatic tumor cells.
Dehydroepiandrosterone metabolism in fresh human prostate: A feasibility study.
Authors: Cesar E. Ercole, Kai-Hsiung Chang, Ghada AboAli, Cristina Magi-Galluzzi, Andrew J. Stephenson, Eric A. Klein, Nima Sharifi
Journal: Journal of Clinical Oncology (2014)

225 Background: Understanding adrenal androgen metabolism in the prostate provides the opportunity to better define mechanisms of resistance for patients with prostate cancer. This is especially important with men who have a recurrence after their initial treatment (e.g., surgery or radiation) and are subsequently treated with androgen deprivation therapy by chemical or surgical castration. Unfortunately, these patients tend to progress to castrate resistant prostate cancer. With the contribution of adrenal androgens in mind, we sought to determine the feasibility of characterizing the metabolites of dehydroepiandrosterone (DHEA) in the human prostate. Methods: With institutional review board approval, tissue procurement occurred via the Department of Pathology at the Cleveland Clinic. We obtained prostate tissue from patients immediately after radical prostatectomy. The tissue was processed in culture withserum free medium in triplicate and was treated with tritiated-DHEA ([ 3 H]-DHEA; 100 nM, 300,000–600,000cpm; PerkinElmer). Media was collected at specific time intervals (6, 24, 48, and 72 hours). Once all the time points were collected, they were treated with a β-glucuronidase and steroids were extracted. These samples were processed and analyzed with high-performance liquid chromatography (HPLC) and a radioactivity detector for comparison with known standards (DHEA, androstenedione, 5α-androstanedione, testosterone, and dihydrotestosterone). Results: Evaluation of the HPLC tracings showed metabolism of [ 3 H]-DHEA to downstream androgen products and correlated with standard peaks. These tracings were reproducible and consistent with each sample’s triplicate and from specimen to specimen. Conclusions: It is feasible to consistently determine the products of DHEA metabolism in fresh prostate tissues. By obtaining a better understanding of how androgen metabolites are formed we can dissect how response and resistance to hormonal therapy are regulated.
Correlation of capecitabine associated hand-foot syndrome (HFS) and objective tumor response in patients with metastatic colorectal cancer (mCRC) treated with sorafenib and capecitabine (SorCape).
Authors: Ellie Chan, Alison Marguerite Ivey, Long H. Dang, Karen Colleen Daily, Wei Hou, Dana Lynn Viviano, Scott Watson, Renee Granicz, Margaret A. McEwan, Hui Yan, Carmen Joseph Allegra, Thomas J. George
Journal: Journal of Clinical Oncology (2013)

568 Background: Capecitabine (cape) associated hand-foot syndrome (HFS) has been previously reported to be a clinical predictor of improved survival or disease control in metastatic colorectal cancer (mCRC) and breast cancer. This study evaluates the relationship between degree of HFS and objective tumor response in patients (pts) receiving capecitabine and sorafenib (sor) for mCRC as part of an ongoing clinical trial. Methods: Pts with refractory mCRC treated on phase II prospective study with SorCape (NCT01471353) were eligible. 24 of 43 planned pts have been enrolled and all are assessable. Adverse events (AEs) related to HFS were graded by CTACE v4 during the first 3 cycles of therapy and scored as mild (graded 0 or 1), moderate (mod) (grades 2 or 3) or severe (grade 4). Independent RECIST criteria measurements of target tumor volumes were recorded with maximal volumetric regression or progression noted. The correlation between degree of HFS and objective RECIST response was analyzed. Results: Total cohort pt demographics and tumor characteristics are presented separately. 5 (21%) had mild HFS and 19 (79%) developed mod HFS. No pts had severe HFS. Baseline characteristics including age were similar in both groups. Univariate analysis showed no significant correlation between KRAS mutational status, baseline serum CEA, or LDH levels. Pts with mild HFS had a mean 25% (1-68% regression) tumor regression compared to a 20% progression (22% regression to 80% progression) with moderate HFS (p=0.046). Progression free and overall survival data are immature for analysis. Conclusions: In this exploratory analysis of an ongoing clinical trial, the degree of HFS negatively correlated with objective tumor response. The combination of overlapping HFS AEs with this specific dual therapy may impact the previously reported clinical predictor. Ongoing patient enrollment and further analysis of this clinical observation is planned. Clinical trial information: NCT01471353.
The impact of time to adjuvant chemotherapy (AC) on survival in colorectal cancer (CRC): A systematic review and meta-analysis.
Authors: J. J. Biagi, M. Raphael, W. D. King, W. Kong, W. J. Mackillop, C. Booth
Journal: Journal of Clinical Oncology (2011)

364 Background: The optimal timing from CRC surgery to initiation of AC is unknown. We report a systematic review and meta-analysis to determine the relationship between time to adjuvant chemotherapy (TTAC) and survival. Methods: A systematic review of literature was done to identify studies that described the relationship between TTAC and survival. Studies were only included if the distribution of relevant prognostic factors was adequately described, and either comparative groups were balanced or results adjusted for the prognostic factors. Hazard ratio (HR) and TTAC for overall survival (OS) and disease free survival (DFS) from each study were converted to a regression coefficient (β) and standard error (SE) corresponding to a continuous representation per 4 weeks of TTAC. The adjusted β from individual studies were combined using a fixed-effect model. Inverse-variance (1/SE 2 ) was used to weight individual studies. The possible effect of publication bias was investigated using the trim and fill approach. Results: We identified 9 eligible studies involving 14,357 patients (4 published articles, 5 abstracts). Two studies were randomized trials and 7 were cohort studies. Six studies reported TTAC as a binary variable and 3 reported TTAC as ≥3 categories. An estimate of HR for OS was derived from all 9 studies and estimate for DFS was derived from 5 studies. Meta-analysis demonstrated that a 4-week increase in TTAC was associated with a significant decrease in both OS (HR = 1.12, 95% CI 1.09-1.15), and DFS (HR = 1.15, 95% CI 1.11-1.20). The analysis showed no significant heterogeneity among studies. These TTAC associations remained significant after analysis for potential publication bias, and when the analysis was repeated excluding the two studies of largest weight. Conclusions: This study demonstrates a 12% increase in the risk of death for each 4 week of delay in the start of AC for CRC. These findings indicate the need for clinicians and health systems managers to take the steps necessary to keep TTAC as short as reasonably achievable. In addition, our results suggest there may be some benefit to AC after a 3-month TTAC delay. No significant financial relationships to disclose.
Imaging characteristics of patients with prostate cancer with favorable 17-gene genomic prostate score on 3T multiparametric prostate MRI.
Authors: Aaron Katz, Corinne Liu, Kaitlin E. Kosinski
Journal: Journal of Clinical Oncology (2016)

14 Background: Our practice utilizes a biopsy-based 17 gene test that is clinically validated as a predictor of favorable pathology and used to guide use of active surveillance for men with very low, low, and intermediate risk prostate cancer. The purpose of this study was to evaluate the imaging characteristics and PIRADS score of prostate cancer patients with a Genomic Prostate Score (GPS) indicating favorable pathology. Methods: 300 consecutive 3T Multiparametric Prostate MRI (MP-MRI) were identified from March 26, 2012, to June 29, 2015. Thirty patients (age 44-84 years) with GPS scores indicating favorable pathology were included in the study. Prostate Imaging Reporting and Data System (PIRADS) scores were assigned to each MP-MRI. MRI index lesions were defined as discrete hypointense T2 signal with at least one anatomically corresponding abnormal functional MRI parameter (diffusion weighted and dynamic contrast-enhanced images). The MRI examinations were evaluated for number and laterality of MRI index lesions and in relation to biopsy pathology findings after the MP-MRI was performed. Results: Out of 30 MP-MRI, 7 (23.3%) PIRADS 5, 10 (33.3%) PIRADS 4, 10 (33.3%) PIRADS 3, 1 (3.3%) PIRADS 2, and 2 (6.7%) PIRADS 1. Thirteen (43%) had bilateral MRI index lesions. Twenty-six (87%) MP-MRI had 1-3 MRI index lesions, 2 (7%) had 4-6 MRI index lesions and 2 (7%) had no index lesions. Six (20%) patients underwent curative treatment. Four (13.3%) patients underwent a transrectal ultrasound guided targeted biopsy and one underwent a prostatectomy after the MP-MRI. One harbored Gleason 7 with a PIRADS 1, 2 harbored Gleason 7 with PIRADS 5, and two were benign with PIRADS scores of 3 and 4. Conclusions: Patients with prostate cancer with a GPS score indicating favorable pathology had PIRADS scores ranging from 5 to 1, with the majority indicating either high or very high likelihood of harboring clinically significant cancer. This may imply that MP-MRI should continue to play an important role in stratifying patients with prostate cancer, even in those with favorable pathology. A study with a larger sample size and biopsy results after the initial MP-MRI to look for tumor upgrading is needed.
Is Major Molecular Response a Safe Haven Against Blast Crisis in Cml Patients Treated with Imatinib?
Authors: Pratap Neelakantan, Dragana Milojkovic, Gareth Gerrard, Letizia Foroni, Jane Apperley, Richard M Szydlo, Alistair Reid, Marco Bua, Katy Rezvani, John M Goldman, David Marin
Journal: Blood (2012)
The identification of the age effects in 1,287 patients with biliary tract cancer.
Authors: Kumiko Umemoto, Shuichi Mitsunaga, Kazuo Watanabe, Hiroyuki Okuyama, Yusuke Hashimoto, Hideaki Takahashi, Izumi Ohno, Satoshi Shimizu, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2015)

244 Background: Age is a mirror for pathogenesis in some of biliary tract cancer (BTC) as liver fluke- or pancreaticobiliary maljunction-associated BTCs. However, the age effects including prognosis in BTC were not fully understood. The identification of the age effects might be helpful for the management of BTC. Methods: For the years 1992-2014, 1287 patients receiving initial treatment for BTC in our institution were reviewed. According to age at diagnosis of BTC, patients were divided into the five age groups as &lt;50, 50-59, 60-69, 70-79, and ≥80. The relationships between overall survival time (OS) and the five age groups were analyzed using wilcoxon test to choose a prognostic cut-off of age. On the basis of a prognostic cut-off of age, the prognostic age classification was constructed. The multivariate analysis with logistic regression modeling was performed to determine the influence of gender, Eastern Cooperative Oncology Group performance status scale [ECOG-PS], primary site, and metastatic site on the prognostic age classification. Results: Median age was 67 years with male 59%. ECOG PS of 0 was 63.7%.The sites of primary tumor included intrahepatic (25.2%) and extrahepatic bile duct (34.0%), gallbladder (31.9%) and ampulla of Vater (8.9%). The prognostic cut-off of age was age less than 60 (21.8% of all). Median OS in younger patients (age&lt;60, median OS: 7.9mo) was shorter than that in elder patients (age≥60, median OS 12.4mo, P&lt;0.01). In univariate analysis, the prevalence of bone metastasis, distal lymph node metastasis and peritoneal dissemination was higher in younger BTC than elder patients. Multivariate analysis revealed that peritoneal dissemination was an independent younger BTC related-factor (OR=1.9, P&lt;0.01). Conclusions: Younger BTC patients (age&lt;60) showed poor prognosis and the high frequency of peritoneal dissemination, compared to elder BTC patients. The relationship between age and peritoneal dissemination of BTC might be a key to elucidate the age effect concomitant with poor prognosis.
Association of serum vascular endothelial growth factor-C (VEGF-C) with lymph node metastasis and prognosis in pancreatic adenocarcinoma
Authors: K. A. Jones, M. A. Firpo, D. G. Adler, L. L. Chen, S. J. Mulvihill
Journal: Journal of Clinical Oncology (2008)

4620 Background: Accurate staging and prognostic information is essential for treatment planning in pancreatic adenocarcinoma (PA). Current methods include endoscopic ultrasound, CT scanning, and serum CA 19–9 levels. Despite these, many patients considered resectable experience early relapse and die from their disease and within this group nodal status correlates with overall survival. For patients metastatic at presentation the prognosis is often variable with limited treatment options. Vascular endothelial growth factor- C (VEGF-C) plays a crucial role in lymphangiogenesis and has been implicated in promoting lymph node metastasis in PA. Prior studies demonstrate diagnostic utility of serum levels of VEGF-C in determining nodal involvement and prognosis in lung, gastric, and cervical cancer. We investigated if serum VEGF-C levels would predict nodal involvement or prognosis in pancreatic cancer. Methods: Pretreatment serum VEGF-C levels were measured in 40 PA patients who were node-negative (N0 =12), node-positive (N1=14) or metastatic (M1=14) at diagnosis using ELISA. Diagnostic accuracy was compared to conventional methods. Kaplan-Meier survival analysis was done for all patients and longitudinal samples were evaluated in 15 patients who were without disease or with early or late relapse. Results: Serum VEGF-C levels were significantly higher in node positive versus node negative disease (p=0.03) or controls (p=0.03). Serum VEGF-C levels correlated with overall survival across all stages regardless of treatment (p=0.04) and there was a prognostic trend seen within stages and on longitudinal sampling. The positive predictive value for nodal involvement was higher for serum VEGF-C than conventional imaging (73% versus 60%) as was the negative predictive value (60% versus 35%). CA 19–9 levels were unrelated to nodal status or survival. Conclusions: Serum VEGF-C levels appear useful in nodal staging and prognosis in pancreatic cancer. The finding that serum VEGF-C was elevated in N1 and M1 subjects, but not in N0 subjects, is consistent with a mechanism in which VEGF-C contributes to disease progression through increased metastasis. Therapeutic agents blocking VEGF-C may have clinical benefit in pancreatic cancer. No significant financial relationships to disclose.
Biomarker profiles and changes from baseline in trastuzumab (T) refractory HER2-positive inflammatory breast cancer (IBC) that predict decreases in tumor burden from lapatinib (L) monotherapy.
Authors: S. R. Johnston, C. Swanton, S. H. Stein, Y. Liu, R. C. Gagnon, M. E. Trudeau, B. Kaufman, A. Martin, V. M. Salazar
Journal: Journal of Clinical Oncology (2010)

10572 Background: L is a reversible, oral small molecule inhibitor of EGFR and HER2. L demonstrated a clinical overall response rate of 39%, median progression free survival (PFS) of 14.6 weeks and median overall survival (OS) of 11.2 months in a monotherapy Phase II study of 126 patients (pts) with HER2+ IBC. Higher baseline levels of pEGFR and TGFα are significantly associated with improved OS and PFS in pts treated with L who had prior treatment with T; in T-naïve pts, higher baseline levels of pAKT and pERK showed significant association with improved OS. In this study, the same series of biomarkers were measured in tumor biopsies obtained before and after start of treatment with L. Methods: Core needle biopsies were obtained at baseline and Day 28, preserved in phosphatase inhibitor buffer, fixed in formalin and embedded in paraffin. Protein expression of total and activated EGFR, HER2, HER3 and downstream markers, as well as markers specific to IBC were determined by standard immunohistochemistry (IHC) techniques yielding manual and optical density (OD) scores. Baseline, Day 28 and changes in expression of each marker were tested for association with OS, clinical benefit rate (CBR) and Week 8 sum of longest diameters (SLD) using proportional hazards and logistic regression models. Results: 94/126 pts had prior T exposure and 32 pts were T-naïve prior to L treatment. OD IHC data indicated that statistically significant decreases were found with pAKT (p = 0.0066) in pts with prior exposure to T. pAKT decreases were associated with decreases in SLD whether pts were T-naïve (p = 0.014) or had prior exposure to T (p = 0.06). Significant decreases were also found with pERK (p = 0.0112) in T-naïve pts; however, pERK decreases were not statistically associated with decreases in SLD (p = 0.21). Significant increases in pErbB3 were observed regardless of prior exposure to T (p = 0.043). No significant relationships were observed in changes from baseline with respect to OS and CBR. Conclusions: L monotherapy is clinically active in the treatment of relapsed/refractory HER2+ IBC. All results confirm the on-target effects of L treatment in these pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Overall survival and resection margin after hepatectomy for intrahepatic cholangiocarcinoma at academic cancer centers versus community cancer centers.
Authors: Nicholas Gerard Berger, Abdulrahman Y Hammad, John Thomas Miura, Fabian McCartney Johnston, Kathleen K. Christians, Susan Tsai, Kiran Turaga, T. Clark Gamblin
Journal: Journal of Clinical Oncology (2016)

339 Background: Margin status is an important prognostic factor of survival following hepatectomy for intrahepatic cholangiocarcinoma (ICC). R0 resection for ICC correlates with improved recurrence-free survival and overall survival (OS). The present study hypothesized that surgical resection margins and survival rates vary between centers. Methods: Patients with ICC undergoing hepatectomy were identified from the National Cancer Database (1998-2011). Treating centers were categorized as Academic Cancer Centers (ACC), and Community Cancer Centers (CCC). Rates of R0 vs. R1/2 resection were examined. OS was analyzed by Kaplan-Meier method, and Cox multivariate modeling identified independent predictors of survival. Results: A total of 2,774 patients were identified. Hepatectomy was most often performed at ACC compared to CCC: 1,928 (69.5%) vs. 846 (30.5%). Hepatectomy at ACC was associated with higher rates of R0 resections compared to CCC (72.5% vs. 68.1%, p= 0.018). Higher 30-day readmission rates were seen following hepatectomy at ACC (9.9% vs. 5.7%, p= 0.002). Improved median OS was seen in ACC across all stages (25.8 months vs. 20.1 months; p&lt; 0.001). After adjusting for age, sex, ethnicity, cirrhosis, alpha-feto protein level, comorbidity, disease stage, and margin status, hepatectomy at ACC was independently associated with improved OS (Hazards ratio: 0.79 [95%CI 0.62-0.99, p= 0.046]). Conclusions: ACC have higher rates of negative resection margins for ICC, but higher readmission rates following surgery. Survival is higher at ACC compared to CCC, suggesting that site of care plays a role in patient outcomes.