tbuckley/cabot-search huggingface dataset:
The FGFR landscape in cancer: An analysis of 4,869 cases.
Authors: Teresa L Helsten, Sheryl Krevsky Elkin, Jennifer Carter, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2014)

11059 Background: Fibroblast growth factor receptors (FGFRs) are highly conserved tyrosine kinase receptors involved in development and carcinogenesis. Humans have 4 FGFRs. Germline FGFR mutations cause craniosynostosis and dwarfism. Methods: DNA extracted from 4869 formalin-fixed, paraffin embedded cancers was assayed by next generation sequencing (CLIA) (mostly FoundationOne, Cambridge, MA). Data were curated and interpreted by N-of-One (Lexington, MA). Histology was defined by ordering physicians. Our objective is to characterize the nature/frequencies of FGFR aberrancies in these cancers. Results: 356 aberrations were identified in 345 cases (7%; some harbored > 1 FGFR aberration). Aberrations in FGFR1 were most common (N = 170), with FGFR3 (N = 93), FGFR2 (N = 70), and FGFR4 (N = 23) less common. The most common abnormalities were amplifications in FGFR1 (N = 152), FGFR2 (N = 35), and FGFR3 (N = 24). The Table shows cancers with ≥ 75 cases. In urothelial tumors, 12% of aberrations were somatic mutations in FGFR3 (the same as those in dwarfism). In lung squamous cell carcinomas, FGFR1 was amplified in 9% and 3% harbored somatic FGFR3 mutations associated with dwarfism; in lung adenocarcinomas, only 4% were FGFR abnormal. Conclusions: Gene amplifications and activating missense mutations are frequent in cancer, suggesting that they may be actionable targets for the FGFR-targeting drugs already available. Cancer N Frequency of aberrations (% of cases) All FGFR1 FGFR2 FGFR3 FGFR4 Amplification Mutation Rearrangement Urothelial 126 33.3 9.5 0.8 23.0 0 9.9 16.7 6.8 Breast 525 18.0 13.8 2.6 0.8 0.6 16.8 0.6 0.4 Endometrial 80 13.8 1.3 10.0 2.5 0 1.3 11.3 1.3 Ovarian 234 8.6 4.7 1.7 1.7 0.4 8.2 0.4 0 Adenocarcinoma unknown primary 267 8.2 1.9 2.6 3.4 0.4 4.9 1.9 1.5 Glioma 144 7.6 3.5 0 4.2 0 0.7 5.6 1.4 Cholangiocarcinoma 115 7.0 0.9 6.1 0 0 2.6 0.8 3.9 Gastric 163 6.8 1.8 3.9 1.2 0 4.9 0.6 1.2 Nonsmall cell lung 675 5.6 2.7 0.4 1.5 1.0 3.7 1.6 0.2 Esophageal 90 5.6 3.3 1.1 0 1.1 5.6 0 0 Pancreatic 175 4.6 1.1 1.1 2.3 0 2.5 1.0 1.1 Colorectal 294 4.4 2.4 0.7 0.7 0.3 3.1 1.4 0 Renal cell 92 4.4 2.2 0 1.1 1.1 3.5 0 0.9 Neuroendocrine 107 3.7 3.7 0 0 0 3.7 0 0 Sarcoma 190 3.7 2.1 0.5 1.1 0 1.6 2.1 0 Head and neck 215 2.3 0.5 0.9 0.5 0.5 0.9 1.4 0 Melanoma 134 1.5 0.8 0.8 0 0 0.8 0.8 0 Leiomyosarcoma 77 1.3 1.3 0 0 0 1.3 0 0
Long-term survival of patients suffering from solid extra-cranial neoplasias after dendritic cell-based cancer immune therapy.
Authors: Friedrich Erhart, Thomas Felzmann, Philipp Funovics, Wolfgang Holter, Leo Kager, Volker Witt, Maria-Carmen Visus-Miguel
Journal: Journal of Clinical Oncology (2014)

3096 Background: Cancer immunotherapy (CIT) based on Dendritic Cells (DC) is developing into a more mature therapy option as clinical trials progress. Our approach involves the microbial danger molecule Lipopolysaccharide (LPS) in connection with Interferon-Gamma (IFNg) to generate mature DCs that release Interleukin-12 (IL12). As the IL12 production is limited to a timespan of about twenty-four hours, we inject DCs that have been exposed to LPS/IFNg for six hours in order to ensure that IL12 release is still ongoing during the in vivo interaction with T cells. Methods: We here report an analysis of 27 patients with advanced solid extra-cranial metastatic malignancies that received our DC CIT approximately ten years ago. The patients come from two phase I clinical trials and were age-matched and disease-matched. To explore potential factors contributing to the extended survival of certain patient groups, we studied a set of immunological variables in the peripheral blood mononuclear cells and the vaccine, where available from these patients. Methods used were flow cytometry, Elispot assays, Cytometric Bead Arrays and qRT-PCR. Statistical techniques included Student's T test, Pearson's correlation, Kaplan-Meier curves and Cox regression. Results: Of the total 27 study participants, six (~22%) were still alive. 20 patients of one of those two phase I trials have already been reported in an interim analysis in 2007. In spring 2013, which is approximately ten years after the advent of the trial, five of the twenty (1/4=25%) were still alive. Immunological variables with significantly different values in patients alive at the time of review include RORgt mRNA levels, GATA3 mRNA levels, CD94+ cells and IL-17 production. Conclusions: Long-term survival has been reached in a subset of patients with advanced metastatic disease that received our DC CIT approximately ten years ago. The immunological variables we studied might be a first hint at future biomarkers that can identify potential long-term survivors. Further studies with an increased number of patients are needed to consolidate our observations.
Clinical, pathological, and immunohistochemical features of pancreatic neuroendocrine tumors.
Authors: Vladimir Sez Trifanov, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Sergey Sergeevich Todorov
Journal: Journal of Clinical Oncology (2014)

e15159 Background: Pancreatic neuroendocrine tumors (Pan Nets) are a heterogeneous group of tumors, which have worse outcomes as compared to neuroendocrine tumors of the gastrointestinal tract (GNET). Pan Nets represent only 3-1% of all pancreatic neoplasms, the incidence of PanNets has increased over the past two decades. The role of combined clinical histopathologic and immunohistochemical approach in the diagnosis and subclassification of primary PanNets was evaluated at a single institution with multidisciplinary expertise in neuroendocrine oncology. Methods: From 1993 to 2013 in Rostov research oncological institute 197 patients underwent radical resections for pancreatic malignant neoplasms. Among them we retrospectively identified 20 patients with PanNets. Clinico-pathologic and immunohistochemicalv data from 20 adult patients, aged: 28-76 yrs (mean 42 yrs years), Patients: 17 M/3 F, with primary Pan Nets who had undergone radical pancreatic resection were included. Results: Immunohistochemistry was useful in supporting the diagnosis of Pan Nets. Chromogranin, synaptophysin, NSE, and CD56 were positive in 19/20 (95%), 17/20 (85%), 17/19 (89%), and 5/14 (35.7%) cases, respectively. Immunoreactivities for other markers for Pan Nets were as follows: CAM 5.2-17/20 (85%), CDX2- 0%. Ki-67 index ranged from 20-70% (median: 45%). There was a strong correlation between mitotic count and Ki-67 index (r +0.9). Treatment modalities for PanNET included surgery (100%), chemotherapy (52%), biologics (everolimus)(2%) and somatostatin analogues (10%). Seventeen patients underwent pancreaticoduodenectomy, 3 had distal pancreatectomy. Postoperative complications occurred in 15 patients (88.2%) after pancreaticoduodenectomy, in 1 patient (33.3%) after distal pancreatectomy. Liver directed therapies were employed in 5 pts with PanNETs. Median survival for PanNETs (all stage) was 6.4 years. Using multivariate analysis, age at diagnosis (p<0.001 for age cohort of <64 yrs) clinical stage and tumor grade (mitotic count combined with Ki-67 index) were found to be significant factors. Conclusions: Patients with pancreatic neuroendocrine tumors can expect long-term survival even in advanced stage.
Association of hand-foot syndrome (HFS), treatment dose reductions (TDRs), and outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs).
Authors: Erin B. Bailey, Srinivas Kiran Tantravahi, Austin Poole, Chesley E. Wells, Julia A. Batten, Joseph Merriman, David D. Stenehjem, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2014)

4580 Background: HFS is a common toxicity of VEGF TKIs, often requiring TDRs. Correlation between HFS, in the context of TDRs, with survival outcomes has not been reported in mRCC. Methods: From a single-institutional database (2004-2013), incidence of HFS and TDRs (for any reason) in mRCC pts receiving VEGF TKIs were recorded and correlated with survival outcomes. Univariate and multivariate analyses were performed using Kaplan-Meier method and COX Proportional Hazard model. Results: Of 123 pts (median age 60 yrs, males 71%), the majority had clear cell histology (71.5%) and were in the MSKCC (71%) and Heng (55%) intermediate-risk groups. Pts received the following TKIs: sunitinib (77.2%), sorafenib (14.6%), pazopanib (7.3%), and axitinib (0.8%). HFS (G1 20.3%, G2 8.9%, G3 9.8%) occurred in 39% of pts. The most common reasons for TDRs were mucositis (38.8%), HFS (29.9%), and fatigue (17.9%). The median progression free survival (PFS) and overall survival (OS) were significantly longer in pts with HFS (Table). The median OS was improved in those who had TDRs for HFS as compared with those who had TDRs for other reasons (Table). Two multivariate analyses were conducted. The first included age, sex, HFS, TSH > 10 mIU/L while on VEGF TKI, and risk criteria. HFS remained significant for improvements in PFS and OS (PFS: HR 0.38, CI 0.19-0.76, p=0.0060; OS: HR 0.37, CI 0.15-0.83, p=0.0157). In the second multivariate analysis, development of HFS was substituted for TDRs for HFS and it was not an independent predictor of survival (PFS: HR 0.58, CI 0.25-1.23, p=0.1601; OS: HR 0.46, CI 0.16-1.14, p=0.0981). Conclusions: HFS in mRCC pts treated with VEGF TKIs predicts improved survival despite TDRs. Thus, VEGF TKI dose reductions for the management of HFS are not expected to negatively impact survival outcomes. Outcomes with HFS and TDRs. n PFS, months OS, months HFS vs no HFS 123 14.1 vs 6 (HR 0.51, CI 0.32-0.79, p=0.0021) 42.8 vs 10.8 (HR 0.39, CI 0.23-0.63, p<0.0001) TDRs for HFS vs TDRs for other reasons 67 21.9 vs 8.5 (HR 0.55, CI 0.28-1.02, p=0.0582) 45.1 vs 13.9 (HR 0.37, CI 0.16-0.76, p=0.0061)
Incidence and mortality rates of breast and gynecologic cancers and human development index in the pan-American region.
Authors: Jeovany Martínez-Mesa, Gustavo Werutsky, Stefan Michiels, Carlos Alberto Sampaio-Filho, Alfonso Duenas, Juan Jose Zarba, Max S. Mano, Cynthia Mayte Villarreal-Garza, Henry Leonidas Gomez, Carlos H. Barrios
Journal: Journal of Clinical Oncology (2014)

1596 Background: Breast and gynecologic cancers incidence and mortality rates differ between geographical regions. We aim to evaluate if disparities in incidence and mortality cancer rates among women in the Pan-American countries could be related to the country human development index (HDI). Methods: This ecological analysis includes 28 countries from the Pan-American region. Age-standardized incidence and mortality rates per 100.000, mortality/incidence ratios for breast , cervical cancer, ovarian cancer and corpus uteri cancer obtained from GLOBOCAN 2012. Data were log-transformed because of strong skewness. The information on HDI was gathered from the UNDP 2012 report. Pearson’s correlation test and simple linear regression were performed in Stata 12. Results: HDI was strongly and positively associated with breast and ovarian cancers incidence and mortality rates. HDI was negative associated with cervical cancer incidence and mortality rates and also with breast and cervical cancers ratio. HDI was not associated with corpus uteri cancer estimative. Linear regression coefficients (β) between HDI and each cancer log-rate are shown in the Table. Conclusions: HDI should be considered as an indicator explaining inequalities in incidence and mortality rates of breast, cervical and ovarian cancer in women between countries in the Pan-American region. Cancer rates per 100,000 (log-transformed) Linear regression coefficient β (95%CI) p-value* Breast cancer incidence 4.03 (2.61;5.45) <0.001 Breast cancer mortality 1.76 (0.32;3.21) 0.019 Breast cancer mortality/incidence ratio -0.26 (-0.42;-0.10) 0.003 Cervical cancer incidence -3.28 (-4.78;-1.78) <0.001 Cervical cancer mortality -4.63 (-6.1;-3.17) <0.001 Cervical cancer mortality/incidence ratio -0.89 (-1.16;-0.62) <0.001 Corpus uteri cancer incidence 2.37 (-0.33;5.06) 0.083 Corpus uteri cancer mortality 0.07 (-2.68;2.82) 0.960 Corpus uteri mortality/incidence ratio -0.07 (-1.06;0.92) 0.885 Ovarian cancer incidence 3.26 (1.78;4.75) <0.001 Ovarian cancer mortality 1.82 (0.44;3.20) 0.012 Ovarian cancer mortality/incidence ratio -0.42 (-0.91;0.06) 0.086 *Wald test.
“Act on Oncology” as a new comprehensive approach to assess prostate cancer centers.
Authors: Wieland Voigt, Riccardo Valdagni, Tiziana Magnani, Josef Hoellthaler
Journal: Journal of Clinical Oncology (2014)

e16095 Background: Multidisciplinary care (MDC) of prostate cancer (PC) is increasingly accepted. Key elements are well organized clinical processes and integration of clinical disciplines and stakeholders in center management. To successfully implement MDC and improve process quality and efficiency, transparency on all existing processes or workflows is mandatory. However, this is often missing in complex specialized PC centers and prompted us to develop a standardized and repeatable assessment tool based on the capability maturity model integration (CMMI). Methods: Key information sources were comprehensive knowledge of medical experts, clinical guidelines, best practice elements (BPE) of renowned cancer centers and scientific literature. Following the CMMI methodology, a branched-type model with 5 categories, 32 key process areas, 172 requirements and more than 1,500 criteria was created. Compliance with requirements was assessed through structured on-site surveys of different stakeholders in patient care, center management, innovation and research. Comparison with BPE allowed recommendation of improvement measures. The approach was applied in a pilot study on a PC center in Europe. The approach employs a structured and predefined interview matrix, which enables reproducibility and low interobserver variability for reassessments to proof efficiency of measures. Results: Several BPE such as multidisciplinary clinics or advanced organizational measures for patient scheduling were observed. Opportunities for improvement were found in other areas such as center management and infrastructure and derived from the best practice model. As a follow up action to the assessment and effect of the evaluation, the PC unit was formalized and personnel and clinical activities described. Conclusions: The Act on Oncology (AoO) approach was feasible and could identify opportunities for process improvements in a pilot study. Measures were derived from the AoO database that might increase the process quality and efficiency after implementation.
Molecular subtyping of colorectal cancer for identification of patients with a mesenchymal tumor type who might benefit from TGF-beta inhibition.
Authors: Ramon Salazar, Paul Roepman, Mireille Snel, Cristina Santos, Stefan M. Willems, Diede Brunen, Udo Kellner, Rachel A Midgley, Alberto Villanueva, Rene Bernards, Iris Simon
Journal: Journal of Clinical Oncology (2014)

3618 Background: Currently, most colorectal cancer (CRC) patients receive chemotherapy treatment, even though many patients do not benefit. Therefore, a better understanding of the biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for all other patients. Methods: A molecular subtype classification (A-, B-, C-type) was developed using expression data of 188 stage I-IV CRC patients and validated in 543 stage II and III patients. Subtypes were correlated to clinical factors, prognosis and treatment benefit (stage III). To determine whether TGF-β signaling is elevated, 78 patient biopsies were analyzed for TGF-beta (receptor) and phospho-SMAD2/3 expression. To analyze the effect of TGF-β activation, we studied the effects of C-type-like cell lines under treatment with Cisplatin, Oxaliplatin or 5-FU. We analyzed the presence of subtypes in all stages (TCGA data, n=218), and investigate the stability of classification in multiple biopsies from the same tumor and in matching primary and liver metastases samples. Results: We developed a diagnostic test that allows the classification of colorectal cancer tumors into different intrinsic molecular subtypes. The heterogeneity of these subtypes is largely based on 3 biological hallmarks of the tumor. Especially C-type CRC is of clinical interest, as C-type patients have the worst outcome, a mesenchymal phenotype and show no benefit from chemotherapy treatment. The C-type subgroup has elevated TGF-β signaling (TGFB1, p=0.0012; TGFBR1, p=0.0005) and increased p-SMAD2/3 staining in the tumor cells (1.9-fold, p=0.0002). In cell line experiments, up-regulation of TGF-β signaling resulted in resistance against chemotherapy. We confirmed the presence of C-type tumors in stage IV CRC (16%) and currently investigate the stability of the subtype phenotype in 33 pairs of matching primary tumor and metastases. Conclusions: The molecular subtypes differ largely in prognosis and response to chemotherapy. A treatment strategy combining standard drugs with agents suppressing TGF-β signaling might benefit C-type patients.
Metastatic colorectal cancer (mCRC) treatment patterns in the Medicare population.
Authors: Jeremy Snider, Ed Wang, Sibyl Anderson, Jordan Steelquist, Greg S Warnick, Catherine R. Fedorenko, Veena Shankaran, Scott David Ramsey
Journal: Journal of Clinical Oncology (2018)

823 Background: Few studies have examined how patterns of care relate to clinical consensus guidelines for metastatic colorectal cancer (mCRC) in real-world settings. This study investigated treatment patterns around systemic therapies for older mCRC patients using SEER-Medicare data. Methods: We utilized data from a linkage of national Medicare claims data with records from the 12 Surveillance, Epidemiology, and End Results (SEER) regions for patients diagnosed with stage IV CRC between 2011 and 2014. Other inclusion criteria included adenocarcinoma histology, being &gt; 65 years of age, and continuous Part A/B enrollment 12 months prior to diagnosis. We conducted bivariate analysis and multivariate modeling to evaluate the association between age, race, gender, SEER region, and comorbidity score with receipt of systemic therapy. We examined first and subsequent lines of therapy, and classified them as adherent or non-adherent to NCCN guidelines. Results: Of 102,461 CRC patients, 6,360 (6.2%) patients had evidence of metastatic disease and met all inclusion criteria. 3,155 (49.6%) received no systemic therapy. Of the 2,976 (46.8%) who received systemic therapy with identifiable regimens, FOLFOX/CAPOX was the most common 1L regimen (32.9%), followed by 5-FU or capecitabine alone (26.4%) – both identified as guideline-adherent therapies. Non-guideline adherent regimens (such as use of single-agent oxaliplatin or bevacizumab) were uncommon as 1L therapies (1.4%). 1,553 patients (52.2%) progressed to a 2L therapy, 715 (24.0%) progressed to a 3L therapy, and 320 (10.8%) to a 4L therapy. A large proportion of 2L (26.9%) and 3L (24.2%) treatments contained bevacizumab. 96 patients (3.2%) received regorafenib, representing 6.7% of 3L and 10.6% of 4L therapies. Patients who did not receive systemic therapy were older (mean age of 80.8 vs 74.9) and had multiple comorbidities (63.1% vs 48.4% with Klabunde score &gt; 1). Conclusions: In a Medicare-insured mCRC cohort, patients generally received systemic therapy adhering to consensus guidelines. However, many patients did not receive systemic therapy – suggesting there may be delays in diagnosis and barriers to treatment which lower systemic therapy utilization.
PI CME driven interventions in an outpatient oncology practice to improve awareness and utilization of advanced care directives.
Authors: Elizabeth Ann Whitt, Monica Copp, Doug Smith, Debbie ELAINE Bihl, Ganapathy S. Krishnan, Jeyanthi Ramanarayanan, Stacie Daugherty, Ralph W. Roach, Jeffrey Bryan VanDeusen
Journal: Journal of Clinical Oncology (2014)

e20508 Background: The completion of advance directives (AD) and the discussion of a patient’s end of life goals result in a more patient-centered approach to care. The Adena Cancer Center developed a clinic where nurse practitioners facilitate the discussion and completion of AD for patients. Herein is described the use of a Performance Improvement Continuing Medical Education (PI CME) program to improve underutilization of an AD clinic in an outpatient hospital based oncology program. Methods: The approach was to break the utilization of Adena’s AD clinic into three stages. In Stage A, providers performed retroactive chart audits to evaluate seven independent metrics. These metrics included how many patients were screened for the need of an AD; of those patients, how many were ordered, scheduled, and received AD education. Additional metrics included tracking the number of patients who completed AD and the ability to locate the documentation in the electronic medical record. In Stage B, barriers to utilization and possible interventions were identified. Barriers included patient reluctance to discuss AD. A standard check-in question addressing whether there was an AD in place was put in place to help encourage patients to discuss the topic with their physician. Also, a reminder was placed in the chart to discuss AD with all patients diagnosed with stage IV disease. In Stage C, providers completed a second chart audit on patients with stage IV disease seen during the intervention period. The audit measured changes in AD clinic utilization after implementation of the above interventions. Results: In Stage A, only 9% of the audited charts met compliance across all 7 metrics. In comparison, Stage C chart audits resulted in 72% of the charts meeting desired compliance with the implemented Advance Directives process across all seven metrics. This indicates a significant improvement of 63% between the initial Stage A and Stage C chart audits. Conclusions: Implementation of simple interventions including intake questions for patients and reminder slips for treating physicians can dramatically improve knowledge and utilization of Advance Directives in an outpatient practice setting.