tbuckley/cabot-search huggingface dataset:
Use of PTEN protein dosage to predict for underlying germ-line PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.
Authors: Joanne Y. Y. Ngeow, Xin He, Jessica Mester, Deepa Radhakrishnan, Junying Lei, Todd Romigh, Mira Milas, Charis Eng
Journal: Journal of Clinical Oncology (2012)

1508 Background: Thyroid cancer is a major component of Cowden Syndrome (CS), a heritable syndrome characterized also by breast, uterine and kidney cancers. CS patients with an underlying germline PTEN mutation have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, &lt;1% of sporadic epithelial thyroid cancer harbor a germline PTEN mutation. Thus, cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. Here, we analyzed the relationship of patient PTEN protein levels in predicting the presence of germline PTEN mutations. Methods: We conducted a 5-year, multi-center prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared PTEN protein expression levels between patients with pathogenic PTEN mutations (PTEN mut+ ), and those with variants of unknown significance (VUS) or wildtype PTEN. PTEN immunohistochemistry (IHC) was performed on available thyroid samples. Results: Of 2792 CS/CS-like patients, 722 had thyroid cancer. PTEN germline pathogenic mutations were present in 36/722 (5%) patients. PTEN mut+ cases presented at an earlier age (35 vs 42 years; p=0.02). PTEN frameshift and truncation mutations accounted for 55% of mutations. 95% (19/20) of PTEN mut+ patients had blood-PTEN protein levels in the lowest quartile as compared to 27% (90/330) of PTEN wildtype/PTEN VUS patients (p&lt;0.001). Low blood-PTEN levels predicted for PTEN mut+ cases with a 99.6 % NPV (95%CI 97.7- 99.9) and a positive test likelihood ratio of 3.5 (95%CI 2.8-4.3). Affected thyroid tissues (n=22) from PTEN mut+ cases showed loss of PTEN protein by IHC, correlating with patient blood PTEN levels (r2=0.30, p=0.016). Conclusions: Our study shows that PTEN protein dosage could serve as a molecular correlate predicting for germline PTEN mutation in CS and CS-like presentations of thyroid cancer. The clinical utility of PTEN IHC in identifying thyroid cancer patients for germline PTEN testing should be further explored.
Factors that affect the suitability of cancer patients for clinical drug trials in Turkey: Final analysis of a multicenter study.
Authors: Mustafa Erman, Saadettin Kilickap, Ahmet Siyar Ekinci, Sinan Koca, Alper Ata, Ayberk Besen, Alper Can, Faysal Dane, Taner Babacan, Berna Oksuzoglu
Journal: Journal of Clinical Oncology (2015)

e17542 Background: The aim in this study was determining the factors that affects the appropriateness of cancer patients (pts) for clinical drug trials in Turkey. Methods: 1316 pts were recruited for the study. Number of the pts were determined according to the annual number of the pts referred to each site. Results: The mean age was 57.2±14.0 yrs, 50% of them were males, and mean age of the males were higher than the females (59.3±13.5 vs 54.1±14.1 yrs, p < 0.001). Most frequent three types of cancers were breast (23%), lung (15%), and colorectal (11%) cancers. 54% of the pts were found to be suitable for participating the clinical trials. Mean age of the pts that were suitable for the clinical trials were lower than the others (55.0±13.1 vs 59.6±14.5; p < 0.001). 58% of the pts in university hospitals, and 51% of the pts in education hospitals were appropriate for the clinical trials (p = 0.015). Females were more suitable for clinical trials than males (57% vs 52%; p = 0.057). Appropriateness for clinical trials was highest in breast (66%) and colorectal (65%) pts, and lowest in sarcomas (39%) (p < 0.001). The levels of appropriateness for clinical trials were 69% in adjuvant treatment, 52% in neoadjuvant treatment, 46% in metastatic pts, and 77% in chemoRT (p < 0.001). The level of appropriateness was found to be decreased with the increasing step of the metastatic treatment (48%; 42%; and 36% for 1st - 3rd step). The most frequent cause that interferes the appropriateness for clinical trials was living in a distance city to the center (45%). The other factors were the absence of histological diagnosis (2%), age (6%), poor performance status (35%), insufficient liver function (6.5%), insufficient renal function (9%), insufficient bone marrow (2%), insufficient cardiac function (4%), cranial metastasis (7%), cord pressure (2%), secondary cancer (4%), and recruitment to a previous clinical trial (3%). Conclusions: The most important factor that prevents the recruitment to clinical trials in Turkey was living in a distance place to the relevant research center. Additionally, poor performance status and insufficiency in organ functions were other factors affecting the appropriateness to clinical trials.
Clinical outcomes of FOLFIRINOX in locally advanced pancreatic cancer: A single center experience.
Authors: Jongchan Lee, Jong-Chan Lee, Hyoung Woo Kim, Jaihwan Kim, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2017)

480 Background: Approximately, one third of pancreatic cancer patients have locally advanced status at diagnosis. Systemic chemotherapy or chemoradiotherapy is the main option for patients with locally advanced pancreatic cancer (LAPC). Recently, many studies have been investigating the efficacy of FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan and leucovorin) in LAPC patients. The aim of this study is to assess the clinical outcomes of FOLFIRINOX in patients with LAPC. Methods: Patients with LAPC who received FOLFIRINOX as an initial chemotherapy were identified via the Seoul National University Bundang Hospital database warehouse retrospectively. Demographic characteristics, disease status, chemotherapy duration and cumulative relative dose intensity (cRDI), conversion to resection and clinical outcomes were reviewed. Resectabilitywas determined based on National Cancer Comprehensive Network (NCCN) guidelines version 1.2016. Results: Fifty-one LAPC patients between Apr. 2012 and Dec. 2015 were enrolled. The median age of the patients was 60 years (30-77 years). The median overall survival (OS) of total patients was 13.3 months. The number of treatment cycles administered was 10 (2-20) and cRDI was 69.2% (35.6-91.2%). Fourteen of 51 patients (27.5%) underwent surgery and R0 resection was achieved in 11 patients (78.6%). Three patients received preoperative radiotherapy. The median OS of resected patients did not reach the 50% mark during the follow-up period compared with 13.3 months of OS in the patients without resection. Eleven of 14 resected patients did not experience recurrence during the follow-up of 10.7 months (1.8-23.5 months). The cRDI was higher in resected patients versus others (71.5 vs. 66.7%). The median time to resection was 6.7 months (3.2-14.3 months). Conclusions: FOLFIRINOX is considerable active regimen in patients with LAPC promising R0 resection rate. Future research should assess adequate duration and dose intensity of FOLFIRINOX and proper point of radiotherapy in the patients with LAPC to achieve higher rate of R0 resection.
Risk factors for severe cancer chemotherapy toxicity in the outpatient setting: Results of a nested case control study using a novel patient cohort
Authors: J. O. Jacobson, S. Brozovic, J. E. Stahl, M. Papi, R. Stankiewicz
Journal: Journal of Clinical Oncology (2009)

6545 Background: Risk factors for severe cancer chemotherapy-related toxicity (resulting in hospitalization and/or death) in the adult outpatient setting are largely unknown. Between 2003–2006, we identified all chemotherapy patients from a single hospital-affiliated outpatient cancer center who required admission to the hospital, and using a structured process that included monthly peer review meetings, we determined which admissions were due to chemotherapy toxicity. Among 2,082 patients who received chemotherapy, 185 required at least one admission. In this study we describe the development of a prediction model for severe chemotherapy-related toxicity. Methods: We undertook a nested case control study by randomly selecting 98 patients admitted to the hospital within 30 days of their last chemotherapy administration and 173 controls. We selected 33 clinical and demographic variables that we hypothesized might predict severe toxicity, and used standard descriptive, univariate and regression methods to characterize the data and develop a prediction model. Results: We were able to identify the following variables that predicted for severe chemotherapy toxicity: increasing age; increasing Charlson Comorbidity index (CCI); treatment with a prior chemotherapy regimen; prior admission for chemotherapy toxicity; decreasing hemoglobin and absolute neutrophil count (ANC) and increasing creatinine, and albumin. Independent variables that did not predict for increased risk for severe toxicity included the following: performance status; chemotherapy intent (curative, adjuvant or palliative); full dose versus reduced dose for cycle I; cisplatin-based chemotherapy; median income (by postal codes). Using logistic regression we created a parsimonious model (ROC AUC of 0.69) that included four clinical independent variables: CCI; prior chemotherapy regimen; ANC; and albumin. Conclusions: This analysis may permit the development of a predictive model which will include CCI, prior chemotherapy regimen, ANC, and albumin to help identify patients prior to the initiation of chemotherapy who are risk for severe toxicity. No significant financial relationships to disclose.
Clinical evaluation of germline polymorphisms (SNPs) associated with capecitabine (C) toxicity (tox) in metastatic breast cancer (MBC).
Authors: Peter H. O'Donnell, Vassily Trubetskoy, Ashley Nurhussein-Patterson, Julianne P. Hall, Dezheng Huo, Gini F. Fleming, James N. Ingle, Ingrid A. Mayer, Phuong Khanh H. Morrow, Anna Maria Storniolo, Andres Forero-Torres, Catherine H. Van Poznak, Douglas E. Merkel, Gary L. Rosner, Olufunmilayo I. Olopade, Mark J. Ratain, Nancy Cox, M. Eileen Dolan, Rita Nanda
Journal: Journal of Clinical Oncology (2015)

1049 Background: C is associated with sometimes severe tox affecting patient (pt) adherence and quality of life, which can result in dose disruption/reduction potentially attenuating effectiveness. We sought to identify pharmacogenomic (PGx) markers of C tox using a novel prospective tox assessment method in a large, multi-institutional study of women with MBC. Methods: Pts were prospectively identified prior to C monotherapy initiation at 2000 mg/m2/d, 14 d on/7 off. Pts completed in-person tox questionnaires (q) on d1 of each cycle (cy) and automated phone-in q on d8, d15 for 4 cy, but met study endpoint earlier if C was dose-reduced or suspended. Genetic analysis of 50 prespecified markers and a separate genome-wide association study (GWAS) were conducted with phenotypes immediate (cy 1) and overall diarrhea or hand-foot syndrome (HFS). Results: N = 259 pts enrolled from 14 institutions (median age 57 yrs, range 25-85). Pt adherence with tox reporting was robust, with 86% (cy 1) and 71% (cy 4) of q completed. Rates of any-grade diarrhea and HFS were 52% and 69%, respectively, including 17% reporting grade 3 diarrhea and 9% grade 3 HFS. Worst tox was identified solely via at-home phone reporting in 39% of pts. Only 29% of pts completed 4 cy without C interruption, dose change, or early discontinuation. In candidate PGx analysis, 3 SNPs associated with development of diarrhea: DPYD*5 (OR 4.9; P = 0.0005, significant after multiple test correction), missense SNP in MTHFR (OR 3.3; P = 0.02), and upstream SNP of MTRR (OR 3.0; P = 0.03). For HFS, GWAS elucidated a novel SNP (OR 3.0; P = 0.0007) upstream of TNFSF4, a gene implicated in systemic sclerosis and graft-versus-host disease of skin, never before implicated in HFS. Conclusions: To our knowledge, this is the first PGx study to use phone-in pt self-reporting, permitting increased accuracy of tox-phenotype characterization. Three germline SNPs previously associated with fluorouracil sensitivity in preclinical/clinical models were identified, and a novel SNP having strong functional relevance was discovered. If further replicated, these markers could improve prediction of pts at highest risk for C tox, reducing morbidity and enhancing outcomes. Clinical trial information: NCT00977119.
Investigations of a novel diagnostic technology for colorectal cancer.
Authors: Hongmei Tao, Xuedong Du, Shijin Ding, Xing Tang, Da Lou, Yue Lin, Chris Chang Yu
Journal: Journal of Clinical Oncology (2017)

564 Background: Currently endoscopy examination takes an important role in the diagnosis of colorectal cancer, and there are no other clinically viable non-invasive diagnostic methods. In this investigation, a newly developed, novel IVD cancer diagnostic technology named Cancer Differentiation Analysis (CDA) Technology was investigated for colorectal cancer diagnosis. CDA is a new technology using multi-level and multi-parameter information which measures information relating to both protein fragments and cellular signals in blood samples in one single test. Methods: Peripheral blood was drawn in EDTA tubes for CDA tests. Intravenous blood samples from individuals with colorectal cancer (n = 193), as well as control samples (n = 705) were collected. Cancer group has been clinically diagnosed, and individuals in control group have been confirmed by physical examinations free of cancer. All blood samples were tested using a CDA device, and collected data were analyzed in the SPSS Packages. Results: Data analysis (using T test) showed a significant statistical difference with P value &lt; 0.05 between colorectal cancer group and control group. Details of CDA test results were given in Table 1. Based on initial data, the area under curve (AUC), sensitivity and specificity of CDA technology for colorectal cancer were determined to be 0.861, 76.7% and 76.7% (cut-off value was set at a level at which sensitivity and specificity are comparable), respectively. Conclusions: CDA technology is able to statistically distinguish control group from colorectal cancer group with reasonably high sensitivity and specificity (both above 75%). As a non-invasive and potentially cost effective method capable of large population screening, CDA technology could be a very promising approach for the screening and diagnosis of colorectal cancer. [Table: see text]
The prognostic and predictive impact of genomic grade index (GGI) versus central grade or molecular class in intermediate-risk breast cancer (BC): Results from the EC-Doc trial.
Authors: Oleg Gluz, Cornelia Liedtke, Helene P. Peyro Saint Paul, Ulrike Nitz, Ronald E. Kates, Jens Bodo Huober, Arndt Hartmann, Hans Heinrich Kreipe, Enrico Pelz, Ramona Erber, Walther Kuhn, Nadia Harbeck
Journal: Journal of Clinical Oncology (2013)

1092 Background: Potential markers for adjuvant taxane-based chemotherapy (CTx) in early, intermediate-risk BC include histologic grade (HG), Ki-67, Genomic Grade (GG) or molecular classification. The randomized EC-Doc trial demonstrated improvements in DFS and OS for EC-Doc vs. FEC in patients with 1-3 positive LN. Methods: Centrally assessed protein expression data by IHC, histology/HG (n=772) and GG (n=476) were obtained. Luminal A/B classes were defined as: ER/PR+/KI-67&lt;20/&gt;20% and/or HER2+. Correlations/concordance of these factors were estimated; impact on DFS and value for predicting taxane-based CTx benefit was assessed. Results: Low, equivocal and high GG (GG-1/-EQ/-3) categories were observed among 54 (11%); 60 (13%); 358 patients (76%) and associated with decreasing 5-yr-DFS rates of 100%, 92% and 82% (p &lt; 0.001).There is only 60% concordance between local (L)/central(C) HG assessments and 63% between GG and C-HG. 37.7% of GG-3 tumors were L- HG3 vs. 72% C-HG3; 79% of C-HG2 and 83% of L-HG2 tumors were re-classified (56-71% to GGI3). Only 5.6-6% of GG1 were HG1 by L/C-HG respectively.GG was prognostic only in L-HG subgroups.In univariate subgroup analyses, EC-Doc was significantly superior to FEC: C-G3 (HR=0.58, 0.39-0.93), high Ki-67 (HR=0.55, 0.32E0.92) and GG-3 (HR=0.58, 0.34-0.99) subgroups. In multivariate analyses of HR+ disease (including age, therapy, GGI category, tumor size, LN status, central/local HG, Ki-67, HER2), either C-HG3 / high Ki-67 (as dichotomous variables) or C-HG3 / GGI (as continuous variable) were identified as independent prognostic factors.In interaction analysis, only C-HG, luminal A subtype and interaction of luminal-B/therapy were significant. If local HG was included instead of C-HG, only GG was as independent prognostic factor. Conclusions: These data support GGI as independent prognostic factor in early HR+ BC and as predictive marker regarding taxane benefit by univariate analysis. There is heterogeneity between L/C-HG and GGI. C-HG and Ki-67 assessment appear similarly informative. A predictive effect regarding benefit of taxane-containing CTx was seen in the IHC-luminal B subtype.
Post-treatment surveillance for ovarian carcinoma patients: The effect of Consolidated Metropolitan Statistical Area (CMSA).
Authors: Varun Singla, David Gardner Mutch, Randall K. Gibb, Katherine S. Virgo, Feng Gao, Robert J. Avino, Frank E. Johnson
Journal: Journal of Clinical Oncology (2015)

e16538 Background: In the USA, ovarian cancer is the eighth most common cancer in women; about 21,000 new cases are diagnosed each year. Many women experience recurrence after curative-intent treatment. Post-treatment surveillance is felt to be useful. Consensus-based surveillance guidelines exist, but high-quality evidence is not available. We recently carried out a survey of the Society of Gynecologic Oncologists which documented marked variation in the intensity of surveillance (Gynecol Oncol 120: 205-207, 2011). We sought to determine whether Consolidated Metropolitan Statistical Area (CMSA) could explain the variation in surveillance intensity. Methods: The 943 SGO members were surveyed to determine their surveillance practices. Our survey offered 4 idealized clinical vignettes and a menu of 11 testing modalities. Responses were stratified by CMSA. Repeated-measures ANOVA was used to generate mean, SD, median, and range. Results: 323 of those surveyed responded; 283 were evaluable. There was statistically significant variation (p<0.05) in only one of the most frequently utilized modalities: CBC. Physicians in the TX CMSA recommended 0.3±0.5 CBCs in year 1; those in the NY-NJ-CT-PA CMSA recommended 1.2±1.5 CBCs in year 1. Conclusions: There is very little variation in the utilization of surveillance modalities among CMSAs. Number of surveillance modalities per year (mean ± SD). Location Number of MDs Office visit Pelvic exam Pap smear CBC Metabolic panel CA-125 level Chest x-ray Abdomen-pelvic CT TX CMSA 10 3.8±0.4 3.9±0.3 1.0±0.0 0.3±0.5 0.2±0.4 3.9±0.3 0.8±0.6 0.3±0.7 NY-NJ-CT-PA CMSA 29 4.2±1.5 4.3±1.8 1.3±1.2 1.2±1.5 1.1±1.5 4.1±1.7 0.5±0.7 0.6±0.8 Other CMSA 185 4.4±1.4 4.4±1.5 1.2±1.2 1.7±2.6 1.2±2.0 4.4±1.7 0.5±0.8 0.6±0.8 Non-CMSA 22 4.3±1.8 4.3±1.8 1.3±1.1 1.9±3.6 1.3±2.8 4.4±1.8 0.4±0.8 0.7±0.9 Total 246 4.4±1.5 4.4±1.5 1.2±1.1 1.6±2.5 1.2±2.0 4.3±1.7 0.5±0.8 0.6±0.8 P-value 0.0599 0.0635 0.7858 0.0426 0.0561 0.0749 0.535 0.6734
Risk of pneumonitis attributable to everolimus in cancer patients: A meta-analysis.
Authors: Linda Phuong Hoang, Shenhong Wu
Journal: Journal of Clinical Oncology (2015)

e13574 Background: Everolimus as an inhibitor of the mammalian target of rapamycin (mTOR) is currently used for the treatment of several cancers. Its use is complicated with pneumonitis. A meta-analysis of randomized control trials (RCTs) was conducted to determine the overall risk of developing pneumonitis attributable to everolimus in cancer patients. Methods: The PubMed database and abstracts presented at American Society of Clinical Oncology (ASCO) meetings up to May 2014 were searched for relevant studies. Inclusion criteria were RCTs in which everolimus was compared to controls in cancer patients. The summary incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated using a random or fixed effects model. Results: A total of 6 RCTS with 2480 patients (everolimus: 1431, controls 1049) with a variety of solid tumors were included. In comparison with placebo, everolimus significantly increased the risk for developing all-grade pneumonitis (RR = 51.56, 95% CI: 7.20-369.07, P < 0.001) and high-grade pneumonitis (RR = 10.74, 95% CI: 1.42-81.04, P = 0.02). The summary incidences of all-grade (grades 1-4) and high-grade (grades 3-4) pneumonitis attributable to everolimus were 9.2% (95% CI: 5.8-14.4%) and 2.9% (95%CI: 2.1-4.0%) respectively. The risk of pneumonitis attributable to everolimus did not vary significantly with tumor types (P = 0.07). However, it varied significantly with concurrent antineoplastic agents (P < 0.001), with the lowest risk seen in chemotherapy (2.5%, 95% CI: 1.2-5.2%) and letrozole (2.9%, 95% CI: 1.1-7.5%), and the highest risk seen in exemestane (12.0%, 95% CI: 9.4-15.3%) and tamoxifen (13.2%, 95% CI: 6.4-25%). Conclusions: Risk of pneumonitis is attributable to everolimus and may be affected by the combination with other antineoplastic agents.
Serum levels of macrophage inhibitory cytokine-1 (MIC1) and matrix metallopeptidase-7 (MMP7) as diagnostic and prognostic markers in gastric cancer (GC) patients (pts).
Authors: Manuel Valladares-Ayerbes, Nuria Tarrío, Moisés Blanco-Calvo, Mar Haz-Conde, Isabel Santamarina Cainzos, Vanessa Medina Villaamil, Teresa Rodríguez-Rigueiro, Angelica Figueroa, Margarita Reboredo, Luis Antón-Aparicio
Journal: Journal of Clinical Oncology (2012)

e14595 Background: MIC1 and MMP7 are secreted cytokines involved respectively in the modulation of immunological processes and in extracellular matrix remodeling. Their expression were found deregulated in different tumors, including GC. However, few data are available about their serum levels, their diagnostic potential, and their prognostic significance in GC pts. Here, we analyze the diagnostic performance of these markers and we present data linking them with short survival in GC pts. Methods: Serum samples were assayed in duplicate for MIC1 and MMP7 levels by ELISA. The diagnostic performance of markers was assessed by ROC curve analysis and the cut-offs were set using the Youden index approach. The cut-offs for prognostic purposes were determined using X-tile software. Differences in progression free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and logrank test. Cox regression was used to determine the prognostic independence of biomarkers. Results: From November 2006 to July 2010, 52 GC pts and 28 healthy donors were consecutively recruited. The follow-up of pts was performed until their death or the end of study (September 2011). The AUCs for MIC1 and MMP7 were respectively 0.897 and 0.865 (p &lt; 0.001). Using the optimal cut-off to diagnose GC pts, we obtained a 73.08% of sensitivity (Ss) and a 92.86% of specificity (Sp) for MIC1, and a 78.85% of Ss and an 85.71% of Sp for MMP7. In the survival analysis, high serum levels of MIC1 and MMP7 were significantly associated with shorter PFS (p &lt; 0.001) and OS (p &lt; 0.001 and p = 0.003, respectively). In univariate analysis, pts with high serum levels of MIC1 and MMP7 had an increased risk of progression (HR = 3.608, p&lt;0.001 for MIC1; HR = 4.172, p&lt;0.001 for MMP7) and death (HR = 3.843, p=0.001 for MIC1; HR = 2.602, p=0.006 for MMP7). However, MIC1 and MMP7 failed to reach prognostic independence in multivariate analysis. Conclusions: We obtained cut-off values of MIC1 and MMP7 in serum for diagnostic purposes in GC. In addition, we established a correlation between increased levels of MIC1 and MMP7 in serum and shorter PFS and OS in GC. These findings justify studies with a larger number of pts.