tbuckley/cabot-search huggingface dataset:
Relationship between physician-adjudicated adverse events (AE) and patient-reported health-related quality of life (HRQoL) in a phase II clinical trial of patients (pts) with metastatic uveal melanoma (UM).
Authors: Thomas Michael Atkinson, Jennifer L. Hay, L. Austin Doyle, Daniel Paucar, Sloane C. Smith, Yuelin Li, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2015)

9555 Background: Clinical trials typically use physician-adjudicated AE assessment with the Common Terminology Criteria for Adverse Events (CTCAE) for decision-making. Since the capture of patient-reported HRQoL data is becoming more frequent, we compared CTCAE and HRQoL ratings for pts treated on one clinical trial to explore how this information may inform clinical trial conduct. Methods: Data from a phase II trial of pts with metastatic UM (Carvajal et al. JAMA. 2014) were analyzed. Pts were randomized to receive Selumetinib (sel), an oral MEK inhibitor (n = 50), or chemotherapy (n = 51); 19 pts received sel without randomization. Those randomized to chemotherapy could receive sel at disease progression. Pts reported HRQoL via the Functional Assessment of Cancer Therapy – Melanoma (FACT-M) at baseline, after 1 month and end of treatment (EOT; n = 118). Independent samples t-tests were used to compare mean FACT-M scores between sel, chemotherapy and crossover pts. Pearson correlations were calculated to determine the association between mean FACT-M scores and whether a patient had their dose reduced due to AEs. Results: 94% (median age = 62; 44% female) had a physician-adjudicated CTCAE grade > 0 for at least one treatment-associated AE of diarrhea, edema, nausea, rash, or vomiting. 20% of these pts had dosage reductions. 38 pts from the chemotherapy group progressed and received sel. Mean FACT-M scores did not significantly differ (p > 0.05) across sel, chemotherapy or crossover groups at each of the three time points. There were no significant correlations between dose reduction status and FACT-M scores (r = 0.07, -0.01 and 0.03 for baseline, 1 month and EOT). Conclusions: Despite the high rate of physician-adjudicated AEs, patient-reported HRQoL was not impacted by treatment. HRQoL did not differ in the subgroup of pts who received dosage reductions due to AEs, indicating that the patient may be willing to tolerate that level of AEs and continue the current dosage (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct. Clinical trial information: NCT01143402.
Genetic variation in CYP19A1 and response to exemestane: Survival in early breast cancer in the Dutch TEAM trial.
Authors: Daniel Houtsma, Duveken Fontein, Judith A. M. Wessels, Caroline M. Seynaeve, Cock JH van De Velde, J. W. R. Nortier, Henk-jan Guchelaar, Hans Gelderblom
Journal: Journal of Clinical Oncology (2012)

10518 Background: In patients with endocrine-sensitive breast cancer treated with adjuvant aromatase inhibitors (AI) it is unclear which patients will develop a recurrence and who will benefit from AI’s. Variations in the aromatase gene (CYP19A1) are associated with altered estrogen levels and altered aromatase activity. The aim of this study was to examine the effect of SNPs in the CYP19A1 gene on survival in a prospective cohort of breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and who were treated with five years of exemestane were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. A significant association with worse RFS was found with two SNPs: rs7176005 and rs16964211, showing hazard ratios (HR) of 3.48 and 5.42 for the homozygeous variant types respectively. These SNPs, as well as a third SNP, rs6493497, were also significantly associated with OS (HR 5.87, 5.3 and 3.36 respectively). Conclusions: Germline variations in the CYP19A1 gene are related to a worse outcome in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. The relation between RFS and SNP’s in CYP19A1. [Table: see text]
MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
Authors: Denghong Zhang, Riccardo Contu, Michael V.G. Latronico, Jianlin Zhang, Roberto Rizzi, Daniele Catalucci, Shigeki Miyamoto, Katherine Huang, Marcello Ceci, Yusu Gu, Nancy D. Dalton, Kirk L. Peterson, Kun-Liang Guan, Joan Heller Brown, Ju Chen, Nahum Sonenberg, Gianluigi Condorelli
Journal: Journal of Clinical Investigation (2010)
Detection of <i>BRAF </i>mutations in urine and plasma cell-free DNA: Application to the diagnosis and management of histiocytic disorder patients.
Authors: Omar Ibrahim Abdel-Wahab, Eli L. Diamond, Minal Patel, Veronica R. Holley, Goran Cabrilo, Raajit Rampal, Latifa Hassaine, Karena Kosco, Jose Baselga, Razelle Kurzrock, Jason Poole, Cecile Rose T. Vibat, Mark Erlander, Filip Janku, David Michael Hyman
Journal: Journal of Clinical Oncology (2014)

11012 Background: Histiocytosis patients (pts) have a high frequency of BRAFV600E mutations and respond to RAF inhibition but low tumor content and stromal contamination make detection in tissue biopsies challenging. Quantitative assessment of BRAFV600E mutations in tumor derived cell-free (cf) DNA may provide a convenient and reliable means of detecting this established biomarker and monitoring response to RAF targeted therapy. Here we compare the results of urine and plasma cfDNA BRAFV600E testing to tissue biopsy mutation testing in a large series of histiocytosis pts. Methods: Quantification of BRAFV600E was performed in cfDNA using droplet digital (dd) PCR (Trovagene, San Diego, CA). BRAFV600E analysis in tumor tissue was conducted using a variety of highly sensitive methodologies including locked nucleic acid and next-generation sequencing in CLIA-certified labs. Concordance between mutational analysis in tissue, plasma, and urine was determined. Results: 22 histiocytosis pts underwent cfDNA mutational analysis (18 Erdheim Chester Disease, 4 Langerhans Cell Histiocytosis). 20 pts also had CLIA-certified BRAFV600E mutational analysis in tissue (10 mutant, 6 wildtype, 4 test failure). All 10 BRAF-mutant pts based on tissue testing had a concordant positive cfDNA result in urine. Similarly, all 6 BRAF-wildtype pts based on tissue testing had a concordant negative cfDNA result in urine. 95% CI for concordance was 79-100%. Urine cfDNA was positive in 2 additional pts where tissue testing was unsuccessful. Plasma cfDNA testing did not identify BRAFV600E mutant pts who were not also positive by urine testing. Conclusions: Detection of actionable BRAF mutations by ddPCR in cfDNA is feasible and was completely concordant with CLIA-certified tumor mutation testing. Moreover, the ability to detect BRAF mutations in the urine of pts with repeated tumor tissue testing failure is potentially practice changing and demonstrates the clinical utility of cfDNA technologies. Mutations in cfDNA should be further investigated for longitudinal assessment of RAF-targeted therapy in pts with histiocytoses.
Long-term results from INT-HER study: Retrospective evaluation of adjuvant trastuzumab in unselected HER2-positive breast cancer patients—Single institution experience.
Authors: Angela Moliterni, Gabriella Mariani, Giulia Carlo Stella, Luigi Mariani, Giulia Valeria Bianchi, Giuseppe Capri, Sara Cresta, Paola Mariani, Silvia Damian, Elena De Benedictis, Francesco Gelsomino, Elisa Zanardi, Matteo Duca, Lorenzo Sica, Anna Tessari, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2014)

e11509 Background: Trastuzumab (T) is associated with significant outcome improvement in HER2 positive early stage breast cancer (BC). Adjuvant T was registered in Italy in 2005 for clinical practice. INT-HER study, single institution experience, report the long term results in unselected HER2-positive BC patients (pts). Methods: We analyze 296 pts with HER2+ve BC (defined as IHC 3+ or HER2 amplification) consecutively treated at the Fondazione IRCCS Istituto Nazionale Tumori from October 2005 to February 2012. T was administered for 1 year (q 3wks) as part of an integrated plan of loco-regional treatment, neo-adjuvant or adjuvant chemotherapy (CT) and hormone-therapy when indicated according to menopausal status. This retrospective study was approved by the Ethics Committee of our institution. Results: The median age at the diagnosis was 51 years (range 26-79). CT included anthracycline (A) and in 71% of pts A plus taxane. More then half of pts had pT1, 47% had pN0, 32.5% pN1-3 and 20.5% pN>4.T and N were not assessed in pts received neoadjuvant CT(24%). Almost 90% of tumours were ductal carcinoma with 70% of grade 3. Hormone receptor positivity was recorded in 61% of pts. T was discontinued in 16 out of 17 pts (5.7 %) for cardiac toxicity and stopped only in 7 pts (2.4 %) because of relapse. At a median follow-up of 71,5 months, the estimate event free survival (EFS) and overall survival (OS) were 77.6 ( 95%CI.72.1-83.2) and 89.3 (95%CI.84.9--93.8) respectively. 50 relapses were reported so far: distant in 30 pts (10%), loco regional in 17 (5%), controlateral BC in 3 (1%) and second tumors in 9 (3%). Nearly an half of distant recurrences occurred in multiple sites. 4 pts (11%) relapsed to CNS and another 10 (28%) had further progression to CNS. The nodal involvement had a significant association with EFS and OS. Short relapse-free interval (relapse during or in 6 months since end to T treatment ) influencing survival after distant relapse. Conclusions: Present study confirms the benefit of adjuvant T in HER2 positive BC population outside clinical trials. Pts at high risk of relapse and/or T resistant warrant further new antiHer2 therapeutic strategy to improve outcome.
Phase II study of S-1 plus docetaxel as first-line treatment for elderly patients with advanced gastric cancer (OGSG0902).
Authors: Jin Matsuyama, Hiroshi Imamura, Ryohei Kawabata, Tomono Kawase, Kazuyuki Okada, Kazuhiro Nishikawa, Yukinori Kurokawa, Kazumasa Fujitani, Toshio Shimokawa, Taroh Satoh
Journal: Journal of Clinical Oncology (2017)

129 Background: There is not enough evidence for the treatment of elderly patients with advanced gastric cancer. S-1 plus CDDP is one of the standard treatment for advanced gastric cancer in japan, but the efficacy remains insufficient due to the drug toxicity such as renal function disorders. The efficacy and safety of S-1 plus docetaxel as first-line treatment for elderly patients with unresectable advanced or recurrent gastric cancer were investigated. Methods: 75 years or older patients with unresectable advanced or recurrent gastric cancer were enrolled. Docetaxel was administered i.v. (40mg/m 2 ) on day 1, while S-1 was administered orally (80mg/m 2 /day, b.i.d.) for 14 days followed by a 7-day rest. This schedule was repeated every 3 weeks. The primary endpoint was response rate (RR) of S-1 plus docetaxel; secondary endpoints were safety, progression free survival (PFS), time to treatment failure (TTF) and overall survival (OS). Sample size was set to be 30, which was determined to reject the response rate of 20% under the expectation of 40% with the power of 90% and two-sided alpha of 5%. Results: 31 patients were enrolled and assessable for efficacy. The response rate was 45.2% (95%CI 27.3-64.0, p = 0.001), and disease control rate was 77.4%. The median progression-free survival time was 5.8 months, the 1-year survival rate was 58.1%, and the median survival time was 16.1months. In 31 patients assessed for safety, the major grade 3/4 toxic effects were neutropenia (58%), febrile neutropenia (13%), anemia (10%), anorexia (10%), and fatigue (6%). Conclusions: These findings indicate that S-1 plus docetaxel as first-line treatment for elderly patients is feasible and shows promising efficacy against advanced gastric cancer. Clinical trial information: UMIN000002785.
Association of single nucleotide polymorphisms in AGT, VEGF, and APOE genes with clinical outcome of target therapy in advanced renal cell carcinoma.
Authors: Li Li Mao, Lu Si, Zhi Hong Chi, Chuan Liang Cui, Xi Nan Sheng, Jun Guo, Bi Xia Tang, Si Ming Li
Journal: Journal of Clinical Oncology (2012)

e15051 Background: Recent evidences have indicated that hypertension and obesity predict longer PFS of targeted therapy in metastatic renal cell carcinoma (mRCC) patients, thus we suppose polymorphisms in hypertension associated genes(angiotensinogen, AGT; vascular endothelial growth factor, VEGF) and obesity associated gene (apolipoprotein E, APOE) may have an effect on treatment outcome in patients treated with targeted therapy for mRCC. Methods: A cohort of consecutive patients (pts) treated with sunitinib or sorafenib were studied. Baseline clinical characters such as age, gender, blood pressure and BMI (body mass index) were recorded. All patients were genotyped for genetic polymorphisms in rs2493137 of AGT, rs699947 of VEGF and rs8106922, rs405509 of APOE from peripheral blood. All the patients were followed up for progression free survival(PFS),overall survival (OS),objective response rate (RR). Results: We studied a cohort of 77 cases, 58 (24.7%) pts were male, 18 (23.4%) pts were ≥65 years and 47 (61%) pts received sunitinib. The distribution of all the tested SNP genotypes were in Hardy-Weinberg equilibrium (p&gt;0·05). With a median follow-up time of 24 months (range: 1.5-36.2 months), 60 pts developed progression and 34 pts died. The rs2493137 TT genotype in the AGT gene showed a trend of prolonging PFS when compared with the CC+CT genotypes, but without statistically significance (p=0.08). No correlations were found among other genotype subgroups (rs699947, rs8106922 and rs405509) on either clinical characters or survival endpoints in this study. Conclusions: Polymorphism in the promoter of AGT gene (rs2493137) might be associated with better clinical outcome in patients treated with targeted therapy for mRCC. Further studies with a larger sample size are needed on the function of this polymorphism.
Predicting time to ovarian carcinoma recurrence using protein markers
Authors: Ji-Yeon Yang, Kosuke Yoshihara, Kenichi Tanaka, Masayuki Hatae, Hideaki Masuzaki, Hiroaki Itamochi, Masashi Takano, Kimio Ushijima, Janos L. Tanyi, George Coukos, Yiling Lu, Gordon B. Mills, Roel G.W. Verhaak
Journal: Journal of Clinical Investigation (2013)
Second malignancies in neuroblastoma patients: A report from the International Neuroblastoma Risk Group.
Authors: Mark A. Applebaum, Tara O. Henderson, Wendy B. London, Navin R. Pinto, Samuel Louis Volchenboum, Julie R. Park, Arlene Naranjo, Andrew DJ Pearson, Barabara Hero, Sharon Diskin, Susan Lerner Cohn
Journal: Journal of Clinical Oncology (2015)

10019 Background: Exposures to radiation and chemotherapy are associated with increased risk of second malignant neoplasms (SMN) in neuroblastoma survivors. However, it remains unclear if modifications in risk-based treatment strategies during the past 25 years have changed SMN rates. Methods: The International Neuroblastoma Risk Group (INRG) Task Force created a database of neuroblastoma patients diagnosed from 1974-2013. SMN risk was measured by cumulative incidence, standardized incidence ratios (SIR) and absolute excess risk (AER) per 10,000 person-years relative to a matched United States population. Poisson regression compared rates of SMN between different groups. Results: Of the 16,520 patients in the INRG database, 9,261 enrolled on Children’s Oncology Group protocols had SMN data available. 79 (0.85%) patients developed SMN, including hematologic malignancies (n = 38), sarcomas (n = 19), carcinomas (n = 10), CNS tumors (n = 10), hepatoblastoma (n = 1), and nephroblastoma (n = 1). The incidence of SMN of the entire cohort was almost 9-fold higher than expected (SIR 8.9 (95% CI: 7.1-11.1), AER 13.3). High-risk patients had more than a 20-fold higher incidence of SMN than expected (SIR 20.1 (95% CI: 14.7-26.9), AER 32.5). Intermediate-risk patients showed a 6-fold rise in SMN (SIR 6.2 (95% CI: 3.3-10), AER 8.3), and low-risk patients trended toward higher than expected SMN rates (SIR = 2.6 (95% CI: 0.95-5.7), AER 2.8). High-risk patients had a significantly higher cumulative incidence of SMN compared to intermediate- or low-risk patients (1.6% vs. 0.98% vs. 0.37%; p = 0.01). The cumulative incidence of SMN for two treatment eras (1: 1990-1996; 2: 1997-2009), corresponding to intensification of treatment regimens for high-risk disease, showed a higher frequency of SMN for those treated in Era 2 compared to Era 1 (1.4% vs. 0.39% at 10-years, p = 0.012). Conclusions: The incidence of SMN is higher than expected in high and intermediate-risk neuroblastoma survivors. The exposure to more intensive treatment likely contributes to the higher incidence of SMN observed in high-risk patients diagnosed after 1996. Genome-wide association studies (n = 5,188) to identify modifiers of SMN susceptibility are ongoing.
Phase II study of Sorafenib (BAY 43–9006) in hormone-refractory patients with prostate cancer: A study of the Central European Society for Anticancer Drug Research—EWIV (CESAR)
Authors: S. Steinbild, K. Mross, D. Morant, D. Köberle, C. Dittrich, D. Strumberg, A. Hochhaus, A. Hanauske, I. Burkholder, M. E. Scheulen
Journal: Journal of Clinical Oncology (2006)

3094 Background: Sorafenib (BAY 43–9006) is a novel, orally active multi-kinase inhibitor with anti-angiogenic and anti-proliferative activity, blocking both Raf/MEK/ERK pathway and receptor tyrosine kinases VEGFR-2 and PDGFR. Activity of sorafenib in hormone-refractory progressive patients (pts) with prostate cancer (PC) was investigated in a Phase II clinical study. Methods: Pts received sorafenib 400 mg bid by continuous oral dosing. Pts with progressive disease during hormonal treatment and no prior chemotherapy therapy for advanced prostate cancer, and either one uni-dimensional measurable lesion according to RECIST-criteria or increasing PSA values reflecting a hormone-refractory situation, were eligible for study entry. Tumor PSA-based response was defined as: increase of PSA from baseline or lowest measured value by 100% = progressive disease (PD); decrease of PSA by &gt;50% in two consecutive measurements = responder; PSA levels in between the two definitions above = stable disease (SD). Primary study objective was the proportion of patients with time to progression of ≥12 weeks (PP-TTP-12) using target lesions and PSA based response evaluation. At least 45 evaluable pts were required to detect an increase in PP-TTP-12 from 20 to 40% in a one stage design. Secondary endpoints were overall response and survival, and toxicity according to Common Toxicity Criteria (CTC v3.0). Results: A total of 55 pts with PC were enrolled between October 2004 and June 2005. The majority of pts (40/55, 72.7%) were treated for at least 6 weeks. Among the 42 pts evaluable for PP-TTP-12, 2 pts (4.8%) had a response and 15 pts (35.7 %) showed SD ≥12 weeks and 25 pts (59.5 %) showed PD. The one-sided binomial test of the null-hypthesis of PP-TTP-12 = 20% can be rejected at a significance level of 5% (p= 0.0019). All 55 pts were included in the evaluation of adverse events. Drug-related serious adverse events (diarrhea (1), constipation (1), fatigue (1), skin (1) cardiac (2) were seen in six patients. Conclusions: These results of a PSA-based evaluation indicate that sorafenib has some clinically useful activity in PC. Further investigations are necessary to evaluate the clinical benefit. Final results will be presented. No significant financial relationships to disclose.
The efficacy and safety of sunitinib in patients with advanced well-differentiated pancreatic neuroendocrine tumors.
Authors: Eric Raymond, Matthew H. Kulke, Shukui Qin, Michael Schenker, Antonio Cubillo, Wenhui Lou, Jiri Tomasek, Espen Thiis-Evensen, Jianming Xu, Dr. Karoly Racz, Adina E Croitoru, Mustafa Khasraw, Eva Sedlackova, Ivan Borbath, Paul Ruff, Paul Eliezer Oberstein, Tetsuhide Ito, Kathrine C. Fernandez, Brad Rosbrook, Nicola Fazio
Journal: Journal of Clinical Oncology (2017)

380 Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) based on a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings. Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with progressive, well-differentiated, unresectable advanced/metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is ongoing. Results: Sixty one treatment-naïve and 45 previously treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG PS 0, 65.1% or PS 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously treated patients (13.2 vs 13.0 months). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%: 21.3% in treatment-naïve and 28.9% in previously treated patients. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥ 20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%). Conclusions: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib. Clinical trial information: NCT01525550.