tbuckley/cabot-search huggingface dataset:
A phase I/II trial of enzalutamide plus the glucocorticoid receptor antagonist mifepristone for patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Russell Zelig Szmulewitz, Chadi Nabhan, Peter H. O'Donnell, Jacob Kach, Theodore Karrison, Elia Martinez, Walter Michael Stadler
Journal: Journal of Clinical Oncology (2016)

TPS5091 Background: Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease with limited therapeutic options. AR targeting therapies such as enzalutamide (Enz) are often effective for the treatment of mCRPC; however, resistance is common. The central hypothesis of this trial is that another nuclear hormone receptor, the glucocorticoid receptor (GR), can compensate for AR that is therapeutically inhibited and lead to disease progression. Studies of patient-derived prostate cancer tissues have shown that expression of the GR increases with AR inhibition (Szmulewitz et al, The Prostate, 2012; Arora et al, Cell 2013). Furthermore, therapeutic blockade of GR signaling with mifepristone (Mif), a steroidal GR antagonist, inhibited CRPC growth and delayed CRPC progression in preclinical models (Isikbay, Hormones and Cancer, 2014). Methods: This is a phase I/II, open label study of Enz in combination with Mif for patients with mCRPC. Major inclusion criteria include metastatic CRPC according to standard Prostate Cancer Working Group (PCWG) criteria, ECOG performance status 0-2, adequate hepatic function, and lack of seizure history. The phase I portion will assess the safety of the two-drug combination along with pharmacokinetic (PK) impact of Mif on Enz exposure. Dose titration will be made based on PK and safety to arrive at the randomized phase II dose (RP2D). For the phase II portion, patients will be randomized after 12 weeks of Enz to stay on Enz alone or to change to Enz plus Mif at the RP2D. The primary endpoint of the phase II study is to determine if Mif when added to Enz delays time to PSA progression, as a pharmacodynamic biomarker of AR and GR antagonism. Secondary objectives include to evaluate the effect of Mif/Enz on serum cortisol and TSH, to determine the effect of Mif addition on PCWG-defined progression, and to explore the role of circulating tumor cells, as a pharmacodynamic biomarker for Mif and Enz in CRPC using the Epic Sciences platform and by RNA sequencing. The study has completed accrual to the third dosing cohort (120mg Enz/300mg Mif daily) and there have been no dose limiting toxicities to date in any cohort. Clinical trial information: NCT02012296.
A study to evaluate immunological response to PD-1 inhibition in squamous cell carcinoma of the head and neck (SCCHN) using novel PET imaging with [18F]F-AraG.
Authors: A. Dimitrios Colevas, Nikita Bedi, Serena Chang, Uriel Yojanan Moreno Nieves, Susmita Chatterjee, Guido Alejandro Davidzon, Shyam Srinivas, Quynh-Thu Le, Aruna Gambhir, John B. Sunwoo
Journal: Journal of Clinical Oncology (2018)

6050 Background: Immune checkpoint blockade has demonstrated remarkable responses in a subset of patients with head and neck squamous cell carcinoma (HNSCC). However, the response rate is only ~20% or less for HNSCC. Currently, there are no good biomarkers to predict and assess responses after patients have initiated therapy. We evaluated the ability of a PET metabolic tracer ([18F]F-AraG), that preferentially accumulates in activated CD8+ T cells, to assess response to anti-PD-1 ab. We hypothesize that uptake of this agent within the tumor will correlate with the accumulation and activation of T cells within the tumor. Methods: Locally advanced HNSCC patients undergoing surgical resection received an infusion of anti-PD-1 ab in a window-of-opportunity study. A novel radiofluorinated AraG imaging agent, [18F]F-AraG (Cellsight), was used to image patients by PET/CT before and 2-3 weeks after their infusion. The tissue volume of interest (VOI) for the pre- and post-infusion [18F]F-AraG PET/CT scans was defined using pre-treatment conventional FDG-PET/CT scans. To assess for correlation of the [18F]F-AraG with immune response, pre- and post-infusion samples of the patients' tumors were obtained and dissociated into cell suspensions. Tumor-infiltrating T cells were evaluated by flow cytometry to determine T cell infiltration and activation. Tumor tissue also underwent whole exome sequencing to assess for potential immune mediated selection and elimination of neoantigens. Results: In a patient with oral cavity HNSCC, there was an approximately 50% increase in total [18F]F-AraG SUV in the VOI representing the tumor volume, following anti-PD-1 ab. Concurrently we observed an approximately 4-fold increase in the proportion of CD8+ T cells and an approximately 5-fold increase in the proportion of CD4+ T cells within the tumor tissue. The CD8+ T cells exhibited an activated state based on surface marker expression. Conclusions: [18F]F-AraG accumulation in the tumor tissue correlates with an increase in T cell infiltration and activation. Further study of this novel PET tracer is underway in HNSCC to assess its utility for predicting clinical response. Clinical trial information: NCT03129061.
Single-cell evolution and molecular characterization of human colorectal cancer stem cells.
Authors: Xiaoyan Zhang, Ling Yang, Qiang Hou, Ming Huang, Hong Fang Zhang, Rui Fei Xie, Rongjing Zhou, Ying Li, Jing Yue, Zhenzhen Jiang, Shi Xiu Wu
Journal: Journal of Clinical Oncology (2018)

e15699 Background: Tumor heterogeneity and internal clonal evolution of human colorectal cancer stem cells (CRCSCs) within cancerous tissues often represents an aggressive feature of cancer progression. Yet, the exact mechanism of tumorigenicity of CRCSCs is unknown. Methods: To perform a high-resolution examination of CRCSCs, we performed single cell whole-exome sequencing (scWES) of 183 sorted cells, including three groups of CRCSCs: EpCAM+basedCD133+CD44+, CD133-CD44+, or CD133+CD44- cells, colorectal cancer cells (CRCCs) (EpCAM+CD133-CD44-), plus one group of normal control cells. We examined the scWES data for driver mutations, clonal evolution, copy-number variation (CNV), loss of heterogeneity (LOH), structural variation (SV) and corresponding overall survival (OS) of CRCSCs-related mutation genes. Results: Clonal evolution analysis showed that all CRCSCs were located at the main clone, and that the CD133+CD44- CRCSCs, which harbored the lowest number of mutations, were the likely origin of CRC before evolving into other groups of CRCSCs/CRCCs. However, most of CRCSCs, with the exception of EpCAM+CD133+CD44+ CRCSCs that owned the least amount of mutations, were more heterogeneous than CRCCs. 131 genes were specifically mutated in CRCSCs, and 109 of them were just mutated in CD133 positive CRCSCs and 18 of them, including CDH1, FN1, ADD2, AHNAK2, FAM127B genes, were shared in three groups of CRCSCs. Significant CNVs included known and novel oncogenes, such as KRAS, PTPRF, PRDM16, ABCG2, SFRP1 and CDH1. SV analysis showed that chromosome structures located on regions of chromosome 1, 4, 5, 8 and 19 were variated only in CRCSCs. Finally, we performed a replication analysis of mutations obtained in this study relevant to survival odds (OS) of an additional 972 CRC patients. The results showed that 26 genes mutated in CRCSCs, including KRAS and 8 other genes (FN1, NAV1, RYR1, KMT2C, GGT1, PAPPA2, ACACB, MON1B and ANKZF1), were significantly negatively-correlated with OS (p < 0.05). Conclusions: The data presented here provide a useful information on single-cell level for understanding the genetic of CRCSCs and CRCs and identifying possibilities for treating it in a CRCSCs-targeted way.
Risk factors for non-communicable diseases (NCD) prevalence before cancer diagnosis: A cohort study of 12,685 new patients assisted at Instituto Oncológico Henry Moore (IOHM) in the past five years.
Authors: Eduardo L. Morgenfeld, Monica Montiel, Flavio Tognelli, Silvina Laura Musini, Mariana Abal, Barbara Kuhne, Claudia Lorena Acuna, Edgardo G. J. Rivarola, Ernesto Gil Deza, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2018)

e13589 Background: In 2013, the Argentinian Ministry of Health (MSNA) published a national survey on NCD risk factors prevalence and breast, cervix and colon cancer screening. This paper aims to describe such factors before cancer diagnosis (DX) in a cohort of patients treated at IOHM in the past five years. Methods: Between 9/26/2012 and 9/26/2017 all new patients (Pt) admitted to IOHM filled out a Past Medical History Form (PMHF) (ASCO 2013 ABST. E17539) with all the preexisting clinical conditions, providing information on NCD risk factors prevalence and tumor screening. Results: A total of 12,865 PMHFs were gathered. Population: Sex: F = 6763 Pt (53.3%)/ M = 5922 Pt (46.7%). Median age at diagnosis: 59y(r = 16-98). Tumors: Breast (25,3%), Urological (22,6%), Gastrointestinal (18,5%), Gynecological (7.9%), Hematological (7.8%), Lung (7.2%), Head&Neck (2,8%), Melanoma (2%), Sarcoma (1.6%), CNS (1.5%) Others (3%). Risk factors: Smokers/former smokers: 7062 Pt (55,7%). Overweight and obesity: 4317 Pt (60.7%). Hypertension: 4774 Pt (37,6%). Diabetes: 1387 Pt (10.9%). Myocardial infarction: 446 Pt (3.5%). Stroke: 339 Pt (2.7%). Tumor screening: Mammogram (62.5%), Papanicolau (68,4%), Colon (29,1%). Compared to MSNA data, IOHM cohort showed greater prevalence of smoking (55,7 % vs 42,7%), overweight and obesity (60,7% vs. 57,9%), diabetes (10.9% vs 9.8%) and hypertension (37,6% vs 34.1%); and similar rates of myocardial infarction, stroke and tumor screening. Conclusions: 1) To our knowledge, this cohort of 12,685 Pt is the largest series in Argentina where risk factor prevalence and tumor screening before cancer DX have been studied. 2) Six out of ten Pt have a history of smoking, overweight or obesity. 3) Only 60% of women get the recommended screening for breast or cervical cancer. 4) Seven out of ten people over the age of 50 do not get colon cancer screening.
Independent prognostic value of the EORTC QLQ-C30 summary score on all-cause mortality: Results from the population-based PROFILES registry.
Authors: Olga Husson, Belle Hadewijch de Rooij, Jacobien M Kieffer, Simone Oerlemans, Floortje Mols, Neil K Aaronson, Winette T.A. Van Der Graaf, Lonneke van de Poll-Franse
Journal: Journal of Clinical Oncology (2018)

10070 Background: Health-related quality of life (HRQoL) has been shown to be a prognostic factor for cancer survival in randomized clinical trials. It is questioned whether this association also holds in the “real world” and which HRQoL scores as measured by the EORTC QLQ-C30 are the best prognosticators. The aims of the present observational, population-based study were to: (1) investigate the association of HRQoL with all-cause mortality; and (2) determine which QLQ-C30 scores (the summary score covering all HRQoL domains, the global QoL or the physical functioning scale) exhibits the strongest association with all-cause mortality. Methods: Between 2008 and 2015, cancer patients (colon, rectum, melanoma, basal/squamous cell, endometrial, ovarian, prostate, thyroid, Hodgkin, non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma) were invited to participate in PROFILES (‘Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship’) disease-specific registry studies (response 69%). In this secondary analysis on a collated patient sample with complete data (n = 6895) multivariate Cox proportional hazard regression models were used to analyze the association between the QLQ-C30 scores and all-cause mortality. Results: In the overall regression model including sociodemographic and clinical variables, the QLQ-C30 summary score was associated significantly with all-cause mortality (HR = 0.77; 95%CI = 0.72-0.82; p < 0.01). In stratified analyses, significant associations between the summary score and all-cause mortality were found for colon, rectal, prostate cancer, non-Hodgkin lymphoma, chronic lymphocytic leukemia and multiple myeloma only. The summary score had a stronger association with all-cause mortality than the global QoL (HR = 0.82; 95%CI = 0.78-0.85; p < 0.01) and the physical functioning scales (HR = 0.81; 95%CI = 0.78-0.84; p < 0.01). Conclusions: Our results indicate that, in a population-based setting, HRQoL, as assessed by the summary score of the QLQ-C30, has prognostic value for a number of cancer patient populations above and beyond that provided by clinical and sociodemographic variables.
P05.31 Plan quality of stereotactic radiosurgery in a multicenter phase III randomized trial in patients with 4 up to 10 brain metastases
Authors: D Hartgerink, A Swinnen, A Bruynzeel, C Hurkmans, D de Ruysscher, P van der Toorn, A Swaak, R Wiggenraad, L Veelen, J Verhoeff, A van der Geest, E Dieleman, A Jonkman, G Wester, J Zindler
Journal: Neuro-Oncology (2018)

Stereotactic radiosurgery is a promising treatment option for patients with multiple brain metastases (BM). A multicenter randomized phase III trial (NCT02353000) is ongoing in patients with 4 up to 10 BM to determine the palliative value of SRS compared to whole brain radiotherapy (WBRT). Optimal SRS plan quality is essential to minimize the risk of radionecrosis (RN) and thereby maintenance of quality of life. This study evaluates the possible differences in the plan quality of the participating radiotherapy centers. An anonymized planning-CT with three BM scenarios was sent to the participating centers to contour targets and make clinical SRS treatment plans. The first, second, and third scenario consisted of 7, 5, and 10 BM, 1x21 Gy, 1x18Gy, and 1x18Gy respectively. Planning Target Volume coverage should be V100≥99%. The maximum allowed gross tumor volume (GTV) to PTV margin was 2 mm. To assess SRS plan quality, the primary endpoint for this study was the Paddick gradient index (ratio of the volume of half the prescription isodose to the volume of the prescription isodose). Several secondary endpoints were calculated, such as the V12Gy of the largest BM (e.g. volume of healthy brain tissue which received 12 Gy or more). For all the endpoints the median and corresponding range were calculated. Data was available for nine centers for the first two scenarios and for eight centers for the third scenario. Eight centers used Volumetric Modulated Arc Therapy (VMAT) as their SRS technique and one center Cyberknife. Only once center used three fractions instead of a single fraction SRS. In the three scenario’s, the median Paddick gradient ranged from 3.5 up to 4.6, the poorest Paddick gradient index from 5.9 up to 7.4 and the optimal Paddick gradient index from 2.6 up to 3.1. Also variation was seen on other endpoints, such as the V12Gy of the largest BM. Clinical relevant variation is seen in SRS plan quality in the participating centers, expressed by the variation in the Paddick gradient index, V12 Gy and the mean PTV dose. A Paddick gradient of less than 3.0 generally reflects a favorable SRS plan quality. Centers are encouraged to further optimize SRS plan quality.
Percutaneous transhepatic biliary drainage in hepatopancreaticobiliary cancer: Contemporary efficacy.
Authors: Ravi Murthy, Varun Rachakonda, Armeen Mahvash, Steven Y Huang, Sharjeel H Sabir, Vivek Subbiah, Filip Janku, Ahmed Omar Kaseb, Milind M. Javle, Asha Murthy
Journal: Journal of Clinical Oncology (2016)

e21637 Background: Hepatopancreaticobiliary cancers (HPBC) are increasing in incidence worldwide with most incurable at diagnosis. Local HPBC progression invariably results in malignant biliary obstruction (MBO) leading to elevated serum excretory products, drug toxicity, pruritus, chemotherapy ineligibility, maldigestion & sepsis. Percutaneous transhepatic biliary drainage (PTBD)via a simple hollow multi-perforated 3-5mm catheteris used to passively divert bile in a gravity dependent fashion leading to dehydration, malnutrition & cancer cachexia. PTBD catheters are technologically unmodified for decades & frequently problematic; leaks, dislodgement & occlusion culminate in hospital admissions & even death. As HPBC incidence increases, the need for effective PTBD for MBO will also increase. We sought to elucidate the contemporary clinical efficacy of PTBD in HPBC pts. Methods: 99 (59M, mdn 62 yrs) consecutive locally advanced, post systemic therapy HPBC pts (pancreas 49, cholangioca 48, hepatocellular 2) who underwent PTBD insertion (62 pts post ERCP attempts & 25 endoprostheses) for MBO to address hyperbilirubinemia, cholangitis, pruritus & post insertion exchange for leaking, dislodgement & occlusion between 2013-2015. Results: 134 PTBD catheters (1-4/pt) were inserted & required 294 exchanges. Serum bilirubin ≤ 2mg/dl was achieved in 59 pts (pre-PTBD mdn 7.9mg/dl); only 19 pts received cancer therapy post-PTBD. Comorbidities precluded cancer therapy in the remaining 40 pts. 68 pts required an unscheduled PTBD catheter exchange (1-4/pt) for dysfunction; commonest was peri-catheter bile leak in 47 pts. 30 pts required admission specifically for PTBD-related dysfunction. Median survival post-PTBD was 74 ds. Conclusions: PTBD is effective to address HBPC MBO associated hyperbilirubinemia, but normalization was an unreliable prognostic indicator of cancer therapy eligibility due to worsening morbidities. Healthcare resource utilization was increased significantly by PTBD catheter-associated morbidity. The abrupt 47-75% decreases in 2016 Medicare PTBD CPT codes further supports the case for a strategic focus on improvements in patient selection and PTBD catheter function.
Pre-planned safety analysis of NORDIC 9: A randomized trial comparing full dose monotherapy (S-1) with reduced dose combination therapy (S-1/oxaliplatin) in older chemo-naive patients with metastatic colorectal cancer (mCRC).
Authors: Stine Brændegaard Winther, Pia J. Osterlund, Ake Berglund, Bengt Glimelius, Camilla Qvortrup, Halfdan Sorbye, Per Pfeiffer
Journal: Journal of Clinical Oncology (2017)

10032 Background: More than half of the patients (pts) diagnosed with mCRC are older, but they are underrepresented in clinical trials. Data about the best treatment strategy in pts who are not candidates for standard full-dose combination therapy is scanty. Here we present a preplanned safety analysis in the NORDIC 9 trial. Methods: NORDIC 9 explores treatment of older mCRC pts (≥70 years) who are not candidates for full-dose combination therapy. Pts receive full dose monotherapy (Arm A: S-1 30 mg/m 2 po bid day 1-14 q3w, followed by irinotecan upon progression or reduced dose (80%) combination therapy (Arm B: S-1 20 mg/m 2 po bid day 1-14 + oxaliplatin 100 mg/m 2 iv day 1 q3w, followed by reduced dose S-1 + irinotecan q3w). Bevacizumab (7.5 mg/kg iv day 1) may be added at the discretion of the treating clinician. Geriatric screening tools (eg G-8 and VES-13) and quality-of-life are evaluated at baseline. Blood samples and tumor tissue are prospectively collected. Primary endpoint is PFS. Secondary endpoints are correlations between the geriatric screening and safety but also efficacy. Results: The safety analysis was performed when 50 pts had received 3 cycles. 12 pts received bevacizumab. Median age was 79 (range 70-88) years, 26 pts were male, performance status was 0 (43%), 1 (38%) or 2 (19%). Five (10%) pts discontinued therapy after only 1 cycle due to toxicity (n = 2) or PD/clinical deterioration (n = 3); 45 pts (90%) continued therapy beyond 3 cycles. Pts receiving only 1 cycle had numerically a worse G-8 and VES-13 score. Grade 3-4 non-hematological toxicity was fatigue (6%), diarrhea (10%), nausea (4%) and vomiting (6%), and was experienced by 10 pts, 6 of them received ≥3 cycles of treatment. There was no hand-foot-syndrome, cardiac or hematological grade 3-4 toxicity. Dose intensity for S-1 was 0.98 (0.7-1.0) (arm A) and 0.93 (0.6-1.0) (Arm B), respectively, and for oxaliplatin 0.99 (0.4-1.0). Conclusions: The safety committee recommends to continue the trial without dose adjustments according to the original design. February 2017, 118 of planned 150 pts had been included. Clinical trial information: EudraCT no 2014-000394-39.
Molecular decision tree algorithms to predict individual recurrence pattern for locally advanced nasopharyngeal carcinoma.
Authors: XiangBo Wan, XinJuan Fan
Journal: Journal of Clinical Oncology (2016)

6046 Background: This study is to design multiple molecular and clinicopathological variable integrated decision tree algorithms to predict individual recurrence pattern patterns (with VS without recurrence) for locally advanced nasopharyngeal carcinoma (NPC). Methods: A total of 136 locally advanced NPC patients, originated from a randomized controlled phase III trial, was included. For each patient, the expression levels of 33 tumor biomarkers in tissue, 3 Epstein-Barr virus related serological antibody titer and 5 clinical clinicopathological variables, were collected to construct the decision tree algorithm. Three algorithm classifiers, augmented by the adaptive boosting algorithm for variable selection and classification, were designed to predict individual recurrence pattern. The classifiers were trained in the training subset and further tested using a 10-fold cross-validation scheme in the validation subset. Results: In total, the expression level of 13 molecules expression in tissue, including AKT1, Aurora-A, Bax, Bcl-2, N-Cadherin, CENP-H, HIF-1α, LMP-1, C-Met, MMP-2, MMP-9, Pontin and Stathmin, and N stage were selected to construct three 10-fold cross-validation decision tree classifiers. These classifiers displayed high predictive sensitivity (87.2-93.3%), specificity (69.0-100.0%), and overall accuracy (84.5-95.2%) to predict recurrence pattern individually. Multivariate analyses confirmed the decision tree classifier was an independent prognostic factor to predict individual recurrence (algorithm 1: HR 0.07, 95% CI 0.03-0.16, P < 0.01; algorithm 2: HR 0.13, 95% CI 0.04-0.44, P < 0.01; algorithm 3: HR 0.13, 95% CI 0.03-0.68, P = 0.02). Conclusions: Multiple molecular and clinicopathological variable integrated decision tree algorithms may individually predict the recurrence pattern for NPC. This decision tree algorism provides a potential tool to select patients with high recurrence risk for intensive follow-up, and to diagnose recurrence at an earlier stage for salvage treatment in the NPC endemic region.