tbuckley/cabot-search huggingface dataset:
Intratumoral heterogeneity of 1p/19q codeletion in brain tumors.
Authors: Maria Martinez-Garcia, Mar Lara, Blanca Espinet, Marta Salido, Beatriz Bellosillo, Maria Carmen Vela, Noelia Vilarino, Alvaro Taus, Sergi Mojal, Ana Rovira, Joan Albanell, Francesc Alameda
Journal: Journal of Clinical Oncology (2014)

2070 Background: Evaluation of 1p and 19q is a relevant diagnostic, prognostic and predictive test for oligodendroglial tumors. The aims of this study were to determine the reliability of core specimens to assess 1p/19q codeletion in brain tumors, as well as to provide additional data on its potential role in glioblastoma (GB). Methods: We evaluated 1p/19q codeletion by FISH using 1p/1q and 19p/19q probes (Vysis) in a tissue microarray (TMA) from brain tumor specimens, mostly GB. Four 1mm-diameter cores were punched from selected areas of each donor block. We used a cutoff value of 50%. In order to compare the percentage of deletion between the four cores the intraclass correlation coefficient (ICC) was calculated. In 23 cases Pearson correlation coefficient was used to compare results from TMA with those from tumor sections. Also, for each sample we extracted DNA for MGMT methylation (MSP-PCR) and IDH1mutation (Real time allele-specific PCR) analysis. Clinical outcome for GB patients was correlated with these biomarkers. Results: We selected 45 grade IV gliomas (42 GB and 3 gliosarcoma). Mean age was 59 years and 29 were men. Fifteen tumors were MGMT methylated (33%) and 7(16%) IDH1 mutated. There were 38 patients (84%) with 1p deletion (at least one of the cores) and 17 (38%) with 1p/19q codeletion. In tumor sections 2/23 (8.6%) had 1p/19q codeletion. There was a low rate of correlation between cores of the same patient. The ICC for 1p and 19q were 0.324 and 0.743, respectively. We observed a high correlation between the mean percentage of deletion in cores and sections. The correlation between the mean of the cores and the sections for 1p was 0.819 and for 19q was 0.810. With a median follow-up of 11 months the OS was 10.5 months. 1p/19q codeletion had no impact on survival and neither did isolated loss of 1p or 19q or MGMT methylation. IDH1mutation was significantly correlated with survival (P= 0.046). Conclusions: Our data show substantial intratumoral heterogeneity of 1p/19q codeletion in grade IV glioma and establishes the need to test for this biomarker in whole sections or in several cores if only TMA is available. The outcome supports the lack of correlation between 1p/19q codeletion and OS in GB.
MicroRNA prognostic signature in malignant pleural mesothelioma.
Authors: Francesco Grossi, Anna Truini, Ernest Nadal, Carlo Genova, Erika Rijavec, Giulia Barletta, Federica Biello, Simona Coco, Maria Giovanna Dal Bello, Irene Vanni, Angela Alama, David G. Beer
Journal: Journal of Clinical Oncology (2015)

7562 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and characterized by a poor outcome (median overall survival (mOS) < 1 year), therefore requiring novel therapeutic approaches. MicroRNA (miR) play a role in tumorigenesis and progression in MPM. This study aimed to identify miR associated with poor prognosis. Methods: We identified 26 unresected MPM patients (11 long survivors (LS), OS > 3 years and 15 short survivors (SS), OS < 1 year). Total RNA, from formalin-fixed paraffin-embedded biopsy and 3 normal pleura (NP) samples, were miR profiled using the Agilent Human miR Microarray including 2006 miR. Expression data were normalized by GeneSpring software (v.12.6). Class-comparison analysis between MPM/NP and SS/LS was performed using a t-test adjusted for multiple comparisons using Benjamini-Hochberg.OS curves were estimated using the Kaplan-Meier method and compared with the log-rank test. In silicovalidation was performed using miRseq data from TCGA portal based upon 16 patients (LS: 8; SS: 8). Candidate miR were assessed by univariate analysis using Kaplan-Meier method and median as cutoff. Results: Patients’ characteristics: median age 67 years (53-77); 81% males, 19% females; 73% epithelioid histotype, 12% sarcomatoid, 12% biphasic, 3% not otherwise specified. No differences in age, gender and histotype observed among LS and SS. Class-comparison analysis reported 30 miR significantly up-regulated and 11 down-regulated in MPM vs NP; univariate analysis reported 14 miR significantly associated with OS and differentially expressed in MPM. A miR signature, based on the top prognostic miR (miR-99a, miR-125b, let-7b, let-7c, let-7i, miR-1224), classified patients into low or high-risk. The latter had a significantly shorter mOS (4.1 months, 95% CI 2.2-5.9) compared to low-risk patients (mOS not reached, Log-rank p < 0.001). In silicovalidation confirmed low expression of miR-99a, miR-125b and let-7c associated with shorter OS. PI3K/AKT, WNT were associated with these top miR by pathway analysis. Conclusions: A prognostic miR signature was identified by profiling a cohort of un-resected MPM, underlying the clinical potential of miR as predictors of survival.
BOLERO-2: Everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone receptor-positive breast cancer.
Authors: Shinzaburo Noguchi, Norikazu Masuda, Yoshinori Ito, Hiroji Iwata, Hirofumi Mukai, Jun Horiguchi, Yutaka Tokuda, Katsumasa Kuroi, Hirotaka Iwase, Hideo Inaji, Shozo Ohsumi, Martine J. Piccart-Gebhart, Gabriel N. Hortobagyi, Hope S. Rugo, Michael Gnant, Mario Campone, Tarek Sahmoud, Kathleen I. Pritchard, Howard A. Burris, José Baselga
Journal: Journal of Clinical Oncology (2012)

540 Background: Estrogen-receptor–positive (ER+) breast tumors can become refractory to aromatase inhibitor (AI) therapy. The mTOR pathway plays a critical role in hormone-resistant advanced breast cancer (ABC). Accordingly, the addition of everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase III study (BOLERO-2) in patients with ER+ aBC refractory to letrozole or anastrozole. This report presents updated analyses from the population of Asian patients enrolled in this study. Methods: Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 mg/day) or with matching placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, quality of life, and safety. Results: EVE + EXE significantly improved PFS versus EXE alone (HR = 0.44; 95% CI, 0.36-0.53; P &lt; .0001) in the overall study population at median follow-up of 12.5 months. Of 143 patients of Asian origin (n = 106; 74% Japanese) enrolled in this study, 98 received EVE + EXE and 45 received EXE + placebo. At the time of database lock, 55 Asian patients (56%) in the combination arm had experienced disease progression compared with 34 patients (76%) in the EVE + placebo arm. Combination therapy reduced the risk of disease progression versus EXE alone by 44% among Asian patients (HR = 0.56; 95% CI, 0.37-0.87; P &lt; .05). Commonly reported adverse events in the combination arm were consistent with previous clinical studies of mTOR inhibitors and included stomatitis (80%), rash (49%), dysgeusia (31%). Adverse events that occurred more frequently in the Asian subset versus Caucasians included stomatitis (80% vs 54%) and rash (49% vs 37%), whereas dyspnea (8% vs 24%) and asthenia (1% vs 17%) occurred less frequently in the Asian subset versus Caucasians. Conclusions: The addition of EVE to EXE significantly prolonged PFS in Asian patients versus EXE alone. Adverse events were higher in the combination arm but generally manageable. Combining EVE with an AI is a safe and effective treatment option for Asian women with non-steroidal AI resistant/refractory ER+ ABC.
Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy.
Authors: Martin H. Schuler, David Planchard, James Chih-Hsin Yang, Joo-Hang Kim, Filippo De Marinis, Yuh-Min Chen, Caicun Zhou, Jaafar Bennouna, Xiaoqing Liu, Ji Feng Feng, Paolo Bidoli, Janos Strausz, Sai-Hong Ignatius Ou, Vikram K. Chand, Bushi Wang, Gerd Michael Munzert, Keunchil Park
Journal: Journal of Clinical Oncology (2012)

7557 Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p&lt;0.0001). The most common grade 3/4 adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 patients remain on treatment. Conclusions: Afatinib monotherapy provided a clinically meaningful benefit in this large, treatment-refractory NSCLC trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs achieved prolonged disease control upon continued ErbB blockade.
Antiemetic recommendations for breast cancer patients receiving highly emetogenic chemotherapy: A systematic review incorporating network meta-analyses.
Authors: Terry L. Ng, Brian Hutton, Iryna Kuchuk, Joseph A. Roscoe, Sasha Mazzarello, Mark Clemons
Journal: Journal of Clinical Oncology (2014)

e17608 Background: Despite consensus group recommendations for anti-emetic use in patients receiving highly emetogenic anthracycline and cyclophosphamide-based chemotherapy (A and C-CT), clinical experience suggests that control of chemotherapy-induced nausea and vomiting [CINV] is suboptimal. Network meta-analysis (NMA) of randomised controlled trials (RCTs) was used to compare the effectiveness of competing anti-emetic regimens. Methods: A systematic literature search of 3 electronic databases for RCTs comparing anti-emetic regimens in breast cancer patients receiving A and C-CT was performed. Two reviewers independently screened all abstracts and full texts. The primary outcome was overall total control of CINV (no nausea, no vomiting, and no rescue anti-emetics for 5 days post-chemotherapy [CT]). Results: From 1,062 citations identified, 152 were retained after abstract screening, and 30 were retained after full-text screening. Most comparisons in the network of treatments were supported by only one RCT. Limitations to performing a network meta-analysis included significant heterogeneity in the number of anti-emetic regimens (n=15), chemotherapy regimen used, and mixed populations of tumour types across trials. We found over 15 different published study endpoints that were variations of our primary outcome. Of the 30 trials that met our inclusion criteria, 6 reported overall total control and 15 reported overall complete response (no vomiting and no rescue medications for 5 days post-CT). Results from NMA failed to identify important differences between competing regimens. Conclusions: We identified marked heterogeneity between trials including variability in study design, sample size, anti-emetic regimens, chemotherapy regimens, and reporting of patient characteristics and outcome measures. Given these limitations, despite the recommendations of consensus groups, NMA was unable to identify an optimal anti-emetic regimen based on all the available evidence at this time.
Phase I trial of the CDK 4/6 inhibitor, P1446A-05 (voruciclib) in combination with the BRAF inhibitor (BRAFi), vemurafenib in advanced, BRAF-mutant melanoma.
Authors: Adi Diab, Alison Martin, Lauren Simpson, Alain Patrick Algazi, Purvi Chawla, Dae Won Kim, Sourav Santra, Vruti Patel, Nitin Jadhav, Dhiraj Abhyankar, Michael A. Davies, Shama C. Buch, Kevin Kim, Adil Daud
Journal: Journal of Clinical Oncology (2015)

9076 Background: P1446A-05 is a potent, selective CDK 4/6 inhibitor with activity in multiple BRAF-mutant and wild type cell lines. The BRAFi have been transformative in the therapy of BRAF-mutant melanoma. However, resistance does develop frequently, often in only a few months. The addition of a CDK 4/6 inhibitor to BRAF inhibitors is supported by extensive preclinical data. Methods: A prospective, multicenter Phase I trial was conducted to determine the safety, maximum tolerated dose (MTD) and dose limiting toxicity of P1446A-05 in combination with Vemurafenib. The Phase I, "dose escalation" part of the trial is reported here. A total of 4 cohorts were planned in the Vemurafenib-arm of this phase in the trial. Vemurafenib was escalated from 720 mg PO BID to 960 mg PO BID and P1446A-05 was planned to be escalated from 150 mg up to 350 mg PO QD. In each cohort, 3 to 6 patients were planned to be enrolled. Extensive PK analysis was conducted. Eligible patients could be BRAFi-naïve or resistant, ECOG PS 0-1, and QTc < 480 at baseline. Results: A total of 9 patients have been accrued to date. The combination has been well tolerated and no significant drug-drug interactions have been seen. Adverse events include fatigue (n = 3), headache (n = 3) and constipation (n = 3); no DLTs have been observed. Cmax for P1446A-05 in combination was observed to be 796 ng/ml on D1 and AUC0-24was 14451 ng.hr/ml, similar to that achieved with the single agent, P1446A-05. Nine patients were assessable for clinical response (3 BRAFi-naïve, 6 refractory). Responses were seen in 3/3 BRAFi-naive patients [1 complete response (CR) and 2 partial responses (PR)]. Conclusions: The combination of P1446A-05 and Vemurafenib is well tolerated. This trial was stopped by the Sponsor after accrual of 9 patients (2 dose escalation cohorts) for non-medical reasons. The MTD was not reached in the trial. Based on the available data, the recommended dose for further testing of this combination is Vemurafenib 960 mg PO BID with 150 mg PO QD of P1446A-05. No drug-drug interactions were observed and the PK parameters for the combination were acceptable. Preliminary evidence of efficacy in the treatment-naïve patients was seen. Clinical trial information: NCT01841463.
Outcomes of stage IA polyp-limited vs endometrium-limited epithelial high grade endometrial carcinoma (EMC).
Authors: Lusha Liang, Alexendar Reinaldo Perez, Nicholas A Cangemi, Qin Zhou, Alexia Iasonos, Kaled M. Alektiar, Nadeem Abu-Rustum, Vicky Makker
Journal: Journal of Clinical Oncology (2015)

e16500 Background: Optimal management of stage IA polyp-limited (PL) vs endometrium-limited (EL) epithelial high grade EMC is unclear and warrants further investigation. Methods: From 10/1995-11/2012, 85 women underwent hysterectomy/salpingo-oophorectomy at MSKCC. 100% of pts were surgically staged with lymph node assessment and had stage IA EMC. Clinicopathologic characteristics/therapies received by pts with clear cell (CC), serous (S), or mixed (M) histology EMC were compared using Kruskal-Wallis test. Univariate PFS and OS analysis were analyzed by Log-Rank test. PFS and OS by treatment type (no adjuvant treatment, IVRT, or platinum-based chemotherapy+/- RT) were determined using landmark analyses by resetting the starting time to 2 months post-op. Results: Histologies: CC (14 pts, 16.5%), S (56 pts, 65.9%), or M (serous/endometrioid or serous/clear cell) (15 pts, 17.6%). 49 pts (57.6%) had PL disease and 36 pts (42.4%) had EL disease. Median follow-up for survivors was 46.5 months (range: 1.98-188.8 mos). There were no significant differences in clinicopathologic characteristics between pts within the 3 treatment groups with regards to: age at diagnosis, mean BMI, ECOG performance status, PL vs EL disease, diabetes, or race. The 3y PFS rate is 94.9% and the 3y OS rate is 98.8%. Univariate PFS and OS analysis revealed that age is a relevant diagnostic factor [(PFS: HR (95%CI):1.13(1.02-1.25); P = 0.022 and OS HR (95%CI):1.19(1.02-1.38); P = 0.03]. Conclusions: Outcomes of surgical stage IA epithelial EMC which are PL vs EL are equally favorable regardless of histologic subtype or adjuvant therapy received. The role of adjuvant therapy in this specific subset of EMC warrants further randomized trial investigation. Select demographics + association table. Treatment Groups Variable All None RT Only Chemo+/-RT p-value* All 85 20 21 44 Age at Diagnosis Median(Mean) 65(65.1) 68(67.1) 64(62.8) 65(65.3) 0.114 Range 46~82 54~77 49~82 46~80 Histology Serous 56(65.9%) 13(23.2%) 11(19.6%) 32(57.1%) 0.022 Clear Cell Carcinoma 14(16.5%) 5(35.7%) 7(50%) 2(14.3%) Mixed 15(17.6%) 2(13.3%) 3(20%) 10(66.7%) Polyp No 36(42.4%) 5(13.9%) 9(25%) 22(61.1%) 0.175 Yes 49(57.6%) 15(30.6%) 12(24.5%) 22(44.9%)
Randomized phase II clinical trial to assess MUC1 specific immune response to L-BLP25 vaccine in addition to standard therapy in newly diagnosed high-risk prostate cancer.
Authors: Nishith K. Singh, Marijo Bilusic, Joseph W. Kim, Christopher Ryan Heery, Martin H. Falk, Bradford J Wood, Peter A. Pinto, William L. Dahut, Aradhana Kaushal, Anna Couvillon, Myrna Rauckhorst, Peter L. Choyke, Ismail B. Turkbey, Jane B. Trepel, Kwong Yok Tsang, Jeffrey Schlom, James L. Gulley, Ravi A. Madan
Journal: Journal of Clinical Oncology (2012)

TPS4701 Background: In high-risk prostate cancer, radiation therapy (RT) + androgen deprivation therapy (ADT) improve survival. Nonetheless, 10-year disease specific mortality is about 25%. L-BLP25 is a cancer vaccine containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may enhance immune targeting of cells that express MUC1 (e.g. prostate cancer). In murine models, RT synergizes with vaccine-induced anti-cancer immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular Fas and co-stimulatory/adhesion molecules). ADT augments T-cell trafficking to prostate. Immune response to combining the three (L-BLP25 + RT + ADT) is not known. The current trial intends to study this immune response to L-BLP25 + RT + ADT and compare it to RT+ADT alone. Using ELISPOT, endo-rectal MRI and serial prostate biopsies, this trial was designed to correlate systemic immune response with changes in tumor imaging and/or tumor microenvironment after treatment with L-BLP25. This trial may provide insight into immune response biomarkers that are most appropriate in this setting. Methods: A randomized (1:1), open-label, phase II trial of 42 pts is planned. Eligibility: Adult males with newly diagnosed high-risk prostate cancer (T3 or Gleason ≥ 8 or seminal vesicle involvement or N1 or PSA&gt;20) and HLA-A2/A3 positivity (to allow for ELISPOT analysis). The vaccine arm will receive RT + 2-year ADT + L-BLP25. Standard arm will receive RT + 2-year ADT. L-BLP25 vaccine schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6 weekly X 4 starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases suppressor T-cells) will be given 3 days before L-BLP25 to enhance immune response in the vaccine arm. The impact of L-BLP25 + RT+ADT on MUC-1-specific systemic immune response will be determined using interval peripheral blood ELISPOT assays. Endo-rectal coil MRI will be done before and after treatment to study prostate signal changes for correlative and predictive analysis. MRI-UltraSound guided lesion-targeted serial prostate biopsies will be obtained to assess immune response in tumor microenvironment. Two pts have been enrolled.
Carboplatin dosing based on estimated Glomerular Filtration Rate (GFR) using IDMS creatinine: A comparison of estimated GFR based on IDMS creatinine in the Cockroft-Gault (CG) formula (IDMS-GFR), with measured GFR using <sup>51</sup>Cr-EDTA (<sup>51</sup>Cr-GFR).
Authors: James R. Whittle, Jonathan Wayne Graham, Huda Ismail, Meir Lichtenstein, Rodney J Hicks, Orla McNally, Linda R. Mileshkin, Diana Zannino, Mark Rosenthal, Danny Rischin, Anne L. Hamilton
Journal: Journal of Clinical Oncology (2015)

2576 Background: 51Cr-GFR is considered a gold standard of GFR assessment, but the CG formula is routinely used to estimate GFR for dosing of Carboplatin. Gynaecological cancer trials adopted the convention that Carboplatin be dosed at AUC5 in patients using 51Cr-GFR, and AUC6 in patients using IDMS-GFR. IDMS-GFR is routinely capped at 125ml/min for Carboplatin dosing, as low IDMS levels in patients with normal renal function can generate spuriously high GFR estimates. Methods: We performed a multicenter retrospective study of patients who had a 51Cr-GFR assessment, with a matched serum IDMS creatinine. IDMS-GFR and 51Cr-GFR were compared in each patient. Carboplatin dose based on 51Cr-GFR in the Calvert formula at AUC 5 was used as the reference. Results: 551 patients were available for analysis. Median age 62 (19 – 90), 64% female. Indication for GFR evaluation: malignancy (85%), assessment for live kidney donation (12%), other (3%). Median ratio of IDMS-GFR : 51Cr-GFR 1.04 (0.43 – 3.38); < 0.8 in 72 patients (13%), > 1.2 in 180 patients (33%). Median (IDMS-GFR - 51Cr-GFR) +3.95ml/min (-81 – +176). Mean percentage error (MPE) was 12%. Despite capping of IDMS-GFR at 125ml/min, its use in the Calvert formula at AUC6 would have underdosed 99 patients (18%) by > 100mg Carboplatin compared to 51Cr-GFR at AUC6, and overdosed 128 patients (23%) by the same amount. 104 patients (19%) would be overdosed by > 20%. The convention of the use of AUC5 in patients who have 51Cr-GFR, and AUC6 in patients who have IDMS-GFR (capped), would lead to differences in planned dose between the 2 methods of > 100mg in 326 patients (59%), and by > 20% in 264 (48%). Univariate analysis identified BMI ( > 35, MPE 39%), gender (female MPE 15%), GFR indication (malignancy MPE 11%) as risk factors for overestimate of GFR by IDMS-GFR, and BMI < 20 for underestimate (MPE -3.5%). Conclusions: IDMS-GFR is an unreliable surrogate for 51Cr-GFR. The convention of considering AUC5 carboplatin based on 51Cr-GFR, and AUC6 carboplatin based on calculated GFR, as equivalent is invalid, and should be abandoned.