tbuckley/cabot-search huggingface dataset:
Clinical validation of the Prosigna breast cancer prognostic gene signature assay on formalin-fixed paraffin embedded breast cancer tumors with comparison to standard molecular markers.
Authors: Roy R. L. Bastien, Cecily Vaughn, Danielle Elsberry, Inge J. Stijleman, Philip Seth Bernard
Journal: Journal of Clinical Oncology (2014)

e11518 Background: The Prosigna Breast Cancer Prognostic Gene Signature Assay is a FDA-cleared test for assessing the risk of cancer recurrence in women with hormone receptor positive breast cancer. The assay is based on the PAM50 gene signature, which generates a numeric risk score (0-100) and a risk category. The studies described here were used to validate the FDA-cleared test for routine use in the clinical laboratory. Methods: Thirty-two FFPE breast tumors with known node status, tumor size and ER/PR/HER2 status by IHC were categorized for risk of recurrence by a molecular pathologist. Outcome data was available for an additional 10 of the breast tumor samples. RNA was extracted from all 42 tumor samples and analyzed on the Prosigna assay. Results of the Prosigna assay - which produces both a risk score and categorization – were compared to the previously determined risk categorizations. To measure reproducibility of the Prosigna scores, two tumor samples were extracted three times each and analyzed on separate runs; one RNA extraction from each sample was also run in quadruplicate across multiple runs. The assay was also performed in duplicate with the upper and lower limits of acceptable RNA input. Results: Of the 32 samples with IHC data, 18 were low, 5 intermediate, and 9 high risk by the Prosigna assay. Concordance with pathologist’s determination based on node status, tumor size, and IHC data was 56%. Ten of 10 samples with outcome data were high risk. Of the 20 node-negative samples with tumor size less than or equal to 2 cm, 60% were stratified as having a low risk of recurrence. Of the 10 node-positive samples whose size was greater than 2 cm, 80% were stratified as having a high risk of recurrence. The average standard deviation for reproducibility was 0.58 units of the Prosigna score between replicates of the same extraction and was 1.05 units between separate RNA extractions. Conclusions: The Prosigna assay met acceptable FDA-cleared indications as a distributed kit to ARUP Laboratory. The established sample set may serve for concordance testing prospectively.
Differential protein expression profile in skin biopsies from patients with hand-foot syndrome who have benefited from topical heparin treatment.
Authors: Analia Rodriguez-Garzotto, Isabel Ruppen, M. Pilar Ximenez de Embun, Lara Iglesias, Cristina Gravalos, Alba Agudo-Lopez, Carlos Perez, Vanesa Diaz Garcia, Jose A. Lopez-Martin, Eva Ciruelos, Luis Manso, Cesar Mendiola, M. Teresa Agullo Ortuno, Hernan Cortes-Funes
Journal: Journal of Clinical Oncology (2013)

9641 Background: Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine (CAP), leading to significant morbidity in patients receiving this agent. Interruption or dose reduction of CAP is the only effective strategy. The purpose of our study is to define the pathophysiology and risk factors predictors of CAP-induced HFS. Previously, we had conducted a clinical trial in patients who developed HFS secondary to CAP. Topical heparin was administered in palms and soles of patients four times/day for three weeks (w), evidencing clinical improvement in 99% of patients. Methods: Paired-skin biopsies of palms at baseline and after 3w from 21 patients were obtained. An iTRAQ (isobaric tags for relative and absolute quantitation) proteomics approach was performed to identify molecular pathways associated with HFS reversion. Results: Comparative analysis between baseline and post-treatment skin samples identified 1876 proteins with high confidence (&gt; 99%). The involvement of the identified proteins in biological networks served to characterize molecular pathways associated with HFS reversion. Conclusions: Several proteins identified in this study have a close relationship with keratinocyte terminal differentiation and keratinocyte intercellular strength. Also, we describe differential expression among proteins involved in inflammatory processes, skin immunity and cell death. In summary, our study not only served to uncover molecular mechanisms associated with HFS reversion, but also to reveal the biomarker role of several proteins in this syndrome. [Table: see text]
Sym004 to circumvent resistance to cetuximab driven by emergence of EGFR extracellular mutations in colorectal cancer.
Authors: Clara Montagut, Israel Cañadas, Elena Gavilan, Oriol Arpi, Beatriz Bellosillo, Alejandro Martinez, Alba Dalmases, Ana Rovira, Joan Albanell
Journal: Journal of Clinical Oncology (2015)

e13600 Background: Metastatic colorectal cancer (MCRC) patients treated with cetuximab invariably develop resistance, which is driven by the emergence of mutations in the extracellular domain (ECD) of EGFR in a subset of tumors. Sym004 is a novel 1:1 mixture of two non-overlapping anti-EGFR monoclonal antibodies that has recently shown clinical activity in MCRC. We used preclinical models of resistance to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Methods: Functional studies in NIH 3T3 cells expressing mutations of acquired resistance in EGFR (S492R, R451C, K467T, S464L, G465R, or I491M) included: drug-receptor binding as assessed by flow cytometry and biochemical studies to assess ligand-dependent activation of individual EGFR mutants in the presence of the drugs. Cell viability and molecular effects of Sym004 were assayed in DiFi-derived cetuximab resistant cells (DCR) harboring the EGFR S492R mutation. Results: While EGFR ECD mutations were not permissive for binding to cetuximab, Sym004 was able to bind effectively to all mutants tested. Of note, the effect of EGFR R451C on cetuximab and Sym004 binding was moderate compared with the other mutants. Molecular studies showed that while cetuximab had very limited or no impact in preventing ligand-mediated activation in cells carrying mutant EGFR, Sym004 effectively abrogated EGFR activation in all mutants tested. In addition, DCR cells resistant to cetuximab maintained sensitivity to Sym004. Sensitivity to Sym004 was consistent with effective suppression of the phosphorylation of EGFR downstream effectors ERK1/2 and AKT as well as cell cycle arrest (cyclin D1 downregulation) and induction of apoptosis (presence of cleaved-PARP). Conclusions: Sym004 is active in MCRC in the presence of EGFR ECD mutations that mediate resistance to cetuximab.
Response to sunitinib in patients with metastatic renal cell carcinoma: Experience of one center.
Authors: Marijana Jazvic, Jasna Radic, Zeljko Soldic, Ante Bolanca, Zvonko Kusic
Journal: Journal of Clinical Oncology (2013)

e15603 Background: Five-years survival of patients with metastatic renal cell carcinoma (mRCC) is only 10%. A complete response (CR) to therapy is rare but has been achieved in minority of patients using high-dose interleukin-2. Sunitinib is an oral multitargeted receptor tyrosin kinase inhibitor and is currently considered the standard of care for first-line therapy of mRCC. CRs and long-term responders (LTR) to sunitinib have been documented in the literature. However, a detailed description and analysis of these patients is lacking. We report LTR, defined as patients achieving ongoing CR or remaining progression-free for ≥ 18 months on sunitinib. Methods: From 10/2008 till 12/2012, 48 patients were treated with sunitinib (50 mg/day, 4 weeks on/2 weeks off) as the first line therapy of clear cell mRCC. Tumor assessments were performed at baseline and every two cycles thereafter until the end of treatment, using RECIST criteria. Results: Nine patients were identified as LTR (18.8%). Retrospective data of these patients are reported in the Table. Conclusions: Sunitinib achieves LTR in a subset of patients with mRCC. Lung metastases and favourable MSKCC risk group may predict LTR. Maintaining full-dose sunitinib and management of therapy- related toxicity are crucial for treatment efficacy. [Table: see text]
Evaluation of gene expression by RNA-seq after single dose of trastuzumab (T) reveals predictors of pathologic complete response (pCR) in HER2-positive early breast cancer.
Authors: Natalie Galanina, Emmet Sprecher, Veerle Bossuyt, Sudipa Sarkar, Ian E. Krop, Eric Winer, David P. Tuck, Can Bruce, Lyndsay Harris
Journal: Journal of Clinical Oncology (2012)

10558 Background: The use of a ‘brief exposure’ to single agent T allows the measurement of dynamic changes in the transcriptome that may predict response to T-based combinations. We have shown that most gene expression changes in HER2+ tumors treated with T occur in tumors that ultimately achieve a pCR. Our further analysis suggests several patterns of transcriptional change in pCR tumors suggesting different mechanisms of action of T. RNA-seq analysis provides more in-depth annotation of these mechanisms. Methods: Fresh tumor core biopsies were taken at a 2 week time point after a single dose of T (8mg/m2) from 80 HER2+ early breast cancer patients enrolled on a clinical trial of T&gt;T+C. Nucleic acids were extracted using Qiagen AllPrep and were analyzed with Illumina HT12v3 Beadchip and Illumina 610 QUAD V1 SNP arrays. RNA was also processed for sequencing using the Ovation RNA-Seq System and paired-end sequenced using an Illumina Genome Analyzer IIxRNA-seq data was analyzed with Tophat/Cufflinks. Network analysis was performed with Metacore. Results: Among pCR tumors, distinct patterns of differential expression pre/post T were observed, in both microarray and RNA-seq data. ERBB2 down-regulation was characteristic of pCR in one subgroup by microarray. In this group, differentially expressed genes belonged to interaction networks involved in apoptosis and cell cycle regulation. In contrast, tumors with no change in ErbB2 showed differentially expressed genes that belonged to networks related to chromatin assembly and regulation of immune pathways. NOLC1, RPL41, ZCHHC17, and B2M had altered alternative splicing product distributions in both groups. In the ERBB2 down-regulated group, genes with changed expression were enriched for targets of STAT3 and YY1. Conclusions: RNA-seq and microarray reveal distinct responses in tumors that achieve pCR to T-containing regimens. These methods provide predictive markers for validation in subsequent clinical trials.
CUDC-907: An Oral HDAC/PI3K Dual Inhibitor with Strong Preclinical Efficacy in MCL Model
Authors: Jordan N Boyle, Caroline R Kim, Hui Guo, Taylor Bell, Shengjian Huang, Carrie J Li, Yang Liu, Hui Zhang, Jack Wang, Victoria Zhang, Makhdum Ahmed, Laura T Lam, Krystle Nomie, Liang Zhang, Dongfeng Zeng, Michael Wang
Journal: Blood (2016)
The impact of interval from surgery to chemotherapy and age in advanced-stage ovarian cancer: A GOG ancillary study.
Authors: Andrew Menzin, James Java, John L. Lovecchio, Dennis Chi, William P. Tew, Michael A. Bookman, Stuart M. Lichtman
Journal: Journal of Clinical Oncology (2012)

5057 Background: To determine if an age group exists for which the interval from surgery to the initiation of chemotherapy influences progression free survival (PFS) and overall survival (OS) among women with advanced ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, randomized trial of first-line chemotherapy in patients with advanced ovarian cancer, including those with optimal and suboptimal residual disease. Patients were randomized to one of five chemotherapy arms, employing combinations of either two or three agents delivered intravenously, with a control arm of paclitaxel and carboplatin. Chemotherapy was to be initiated within 12 weeks of primary surgery. A retrospective analysis was approved by the GOG Ancillary Study Committee to investigate the influence of age on treatment and outcomes. In that analysis, Cox regression was used to identify independent prognostic factors and estimate their covariate effects on the adjusted PFS and OS of the study population. Statistical significance was set at p&lt;0.05. Results: The primary analysis of GOG 182 showed no differences in PFS or OS for any of the experimental arms when compared to the control regimen, and it was felt that the data from all arms could be aggregated for this analysis. Data for all regimens was pooled, and the time interval from surgery to chemotherapy was examined as a prognostic factor of survival. The interval had no statistically significant association with PFS (p=0.105). In the OS model, though, the functional form of the log interval was both significantly linear and nonlinear (p&lt;0.001). After being flat until about 20 days (21.2 days; 95% CI, 15.0–28.2 days), the plot of log interval against log hazard increases, suggesting a changepoint time after which the associated risk of death increases. Conclusions: In this study, time interval from surgery to chemotherapy had no impact on PFS, but there was evidence of a potential time-dependent relationship with OS, which might be elucidated with a meta-analysis incorporating data from other prospective trials. Our observations did not appear to be influenced by patient age. Overall, these findings can reassure patients who are recuperating from extensive cancer surgery.
PACIFIC trial: A randomized phase II study of apatorsen and abiraterone in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) who have had PSA progression while receiving abiraterone (ABI).
Authors: Kim N. Chi, Mark T. Fleming, Katherine Sunderland, Costantine Albany, Joel Gingerich, Fred Saad, Scott A. North, Alexander Starodub, Richard C. Lauer, Joseph D. Ruether, Madelaine Miranda Sgroi, Mark C. Scholz, Christopher Sweeney
Journal: Journal of Clinical Oncology (2017)

146 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 chaperones androgen receptor (AR) and enhances transactivation of AR-regulated genes. Apatorsen is a 2nd generation antisense that inhibits Hsp27 expression with clinical activity demonstrated in pts with mCRPC. Methods: mCRPC patients with PSA-only progression on ABI + prednisone (P) 10-20 mg daily were randomized to continuing ABI + P (Control Arm) or ABI + P with Apatorsen 600 mg IV x 3 loading doses then 800 mg IV weekly (Study Arm). Control Arm pts could cross over to receive apatorsen at time of progression. Primary endpoint was the proportion of pts progression free (PSA, clinical and radiologic) at day 60. Assuming a 25% increase in proportion of pts progression free and a null hypothesis of 5%, the planned sample size was 74 patients (type I error 20%, type II error 10%). Results: 72 pts were randomized: 36 to Control Arm, 36 to Study Arm. Baseline characteristics were similar in both arms: median age was 72 years (53-89); ECOG PS 0/1 in 44/56% of pts; median PSA of 29.4 (2.5-470.0); metastases to bone/lymph nodes/liver or lung occurred in 63/27/10%; elevated LDH and alkaline phosphatase in 26% and 26% ; 47% had ≥ 5 CTC/7.5 mL. Adverse events (AEs) were mainly grade 1-2 infusion reactions. 18 pts had grade 3/4 adverse events considered apatorsen related including: dyspnea (14%), fatigue (14%), increased ALT (9%), increased AST (9%), and thrombocytopenia (9%). Primary and secondary outcomes are summarized in the Table. Conclusions: Apatorsen may have activity when added to abiraterone for mCRPC patients progressing on abiraterone. Establishing predictors of response should be a priority for future studies. Clinical trial information: NCT01681433. [Table: see text]
A randomized multicenter phase II study on neoadjuvant chemotherapy with carboplatin and docetaxel in advanced ovarian carcinomas (PRIMOVAR)
Authors: T. Park-Simon, F. Jänicke, O. Ortmann, J. Hilfrich, G. Breitbach, C. Höss, V. Möbus, C. Thomssen, K. Diedrich, W. Kuhn
Journal: Journal of Clinical Oncology (2006)

15025 Background: In the past years the concept of neoadjuvant chemotherapy and interval laparotomy has emerged for patients with advanced ovarian cancer and unfavorable prognosis (e.g. diffuse peritoneal carcinosis). In a recent study on neoadjuvant chemotherapy higher tumor resection rates and longer median survival were demonstrated in patients with advanced ovarian carcinoma and ascites &gt;500ml. Most studies use three cycles of preoperative chemotherapy. However, chemoresistant tumorclones may be induced by increasing number of preoperative chemotherapy cycles. The purpose of this study is to evaluate the optimal number of cycles prior to interval laparotomy. Methods: 67/73 patients with advanced serous ovarian carcinoma (FIGO IIIc n = 48, FIGO IV n = 19) and ascites &gt;500ml were randomized into two arms, receiving either 2 (n = 33) or 3 (n = 34) cycles of Carboplatin (AUC5) and Docetaxel (75mg/m 2 ) before interval laparotomy. Postoperatively, they received either 4 or 3 additional cycles. Response rate and postoperative residual tumor were evaluated. Results: Surgical response was assessed during interval laparotomy. At present 32 patients underwent tumordebulking. Partial remission was observed in 28/32 patients irrespective of the number of preoperative chemotherapy cycles. Two patients in each arm showed stable disease. Optimal cytoreduction was achieved in 25/32 patients. No severe adverse events were reported. Six of 73 patients were not eligible. Two patients were excluded due to therapy-unrelated events. In 4 patients ovarian cancer was excluded by laparoscopy prior to neoadjuvant chemotherapy. Conclusions: Neoadjuvant chemotherapy followed by interval laparotomy was safe and well tolerated. Diagnostic laparoscopy prior to neoadjuvant chemotherapy allowed differentiation of primary ovarian cancers from tumors of other origin. In these cases laparotomy could be circumvented. Optimal tumor reduction was achieved in a significant number of patients. Response rate and postoperative residual tumor were essentially the same in both arms. Our data indicate that two cycles of preoperative chemotherapy may be the preferential choice of therapy for future studies. No significant financial relationships to disclose.
Epstein-Barr Virus and Kaposi's Sarcoma Herpesvirus Lytic Cycle Induction with Bortezomib Is a Response to ER Stress
Authors: Courtney O'Farrell, Meir Shamay, Nene Kalu, Andrew DuFresne, Sunetra Biswas, Richard F. Ambinder
Journal: Blood (2010)
Serial application and development of a new treatment paradigm for pancreatic cancer.
Authors: Jeanetta Stega, Howard Bruckner, Myron E. Schwartz, Azriel Hirschfeld
Journal: Journal of Clinical Oncology (2012)

e14729 Background: New "paradigm driven" treatments (rx) “doubled” phase II survival (S) for 250 pts (ASCO, Bruckner 01, 04, 05, 08, 11). Addition or repartnering of drugs which failed trials or individual use (all in cost saving doses) produced synergism and reversed drug resistance. New rxs and safer doses were rapidly discovered by application of game theory to models of rxs, testing human pancreatic ca (PC) in vitro. Some measures of response (R) and extreme drug resistance as selection criteria were downgraded. Priority went to disease specific in vitro “R” rate (RR), increased number of simultaneously impacted drugs, activity at low doses and avoiding both duplication of targeting and antagonism. Clinical objectives now included wider eligibility, safety and 50% cost saving. Methods: With prospective registration and IRB consent rxs evolved: GFLIP&gt;GFLIO&gt;GFLIO -/+ docetaxel (D) -/+Mitoymcin-C (M). GFLIO and on progression GFLIO-D-M was the rx for 107 new tests (biopsy high risk ductal PC, PS 0-2, no active obstruction). Pts: unresectable (U) or metastatic (IV), G1; failing prior rx with some rx drugs, G2 or resected PC +/- margin G3 (G1, G2 all with progressive disease). Serial findings were compared (ASCO 05, 08). Results: OS for U/IV (G1 and G2) adding D-MMC to GFLIO was: n=70, at 24 mos 22/38 (S) (61%) alive; at 36 mos 8/20 (40%) vs prior 32 and 21%. Adjuvant, G3: n=37 at 18 mos 15, (50%) PFS, 28/30 S; alive S at 24 mos 10, (43%) PFS 20/23 S; at 36 mos 6, 40% PFS 14/15 S. Cumulative RR depending on R criteria meet models for 40-60% R per treatment with benefit rx (61-84%). Rxs were safe, no induction hospital AEs. Conclusions: This 350 pt prospective Phase II further supports testing of low dose rx; use of D-MMC as additions and adjuvant GFLIO rx (see Reni, Fine, Isakoff). The pts large N and long OS have testworthy practice changing: consent, reimbursement and trial (algorithm) “design” implications. Cost of drugs per unit of survival (S) can often be saved, safely while possibly improving QL and OS. Palliative applications of dose intensity, drug efficacy, tumor resistance and one drug at a time testing as rx concepts are (sometimes) questionable. improving QL and OS.
Oral medication adherence in cancer interventional studies.
Authors: Catherine Lam, Meaghann Shaw Weaver, Scott C. Howard
Journal: Journal of Clinical Oncology (2015)

e17505 Background: Given the increasing role of oral agents in cancer control and the implications of medication non-adherence on health system costs, outcome evaluations and patient outcomes, systematic analysis of patients’ medication adherence is vital. However, the status of oral medication adherence in clinical trial outcome evaluations is unclear. Methods: All open cancer drug interventional studies registered on ClinicalTrials.gov as of January 2015 were screened for adherence/compliance keywords and outcomes. Trial attributes including patient inclusion, study phase, and funding were analyzed. Studies including medication adherence were extracted for attributes including location, enrollment, conditions and drugs assessed, and adherence-targeted interventions and outcomes. Results: Of 6805 trials screened, 104 protocols (1.5%) included adherence keywords or outcomes, and 56 (0.8%) discussed oral medication adherence. Compared with all screened trials, the 56 that included oral medication adherence outcomes were likelier to be gender-specific (32% vs 16%, odds ratio [OR] 2.23; p = 0.006), non-phase 1 (80% vs 63%, OR 2.29; p = 0.023), National Institutes of Health-funded (25% vs 14%, OR 2.01; p = 0.025), and were similarly pediatric-inclusive (9% vs 10%, p > 0.05). Of the 56 trials from 15 countries, 26 included U.S.-based sites, with total enrolment targeting 9348 patients; nearly one-quarter specified criteria excluding patients at risk of non-adherence. Most trials (n = 36) involved solid tumors; 8 involved leukemia/lymphoma, and 12 involved other conditions. The majority studied a single oral medication (n = 39); most (n = 46) did not include adherence-aimed interventions. In 11 studies, adherence outcomes were designated as a safety issue. Methods to evaluate oral medication adherence were specified in 24 instances (0.4%), including pill counts, electronic monitoring systems, patient-reported outcome tools and logbooks, and biomarker assays. Conclusions: Current clinical drug trials in oncology include adherence outcomes < 2% of the time, and even when included, do not consistently specify standardized measures to document outcomes. Increased integration of adherence-inclusive interventions and outcomes is warranted.