tbuckley/cabot-search huggingface dataset:
Health-related quality of life (HRQoL) of pembrolizumab (pembro) vs chemotherapy (chemo) for previously treated advanced urothelial cancer (UC) in KEYNOTE-045.
Authors: Ronald De Wit, Dean F. Bajorin, Joaquim Bellmunt, Yves Fradet, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang, Miguel Ángel Climent, Daniel Peter Petrylak, Toni K. Choueiri, Andrea Necchi, Winald R. Gerritsen, Howard Gurney, David I. Quinn, Stephane Culine, Cora N. Sternberg, Yabing Mai, Haojie Li, Rodolfo F. Perini, David J. Vaughn
Journal: Journal of Clinical Oncology (2017)

4530 Background: In KEYNOTE-045 (NCT02256436) (N = 542), pembro 200 mg Q3W significantly improved OS over investigator’s choice of paclitaxel, docetaxel, or vinflunine as second-line therapy for advanced UC following platinum-based chemo (HR 0.73; P = 0.0022). Fewer treatment-related AEs were reported with pembro. We present results of the prespecified HRQoL analysis of KEYNOTE-045. Methods: The EORTC QLQ-C30 HRQoL instrument was administered electronically at cycles 1–4, then every 2 cycles for up to 1 y and 30 d after discontinuation. The key HRQoL end points were 1) change from baseline to wk 15 and 2) time to deterioration (TTD) (defined as ≥10-point decrease from baseline) in the QLQ-C30 global health status/QoL score. HRQoL was assessed in patients (pts) who received ≥1 dose of assigned study treatment and completed ≥1 HRQoL instrument (N = 520). Score change from baseline was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log-rank test and Cox proportional hazards model. Results: Baseline global health status/QoL scores were similar between arms. HRQoL compliance at wk 15 was 88% for both arms. From baseline to wk 15, scores were stable for pembro (n = 266) (least squares [LS] mean +0.75 [95% CI –2.34 to +3.83]) but worsened for chemo (n = 254) (LS mean –8.30 [95% CI –11.76 to –4.83]); the difference in LS means between arms was 9.05 (95% CI 4.61-13.48; nominal 2-sided P &lt; 0.001). At wk 15, pts without PD had improved scores with pembro but worsened scores with chemo (LS mean +5.97 vs –4.31), while pts with PD had less worsening with pembro (LS mean –3.54 vs –13.95). TTD was prolonged with pembro (HR 0.70; 95% CI 0.55-0.90; nominal 1-sided P = 0.002; median 3.5 mo vs 2.2 mo). Rates of improvement (defined as ≥10-point increase from baseline) at wk 15 were 31.2% with pembro and 22.0% with chemo; rates of deterioration were 28.9% and 40.6%, respectively. Conclusions: Pembro was associated with substantially better HRQoL for a longer duration than investigator-choice chemo in pts with previously treated advanced UC. Along with superior OS, these data support pembro as a new standard-of-care in this population. Clinical trial information: NCT02256436.
Clinical outcomes in patients receiving palbociclib + fulvestrant as first line treatment for ABC/MBC in real world settings in the United States.
Authors: John Waller, Debanjali Mitra, Gavin Taylor-Stokes, Katie Gibson, Gary Milligan, Shrividya Iyer
Journal: Journal of Clinical Oncology (2018)

e13041 Background: Palbociclib in combination with fulvestrant is approved in women with HR+/HER2- advanced/ metastatic breast cancer (ABC/ MBC) with disease progression following prior endocrine therapy. In this analysis we seek to assess the real world effectiveness of palbociclib + fulvestrant in women who had failed endocrine therapy in adjuvant settings and had received Palbociclib + fulvestrant as first line treatment for ABC/ MBC. Methods: Medical records of adult female patients in the US with HR+/HER2- ABC/MBC who received palbociclib + fulvestrant were reviewed by their treating physicians as part of the Ibrance Real World Insights (IRIS) study. Data on demographic and clinical characteristics, treatment patterns, and clinical outcomes were abstracted. Progression free rate and survival at 6 and 12 months were estimated via Kaplan-Meier analysis. Results: Medical records of 652 patients receiving palbociclib were abstracted by 65 physicians, of which 63.1% were from community settings. Of the 292 patients who received palbociclib + fulvestrant, 106 patients (36.3%) received it as first line treatment for ABC/ MBC. The mean (SD) age of patients at palbociclib initiation was 60.8 (13.2) years (median, 62.0 years) and ECOG performance status was mostly 0 (37.7%) or 1 (42.5%). Visceral disease was seen in 40.8% of patients and 78.9% of patients had bone metastases. The median duration between initial breast cancer diagnosis and ABC/ MBC diagnosis was 42.9 months. Most patients (77.4%) started at an initial dose of 125 mg/ day, while 12.3% and 10.4% started at 100 mg/ day and 75 mg/ day respectively. Dose reductions were seen in 14 patients (13.2%). Based on physician assessment, the majority of patients (75.9%) had partial response or stable disease. The 6 and 12 month progression free rates were 97.1% and 89.6% respectively. The survival rates at 6 and 12 months were 100% and 91.1% respectively. Conclusions: Rate of dose reductions for palbociclib in clinical practice was found to be low. Palbociclib + fulvestrant appears to be effective and well tolerated in first line ABC/ MBC settings in women who have previously failed endocrine therapy. Funding: Pfizer, Inc
Inhibition of mTORC1 in pediatric low-grade glioma depletes glutathione and therapeutically synergizes with carboplatin
Authors: Brad Poore, Ming Yuan, Antje Arnold, Antoinette Price, Jesse Alt, Jeffrey A Rubens, Barbara S Slusher, Charles G Eberhart, Eric H Raabe
Journal: Neuro-Oncology (2018)

Pediatric low-grade glioma (pLGG) often initially responds to front-line therapies such as carboplatin, but more than 50% of treated tumors eventually progress and require additional therapy. With the discovery that pLGG often contains mammalian target of rapamycin (mTOR) activation, new treatment modalities and combinations are now possible for patients. The purpose of this study was to determine if carboplatin is synergistic with the mTOR complex 1 inhibitor everolimus in pLGG.We treated 4 pLGG cell lines and 1 patient-derived xenograft line representing various pLGG genotypes, including neurofibromatosis type 1 loss, proto-oncogene B-Raf (BRAF)-KIAA1549 fusion, and BRAFV600E mutation, with carboplatin and/or everolimus and performed assays for growth, cell proliferation, and cell death. Immunohistochemistry as well as in vivo and in vitro metabolomics studies were also performed.Carboplatin synergized with everolimus in all of our 4 pLGG cell lines (combination index <1 at Fa 0.5). Combination therapy was superior at inhibiting tumor growth in vivo. Combination treatment increased levels of apoptosis as well as gamma-H2AX phosphorylation compared with either agent alone. Everolimus treatment suppressed the conversion of glutamine and glutamate into glutathione both in vitro and in vivo. Exogenous glutathione reversed the effects of carboplatin and everolimus.The combination of carboplatin and everolimus was effective at inducing cell death and slowing tumor growth in pLGG models. Everolimus decreased the amount of available glutathione inside the cell, preventing the detoxification of carboplatin and inducing increased DNA damage and apoptosis.
Increased detection of germline cancer susceptibility mutations subsequent to tumor profiling.
Authors: Virginia Speare, Alexandria Meyer, Patrick Reineke, Holly LaDuca
Journal: Journal of Clinical Oncology (2018)

e13613 Background: In addition to guiding targeted therapy, tumor profiling may incidentally reveal germline mutations leading to the diagnosis of hereditary cancer predisposition. When somatic and germline analysis is performed in tandem, 4-13% of patients are found to carry a mutation in a cancer-susceptibility gene. However, the rate of pathogenic mutations is significantly higher (17.5%) when germline testing is performed subsequent to tumor profiling. We sought to examine the frequency and clinical significance of germline testing subsequent to tumor profiling when performed at separate laboratories. Methods: Retrospective review of a laboratory database revealed 175 germline test orders following reported external somatic tumor analysis between June 2014 and April 2017. A description of the patient’s tumor, including associated somatic mutations, was obtained from test requisitions. Germline targeted sequencing was performed with DNA isolated from blood or saliva. Pathogenic and likely pathogenic mutations identified in hereditary cancer predisposition genes were included for analysis. Results: Of 175 germline test orders subsequent to molecular tumor profiling, 46 patients (26.3%) were found to carry one or more germline mutation(s) in a hereditary cancer predisposition gene. Of those, 42 (91.3%) of the patients’ results were concordant with the somatic mutations detected in their tumor. The remaining 4 patients (2.3% of the total population) had germline mutations detected with no corresponding somatic alteration detected in their tumor. Conclusions: The pathogenic mutation rate in this cohort (26.3%) is higher than that typically seen for patients referred for germline testing based on clinical criteria, demonstrating the importance of confirmatory germline testing following tumor profiling. These results also demonstrate the potential for germline testing to identify mutations not indicated by tumor profiling. The detection of pathogenic germline mutations may indicate different medical management guidelines for patients as compared to the finding of somatic tumor profiling alone, and therefore optimal management is achieved when results of both are provided.
Impact of a comprehensive geriatric assessment to manage elderly patients with locally advanced non-small-cell lung cancers: An open phase II study using concurrent cisplatin - oral vinorelbine and radiotherapy (GFPC 08-06).
Authors: Hervé Le Caer, Nicolas Pourel, Henri Berard, Jean-Bernard Auliac, Isabelle Monnet, Renaud Descourt, Alain Vergnenegre, Isabelle Martel Lafay, Laurent Greillier, Christos Chouaid, Chrystele Locher
Journal: Journal of Clinical Oncology (2018)

e20513 Background: Few data have been published on the optimal management of elderly patients with locally advanced non-small–cell lung cancers (La-NSCLC). This prospective, multicenter, phase II study was undertaken to evaluate the ability of a comprehensive geriatric assessment (CGA) to select the elderly La-NSCLC patients who potentially may benefit from concurrent radio-chemotherapy. Methods: The main inclusion criteria were: La-NSCLC, > 70 years old, at least one measurable target, ECOG performance status (PS) 0/1 and normal CGA. Weekly cisplatin (30 mg/m²) and oral vinorelbine (30 mg/m2) were combined with standard thoracic radiotherapy (66 Gy, 33 fractions) for 6.5 weeks. The primary evaluation criterion was < 15% of patients with (on compte le nombre de patient ayant présenté une toxicité et non le nombre de toxicité) clinically relevant grade > 2 toxicity. Secondary criteria were response rates, overall survival (OS) and progression-free survival (PFS). Results: Among the 49 patients screened, 40 were included: 87.5% men, median age: 74 (70-84) years, 67.5% with PS 0, 52.5% squamous cell carcinomas. The full concurrent regimen was administrated in 77.5% of the cases (chemotherapy: 85%, radiotherapy: 90%); 27.5% of the patients experienced toxicity grade > 2 (with three treatment-imputed deaths), 17.5% when restricted to clinically relevant > 2 grade toxicities. One (2.6%) patient achieved a complete response, 53.8% had partial responses and 35.9% stable disease. Median PFS was 15 (95%CI: 8,7 - 35,2) months, OS 21.8 (95%CI: 16 – NR) months and 1-, 2- and 4-year survival rates were 77.5%, 45% and 34.8%. Conclusions: CGA was able to select elderly patients with La-NSCLCs eligible for concurrent chemoradiotherapy with a satisfactory risk/benefit ratio. Clinical trial information: NCT01029678.
Computer extracted features of gland morphology on H&E surgically resected tissue images as predictive of biochemical recurrence and rate of expression in African American compared to Caucasian American men.
Authors: Patrick Leo, Nafiseh Janaki, Rajat Thawani, Robin Elliott, Sanjay Gupta, Natalie Shih, Michael D Feldman, Anant Madabhushi
Journal: Journal of Clinical Oncology (2017)

e16559 Background: Prostate cancer (PCa) is 1.7 times more prevalent and 2.3 times more lethal in African American (AA) men than in Caucasian American (CA) men. Additionally there is a higher incidence (when controlling for relative population size) of more aggressive PCa in the AA compared to the CA population which has led a number of groups to investigate whether there are molecular differences in the disease phenotype between the two groups. In this work we investigate whether computer extracted features of glandular morphology from digitized pathology images of surgical specimens identified as predictive of biochemical recurrence are also differentially expressed between AA and CA patients. Methods: Two cohorts were gathered. Cohort 1 (C1) contained digitized whole mount Gleason 7 radical prostatectomy specimens (RPS) from 72 patients (46 CA, 26 AA). Cohort 2 (C2) comprising quarter and whole mount RPS from 145 patients (135 CA, 10 AA), who either had biochemical recurrence in 5 years (47) or did not (98). A pathologist annotated each image in both cohorts for a representative cancerous region. Glands were automatically segmented and 216 features describing gland arrangement, shape, and disorder were extracted from every image. Features were tested for significance by Wilcoxon rank sum test at p &lt; .05. Results: 8 features of gland morphology were significantly different between AA and CA groups and also predictive of biochemical recurrence (Table). Conclusions: We identified 8 computer extracted features of gland morphology that were both differentially expressed between AA and CA men and predictive of biochemical recurrence, suggesting that there are histomorphometric differences in prostate cancer appearance between AA and CA men. [Table: see text]
Effect of Wnt5a on aggressiveness of ER-positive breast cancer and cancer cell migration through JNK-ALCAM pathway.
Authors: Yoshie Kobayashi, Takayuki Kadoya, Ai Amioka, Noriko Gohda, Miho Kono, Shinsuke Sasada, Keiko Kajitani, Norio Masumoto, Morihito Okada
Journal: Journal of Clinical Oncology (2017)

11614 Background: Wnt5a is a representative ligand that activates β-catenin-independent pathways and involved in cell motility and cell polarity, and the like, being mediated by JNK. We elucidated the implication of Wnt5a expression in breast cancer. Methods: One hundred seventy eight breast cancer patients (mean age ± SD: 60.0 ± 13.2 years) with clinical Stage I-III between January 2011 and February 2014, were prospectively evaluated. We examined relationships between Wnt5a expression and clinicopathological factors by immunohistochemical analyses. 5-year relapse-free survival rates and sites of recurrence were analyzed. In addition, molecules induced by Wnt5a in cultured cells were identified by DNA microarray analysis. Results: Wnt5a expression was significantly more frequent when estrogen receptor (ER) was present, 68/153 (44%) than when ER was absent, 1/25 (4%) (P &lt;0.001) (Table). In ER-positive breast cancer, a significant interaction between expression of Wnt5a with lymph node metastasis (P&lt;0.001), high nuclear grade (P=0.004), and lymphatic invasion (P=0.001). 5-year relapse-free survival rates were 81.1% and 100% in Wnt5a-positive and Wnt5a-negative breast cancers, respectively (P = 0.024). All recurrent breast cancer patients in this study had bone metastasis. We established MCF7 stably expressing Wnt5a (Wnt5a/MCF7 cells) and microarray analyses identified several genes induced by Wnt5a (&gt;3.0 fold), involving activated leukocyte cell adhesion molecule (ALCAM). ALCAM is known to be related with apoptosis, invasion and prognosis of breast cancer. We focused on ALCAM and investigated its protein expression by Western blotting, and found remarkable increase of ALCAM in Wnt5a/MCF7 cells. Conclusions: Wnt5a expresses in ER-positive breast cancer and is associated with high-grade malignancy and a poor prognosis through JNK-ALCAM pathway. Wnt5a could be a novel prognostic factor of ER-positive breast cancer. [Table: see text]
Health care utilization and end of life care in patients with primary malignant brain tumors.
Authors: Sunil Mahesh Bhatt, Areej El-Jawahri, Ryan David Nipp, Tracy Batchelor, Jennifer S. Temel, Deborah Anne Forst
Journal: Journal of Clinical Oncology (2018)

e14072 Background: Patients with primary malignant brain tumors experience high symptom burden and short overall survival. However, their utilization of health care services at the end of life is not well characterized. Methods: We conducted a single-center, retrospective analysis of deceased patients diagnosed with primary malignant brain tumors between 1/1/12 and 8/31/15. We assessed health care utilization at the end of life including hospitalizations, chemotherapy use, intensive care unit (ICU) admissions, utilization of palliative care services and hospice enrollment. Results: We analyzed data from 200 consecutive patients with primary malignant brain tumors. Most (84%, 168) had a diagnosis of glioblastoma. The majority of patients were white (92%, 184), non-Hispanic (83%, 166), and male (59%, 117). The median survival for the cohort was 14 months. The median number of unplanned hospitalizations from diagnosis until death was 2 (range 0-9), with 83% (166) having at least one unplanned hospitalization. In the last 30 days of life, 32% (64) of patients were hospitalized and 7% (14) were admitted to the ICU. A small minority (7%, 14) died in the hospital. During the last 30 days of life, 22% (44) of patients received chemotherapy. Notably, only 29% (58) of patients ever received a palliative care consultation, with 76% (44/58) of consultations occurring in the inpatient setting. The median time from palliative care consultation to death was 32 days (range 0-354). Most patients were enrolled in hospice prior to death (77%, 153), with a median length of stay in hospice of 24 days (range 0-399). The majority of patients (56%, 111) died at home, while 29% (58) died in a skilled nursing or hospice facility. Conclusions: Patients with primary malignant brain tumors have a short life expectancy and significant health care utilization at the end of life. Despite their poor prognosis and the high symptom burden documented in this population, palliative care consultations occur infrequently and late in the disease course. Interventions are needed to reduce health care utilization and increase earlier use of palliative care for these patients.
Prognosis of thoracic radiation-induced metastatic NSCLC.
Authors: Marie Florescu, Normand Blais, Mustapha Tehfe, Ariana Mustillo
Journal: Journal of Clinical Oncology (2018)

e21095 Background: Radiation is known to be the main risk factor for secondary malignancies. However, metastatic lung cancer prognosis when thoracic radiation was previously given is unknown. Methods: The OACIS and SARDO patient databases were used to identify 1365 patients who received treatment at the University Health Center in Montreal (CHUM) hospital for metastatic NSCLC between 2006 and 2014. To control for genetic susceptibility, we divided our population in three groups. Group A: patients who received previous thoracic radiation, group B: patients with previous cancer but no thoracic radiation, group C: metastatic lung cancer with no history of cancer or thoracic radiation. Results: In group A, the most frequent cancer that received thoracic radiation previously was breast cancer (42%). In group B, the most frequent cancer treated without thoracic radiation was genito-urinary tract cancers (prostate cancer 43%). Group A had the best mOS 8 months compared to group B 6 months and to group C 4 months (P = 0.005). In group A only, women had significantly longer mOS (12 months) than men (5 months) (P = 0.026), but not in groups B and C. Only. 65% of patients of our population received systemic treatment with no difference between groups. Amongst treated patients, the mOS was significantly higher in group A (14 months) compared to group B (9 months) and group C (7 months) (P = 0.015). There was no significant PFS difference between the groups (8 months vs. 6 months vs. 6 months; P = 0.05). Conclusions: Surprisingly, previous thoracic radiation before metastatic lung cancer had a better prognosis than patients with genetic susceptibility to cancer or the control arm with no previous cancer that developed metastatic lung cancer. Radiation-related lung cancer should not be an obstacle to treat these population with aggressive treatment.
Prospective study on the role of cytidine deaminase activity in lung cancer patients treated with gemcitabine-platinum-based chemotherapy.
Authors: Elisa Giovannetti, Marcello Tiseo, Richard J. Honeywell, Luca Boni, Myriam Chartoire, Andrea Camerini, Francesca Mazzoni, Fausto Barbieri, Isabella Vittimberga, Godefridus J. Peters, Christian Diego Rolfo, Carmelo Tibaldi
Journal: Journal of Clinical Oncology (2018)

e24078 Background: Cytidine deaminase (CDA) plays a crucial role in gemcitabine degradation. In previous mono-/multi-center retrospective studies CDA activity emerged as the strongest biomarker of activity and efficacy of platinum-gemcitabine-based chemotherapy in NSCLC pts. Within an EORTC-PAMM collaboration we validated a spectrophotometric assay for a reliable measurement of CDA. Then, we planned the present multicenter prospective study to demonstrate a response rate of 40% in the group of pts with low CDA activity versus 14% in the group with high activity and to demonstrate a relative reduction of progression or death by at least 50% (HR = 0.5). Methods: CDA activity was measured in plasma from 121 stage-IIIB/IV NSCLC pts treated with gemcitabine-cisplatin/carboplatin, enrolled from 9 hospitals. Responses were assessed by CT-scan every 3 cycles using RECIST-1.1. Data were analyzed by t-test, log-rank test and Cox proportional hazards models. Results: The distribution of CDA levels according to optimal and median distribution cut-off levels (8.35 and 7.20 U/mg, respectively), showed that high activity correlated with response (25 vs. 54.1%, P = 0.0015) as well as with significantly shorter OS (8.9 months (95%CI, 7.5-10.3), vs. 16.4 months (95%CI, 13.0-19.9, P < 0.001)). Similar data were observed for PFS. The multivariate analysis confirmed the prognostic significance of CDA activity. Data on toxicity are undergoing extensive examination. Conclusions: Recent advances for NSCLC treatment have been obtained through the discovery of targeted drugs or immunotherapeutic approaches, highly active in selected subgroup of patients. However, a challenge of research is to find predictive biomarkers of efficacy for established chemotherapy regimens. This is the first prospective evidence about the predictive role of CDA enzymatic activity in terms of outcome in patients treated with gemcitabine-based chemotherapy. These results can have important clinical applications, such as guiding the choice of alternative chemotherapeutic regimen and/or the modulation of the dose of gemcitabine according to CDA activity.