tbuckley/cabot-search huggingface dataset:
Poor prognosis of triple negative phenotype in endometrial cancer patients.
Authors: Rosa Porzio, Claudia Cordini, Francesca Brigati, Annamaria Rodolfi, Manuela Proietto, Carlo Paties, Camilla di Nunzio, Luigi Cavanna
Journal: Journal of Clinical Oncology (2016)

e17112 Background: Like breast cancer, endometrial cancer can be divided into subgroups based on immunohistochemical markers such as estrogen receptors (ER), progesterone receptors (PR) and HER2. Actually, these markers have no predictive or prognostic value. The objective of this study is to evaluate the prognostic significance of triple negative phenotype (TNP) of endometrial cancer patients. Methods: This is a retrospective study and includes 220 cases of endometrial cancer of patients who underwent to surgery at the Guglielmo da Saliceto Hospital of Piacenza between years 2000 and 2010. Surgical specimens were revised and tested for ER, PR and HER2 expression. Fluorescent in-situ hybridation (FISH) was also used to test HER2 amplification according to breast cancer guidelines. Pearson’s chi-square was used to evaluate the association of the TNP with variables associated with a poor prognosis. Overall survival (OS) was analyzed with Kaplan-Meier curves. Results: twelve percent of patients had the TNP. These patients showed correlation with high grade disease (50%), myometrial invasion ( > 50%) (42.3%), non endometrial histology including clear cell and papillary serous carcinoma (42.3%) compared to TNP negative (p < 0.005 for all). The progression free survival (PFS) and OS were significantly worse in TNP. The 5 year OS rate was 50% in TNP compared to 90% in control group (p < 0.005). Conclusions: In this study TNP correlate with poor prognostic factors: high grade disease, myometrial invasion high, risk histology as well as advanced disease. This subgroup showed more aggressive behavior was associated with significantly shorter OS. Similarity to breast cancer the correlation between the TNP and poor prognosis could potentially predict a lack of response to specific therapies also in endometrial cancer. It is imaginable that the molecular phenotype in TNP in these disease may lead to good responses to novel class of antineoplastic agents such as PARP inhibitor similarity to breast cancer. Moreover we suggest that adjuvant therapy could be personalized on receptor status.
Prognostic value of histopathological tumor-stroma ratio and a stromal gene expression signature in human solid tumors.
Authors: Jakob Nikolas Kather, Pornpimol Charoentong, Inka Zoernig, Dirk Jaeger, Niels Halama
Journal: Journal of Clinical Oncology (2018)

e24113 Background: Cancer-associated fibroblasts have a major impact on tumor growth, tumor evolution and immune escape. Generally, a high percentage of fibrotic stroma is reported to negatively impact clinical outcome. Published studies have used diverse methods to quantify stromal abundance, including gene expression signatures of cancer-associated fibroblasts (CAF) and subjective scoring of stromal percentage in histopathological tissue slides. To our knowledge, there is no systematic pan-cancer analysis of CAF signatures versus histopathological tumor-stroma ratio. Methods: We have analyzed data from The Cancer Genome Atlas (TCGA) cohort, comprising 5692 patients with 20 different cancer entities. We used publicly available histopathological annotations of tumor-stroma ratio as well as a CAF gene expression signature and analyzed their relation to overall survival at different cutoff levels. Results: Setting the cutoff at the median CAF score, a high CAF score was significantly (p < 0.05) associated with poor overall survival (OS) in bladder cancer (BLCA) and papillary kidney cancer (KIRP) but not in any of the other 18 investigated cancer entities. Setting the cutoff at the 75th percentile, a high CAF score was significantly associated with poor OS in colorectal cancer (CRC), but not in any of the other 19 entities. Using histopathological annotations of tissue sections, a stroma percentage above median was significantly associated with poor OS in colorectal cancer (CRC), but not in any other tumor type. Setting the cutoff at the 75th percentile, high stroma was again significantly associated with poor OS in CRC, but not in any other tumor type. Interestingly high stroma was significantly (p < 0.05) associated with longer OS in breast cancer (BRCA) in this analysis. Conclusions: A high stroma-tumor ratio and a high CAF gene expression signature are consistently associated with poor overall survival in CRC. For other tumor types, gene expression analysis and histopathological scoring yields diverging results. These results highlight the complex role of stroma in human solid tumors. There is a need for better morphological and functional characterization of the stromal compartment.
Identification of exosomal proteins from a prostate cancer cell line by Adaptive Dynamic Artificial Polyligand Targeting (ADAPT).
Authors: Tassilo Hornung, Stephen C. Logie, Aniket S. Bondre, Jelena Zarkovic, Teresa T. Tinder, Varun Maher, Melissa N. Richards, Heather A. O'Neill, Mark Robert Miglarese, David Spetzler
Journal: Journal of Clinical Oncology (2016)

e23050 Background: Exosomes are small (40 – 100 nm) vesicles secreted by various cell types detected in a multitude of body fluids. Exosomes have protein profiles characteristic of their cells of origin and play a role in cell-to-cell communication making them attractive targets to identify early disease stage biomarkers. Due to the heterogeneity of cancer, it is unlikely to find a single cancer marker that will identify the majority of individuals with a morphologically-defined cancer type. We developed the highly multiplexed ADAPT platform to capture systems-based biological signatures that may reflect the molecular heterogeneity of various cancer types. Exosomes from two prostate cancer cell lines, VCaP and LNCaP, were used to train ssDNA libraries to discriminate them. Methods: A library of 1012 oligonucleotides (ODNs) was subjected to five rounds of positive and negative selection against exosomes from VCaP and LNCaP prostate cancer cell lines. From the remaining ~3x105 sequences, ODNs that were bound preferably to exosomes from VCaP cells were identified by NGS. A subset of individual ODNs was resynthesized and binding of co-precipitated ODNs to VCaP exosomes was verified by qPCR. ODN-bound proteins were identified by affinity purification and LC-MS/MS. Results: Cognate binding partners of ODNs bound to VCaP exosomes were identified, including ESCRT endosomal sorting proteins (CHMP1b/2a/4b, VPS28, Syntenin-1). Components of ESCRT participate in exosomes biogenesis and are overexpressed in human cancers. In addition, we found the chemokine I-TAC, which is overexpressed in blood and tissue of men with advanced prostate adenocarcinomas. Finally, we identified hnRNP-1, a cancer associated splicing factor, and the cold shock proteins RNPL and A18 hnRNP. Knock-down of these cold shock proteins has been shown to enhance chemotherapeutic cell killing of prostate cells. Conclusions: ADAPT is an unbiased profiling platform that identifies cancer associated proteins expressed on exosomes. This platform can be deployed against multiple cancer types and offers broad potential applications in biomarker discovery.
Multicenter Phase II Study of Lurbinectedin in <i>BRCA</i>-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy
Authors: Cristina Cruz, Alba Llop-Guevara, Judy E. Garber, Banu K. Arun, José A. Pérez Fidalgo, Ana Lluch, Melinda L. Telli, Cristian Fernández, Carmen Kahatt, Carlos M. Galmarini, Arturo Soto-Matos, Vicente Alfaro, Aitor Pérez de la Haza, Susan M. Domchek, Silvia Antolin, Linda Vahdat, Nadine M. Tung, Rafael Lopez, Joaquín Arribas, Ana Vivancos, José Baselga, Violeta Serra, Judith Balmaña, Steven J. Isakoff
Journal: Journal of Clinical Oncology (2018)

This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance.Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors.ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts.Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.
A phase I study of chemo-radiotherapy with plerixafor for newly diagnosed glioblastoma (GB).
Authors: Reena Parada Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Zachary Corbin, Linda Wei Xu, Cathy Kahn Recht, Sophie Bertrand, Vani Jain, Brenda Acevedo, Martin Brown, Lawrence David Recht
Journal: Journal of Clinical Oncology (2016)

2068 Background: Preclinical studies indicate that local recurrence after radiotherapy (RT) of Glioblastoma is dependent on recovery of tumor vasculature following RT via hypoxia-driven SDF-1 (CXCL12) secretion. We hypothesize that blocking the CXCL12/CXCR4 axis would improve local control. Methods: Newly diagnosed Glioblastoma patients were recruited to this Phase I study of a 4 week intravenous infusion of Plerixafor (Mozobil), a CXCR4 antagonist, with concurrent Temozolomide (TMZ) and radiation therapy. Three patients were treated with Plerixafor at 8.3 µg/kg/hr and six patients at 16.6 µg/kg/hr, while being monitored for dose limiting toxicities (DLTs) including grade ≥ 3 hematologic or non-hematologic adverse events. Patients underwent dynamic susceptibility contrast perfusion MRI (DSC-MRI) for quantification of relative cerebral blood volume (rCBV) values by region-of-interest analysis. Pharmacokinetic (PK) analysis of Plerixafor plasma levels were collected. Results: Since August 2014, 9 patients completed therapy with upfront RT/TMZ and Plerixafor with no DLTs observed, leading to the recommended phase II dose of 16.6 µg/kg/hr. Currently, 7 of 9 patients are alive, with the longest survival since diagnosis being 18 months. Plasma Plerixafor levels reached our target of 100 ng/ml at the first time point, 7 days into therapy. DSC-MRI at 1 and 6 months post-RT revealed lower rCBV in the tumor bed compared to the postoperative pre-RT scan (P < 0.02, one way ANOVA). Conclusions: Plerixafor was safely escalated to the target dose of 16.6 µg/kg/hr with no DLTs observed. A marked decrease in rCBV in the radiation treatment field suggests enhanced local treatment effect in support of our hypothesis that inhibition of the SDF1/CXCL4-mediated vasculogenesis pathway in the post-RT period enhances radiation. Recruitment into the phase II study is ongoing to evaluate these preliminary observations. Clinical trial information: NCT01977677.
Evaluation of self-reported symptoms and interference issues in patients with prostate cancer.
Authors: Mahdi Taha
Journal: Journal of Clinical Oncology (2017)

e16547 Background: Prostate cancer (PC) is a leading cause of global mortality and is expected to become the leading cause of death among men in the U.S.A. Both the disease and its treatments produce a variety of symptoms (sx) that impact PC outcomes, of which the more common sxs are in relation to sexual dysfunction. A large body of literature has established that systematic patient (pt) reporting of symptoms during routine oncology care leads to clinical benefits. At our comprehensive cancer center we evaluate pts’ reported sxs using the Symptom Inventory Tool (SIT), an assessment (asst) tool that captures the pts’ perceived sx burden for real-time clinical intervention taken at the point of no intervention (baseline) and every ≥ 21 days thereafter. Methods: The 27-question SIT is comprised of the M.D. Anderson Symptom Inventory Tool (MDASI), a validated asst instrument, with 8 supplementary questions by Cancer Treatment Centers of America (CTCA). Sxs are rated “at the worst” on a numeric scale ranging from 0 (“none present”) to 10 (“as bad as you can imagine”), as experienced by pts in the past 24 hours. Results: Over a 45 month period (9/1/2012 to 05/31/2016), PC pts at CTCA completed the SIT at intake and again ≥ 21 days after. A total of 2,937 assts were analyzed. The assts consisted of 1,065 completed at baseline (BL), 1,065 completed at the 2nd follow up (FU), and 807 completed at 3rd FU or greater. BL mean, standard deviation (STD), and interquartile ranges (IQR) are shown in Table 1. Further analysis of assts identified that pts who rated their sxs as “very burdensome” (≥ 5) at BL would be more likely to report a significant decrease (dec) in their sxs burden than the average PC pt population. Conclusions: The SIT was successful in identifying sxs burden and interference with life issues in PC pts. Sexual dysfunction and disturbed sleep were the most common reported sxs. Early identification of pts with heavy sx-burden allowed immediate intervention and improvement in 1/4 to 2/3 of pts. [Table: see text]
18F-RGD PET/CT maybe useful to predict antiangiogenic response and adverse events.
Authors: Li Li, Shuanghu Yuan
Journal: Journal of Clinical Oncology (2018)

e24024 Background: No currently clinically recognized biomarkers can predict the efficacy of antiangiogenic therapy, this trail aims to explore response and adverse events of antiangiogenic therapy using 18F-ALF-NOTA-PRGD2 (RGD) PET/CT. Methods: Patients with measurable lesions scheduled for second- or third-line single agent of apatinib therapy were prospectively enrolled in the trail. All patients underwent 18F-RGD PET/CT pretreatment. Standardized uptake values (SUV) were obtained in regions of interest (ROIs) of tumors and normal structures. The ndependent sample T test, the Mann-Whitney U Test, the receiver-operating characteristic (ROC) curve analysis and Kaplan-Meier method were used. Results: Thirty-eight patients were included in the study. After the follow-up, 25 qualified patients with 42 measurable lesions were included in statistical analysis. The median follow-up time was 3 months (range 1-10). The median PFS was 3 months (95% confidence interval [CI], 1.04 to 4.96). SUVpeak and SUVmean in lesions were significantly higher in responders than in non-responders (4.98±2.34 vs. 2.99, 1.90, P = 0.048; 3.06, 2.22 vs. 2.95±0.49, P = 0.036). According to ROC curve analysis, SUVmean (AUC = 0.700) was better parameter for predicting response. Using threshold value of 3.82, high SUVmean was associated with improved progression free survival (PFS) (5.0 vs. 3.4 months, log-rank P = 0.036). The most frequently occurred AEs were fatigue, hypertension (HPS), nausea. Metabolic uptakes of thyroid (SUVthyroid), liver (SUVliver), cardia (SUVcardia), stomach body (SUVstomach body), stomach pyloric portion (SUV stomach pyloric portion) and spleen (SUVspleen) were predictive for fatigue, HPS and nausea. According to ROC curve analysis, the most significant predicting couples were 18F-RGD SUVmax-liver (AUC = 0.832) and fatigue, SUVmax-spleen (AUC = 0.743) and HPS, SUVmax-cardia (AUC = 0.908) and nausea, respectively. The threshold of SUVmax-liver, SUVmax-spleen and SUVmax-cardia were 4.57, 6.41 and 2.2, respectively. Conclusions: In summary, on the basis of the findings of this study, high lesional RGD uptakes indicated better response and high RGD uptakes of normal structures revealed less AEs during aptinib therapy.
Prospective blinded evaluation predicting efficacy of adjuvant cisplatinum and vinorelbine by a multigene assay after radical surgery in non-small cell lung cancer.
Authors: Ida Kappel Buhl, Eric Santoni-Rugiu, Jesper Ravn, Anker Hansen, Ib Jarle Christensen, Thomas Jensen, Peter Buhl Jensen, Jon Askaa, Steen Knudsen, Jens Benn Soerensen
Journal: Journal of Clinical Oncology (2016)

e20007 Background: This study evaluated the predictive effect of a mRNA-based Drug Response Predictor DRP in the adjuvant setting of non-small cell lung cancer (NSCLC). We apply a mathematical method combining in vitro sensitivity with gene expression patterns in tumors (Knudsen et al PLoS ONE 2014 9(2): e87415.). The cisplatinum DRP has previously been tested in three independent datasets (ASCO Abstract 2015 e18502). Methods: RNA was isolated from formalin-fixed paraffin embedded tumor tissue obtained after radical surgical resection in 95 consecutive stage Ib-IIIb NSCLC patients of different histotypes. Adjuvant chemotherapy was four courses of i.v. cisplatinum and vinorelbine. Affymetrix HG-133_Plus_2 microarray method was applied. Multigene biomarker profiles for cisplatinum and vinorelbine were evaluated blinded on the samples. Primary endpoint was overall survival (OS). Results: Baseline demographics are representative of a NSCLC population. Follow-up time was in median 76.6 months (range 3.5-7 years) after surgery. Statistical analysis suggested that time-dependent analysis of OS was warranted. Using a time dependent Cox model stratifying at 3 years, the hazard ratio (HR) for OS up to 3 years was 0.50 (95% CI: 0.30-0.84, p = 0.008) and the HR for cancer-specific death was 0.46 (95% CI: 0.27-0.78, p = 0.004). Results for multivariable analyses for OS are shown in the table. The DRP remained significant in the multivariable analysis for each endpoint. Conclusions: The DRP for the combined cisplatinum and vinorelbine adjuvant treatment of resectable NSCLC offers definite prediction of effect of the two drugs since it is significant within 36 months after surgery. Clinical trial information: HB-2007-099.Covariate Hazard ratio (95 % CI) P-value DRP < 36 months 0.49 (0.28-0.86) 0.013 DRP > 36 months 1.26 (0.76-2.10) 0.38 Stage II vs I 3.20 (1.46-7.02) 0.004 Stage III vs I 4.08 (1.72-9.70) 0.001 Age/10 year difference 1.52 (0.99-2.33) 0.053 Gender M vs F 1.04 (0.53-2.03) 0.92 Histology* ASCC 0.22 (0.05-0.98) 0.047 Histology* Other 1.48 (0.48-4.55) 0.49 Histology* SCC 0.37 (0.12-1.14) 0.08 *Vs. adenocarcinoma. ASCC = adenosquamous cell carcinoma, SCC = squamous cell carcinoma.
The role of diffusion tensor imaging for non-invasive IDH phenotyping in gliomas.
Authors: Diana Roettger, Jialin Yuan, Laura Mancini, Steffi Thust, Sebastian Brandner, Jeremy Rees, Andrew McEvoy, Sotirios Bisdas
Journal: Journal of Clinical Oncology (2018)

e24174 Background: Isocitrate dehydrogenase (IDH) mutant type gliomas are strongly associated with better prognosis comparing to IDH wild-type gliomas. Our research explored whether diffusion tensor imaging (DTI) metrics can differentiate IDH mutation status in gliomas. Methods: We retrospectively reviewed 76 IDH mutant type and 27 IDH wild-type gliomas histopathologically verified with pre-treatment DTI. Fractional anisotropy (FA) and mean diffusivity (MD) values were obtained for each voxel of the segmented tumours. We used either Welch two sample t-test or Wilcoxon rank sum test depending on the underlying distribution to filter out histogram parameters of FA and MD maps that correlated with IDH mutation status. To calculate the optimal thresholds, we used receiver operating characteristic analysis. Results: Among the histogram parameters, the MD median value was significantly higher and the FA median value was significantly lower in the IDH mutant group compared to the IDH wild-type group. The MD median value was a robust predictor for IDH mutation status [area under the curve (AUC) = 0.82]. Our logistic regression model, which combined the top 5 correlating histogram parameters and the patient age, indicated better diagnosis performance (AUC = 0.85) compared with the prediction using parameter of the MD median value alone. Conclusions: We found that in gliomas, IDH mutant type and wild-type gliomas have significant differences in DTI metrics. The integration of the DTI metrics with demographic information may help to provide a non-invasive molecular stratification of the gliomas.
Variation in the administration of early chemotherapy for indolent lymphomas: Analysis of the National Cancer Data Base (NCDB).
Authors: Jaleh Fallah, Adam J. Olszewski
Journal: Journal of Clinical Oncology (2016)

e18005 Background: Guidelines recommend watchful waiting for the initial management of asymptomatic, low-burden follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or Waldenström’s macroglobulinemia (WM). However, adherence to this strategy may be affected by patients' (pts) or physicians' preferences. We analyzed variation in the application of chemotherapy (Ch) among academic and community centers using the NCDB—a registry capturing > 70% of cancer cases in the United States (US). Methods: We selected pts with stage 3/4 FL, any CLL or WM, reported to the NCDB between 2000 and 2012, excluding pts who died within 1 month of diagnosis or those with medical contraindications to Ch. We defined early treatment as Ch administered within 90 days of diagnosis. Trends and proportions were modeled by robust Poisson regression, reporting risk ratio (RR) with 95% confidence intervals (CI), or P values for trends and interactions. Results: Early Ch was applied in 67% of FL, 23% of CLL and 54% of WM pts. Adjusting for age, sex, race, income, and health insurance, the proportion of pts receiving early Ch was significantly lower in academic programs compared with community centers (Table). This proportion did not significantly change between 2000 and 2012 in FL (P = .17), while it steadily decreased in CLL (P< .0001) and increased in WM (P< .0001). Trends were parallel for academic and community centers in FL (P for interaction with time = .11) and WM (P= .77), but not in CLL (P= .0014), where the decrease was larger in community centers. Among pts starting Ch, the proportion receiving a multi-agent regimen markedly increased over time in CLL (from 39% to 65%, P < .0001) and WM (from 36% to 57%, P< .0001), and less so in FL (from 78% in 2000 to 82% in 2012, P < .0001). Conclusions: Administration of early Ch varies among histologies, academic and community cancer programs, and over time, which may reflect differences in the propensity to treat, or in the proportion of symptomatic pts. Multi-agent Ch is increasingly applied for indolent lymphomas in the US. Subtype N Early Ch, community Early Ch, academic Adjusted RR CI P FL 39,756 69% 63% .90 .89-.92 < .0001 CLL 74,021 25% 21% .81 .79-.84 < .0001 WM 8,859 55% 52% .93 .89-.97 .0006