tbuckley/cabot-search huggingface dataset:
Effect of RNAi-based β-catenin inhibition on immunosuppressive Wnt-activated tumors in combination with IDOi/PD-1 immunotherapy.
Authors: Shanthi Ganesh, Serena Shui, Kevin Craig, Weimin Wang, Bob D Brown, Marc Abrams
Journal: Journal of Clinical Oncology (2018)

e15038 Background: Wnt/β-catenin pathway activation has been correlated with T-cell exclusion across most human tumors. Additionally, Wnt signaling promotes constitutive IDO1 expression in some tumor contexts, which in turn promotes recruitment and expansion of immunosuppressive cell types to the tumor microenvironment. Therefore, inhibition of both β-catenin and IDO1 may be an effective strategy to sensitize tumors with dysregulated Wnt to checkpoint inhibition. Epacadostat is an IDO1 inhibitor (IDOi) that is being currently evaluated in advanced clinical trials. DCR-BCAT is an RNAi-based experimental medicine targeting classically-undruggable β-catenin formulated in a tumor-selective nanoparticle. Methods: Syngeneic murine models with/without Wnt activation (4T1 and B16F10) were treated with DCR-BCAT, epacadostat, αPD-1 as monotherapies or in combination. In combination studies, animals were pre-treated with IDOi and/or DCR-BCAT to modulate the immune cell populations in the tumor microenvironment before treating with αPD-1. Tumor growth kinetics, as well as pharmacodynamic biomarkers were evaluated. Results: In Wnt-activated 4T1 tumors, treatment with single agents showed modest anti-tumor efficacy. Combination therapy with DCR-BCAT and αPD-1 or IDOi demonstrated tumor stasis. Remarkably, mice that were treated with all three agents demonstrated tumor regression with pronounced reduction of the tumor volume, coinciding with an increase in CD8+ T cells and a reduction of immunosuppressive T-regulatory cells. Responses were significantly different in non-Wnt activated B16F10 tumors: single agents and DCR-BCAT/IDOi were ineffective, whereas the other double and triple combinations demonstrated stasis but not regression. Conclusions: These data offer proof-of-concept for conversion of highly immunosuppressive non-inflamed tumors to inflamed, checkpoint-sensitized tumors by dual inhibition of β-catenin and IDO1. This study provides a strong rationale for clinical evaluation of this RNAi-based combination therapy in tumors with Wnt/IDO1 dysregulation.
Differences in the expression of PTP-1B phosphatase in prostate cancer (PC) patients with and without adverse pathologic features (APF).
Authors: Maria Teresa Bourlon, Mauricio Mora Pineda, Shaddai Urbina Ramírez, Eucario Leon Rodriguez, Yemil Atisha-Fregoso, Jazmin De Anda Gonzalez
Journal: Journal of Clinical Oncology (2017)

e16543 Background: Localized PC is a heterogeneous disease. Currently, clinical markers are insufficient to predict the presence of APF before prostatectomy. PTP-1B phosphatase is implicated in insulin/leptin receptor activity and in cancer cells migration and invasion. PTP-1B could be a predictor marker of APF in PC. The aim was to compare the expression of PTP-1B in PC patients with vs without APF. The secondary aim was to evaluate PTP-1B as an independent predictive factor. Methods: Radical prostatectomy samples of patients with localized PC performed in a single center were identified (1990-2015). Pathologic features were re-evaluated by an expert pathologist. APF was defined as: seminal vesicle invasion or extra-capsular invasion or positive surgical margins. Tissue microarrays (TMA) immunohistochemistry for PTP-1B was done and evaluated in a 0-9 score. Statistics: Mann Whitney U-test was used to compare variables, and Spearman´s rho for correlation. To evaluate the association of PTP-1B score with the outcome of APF, a logistic regression analysis with two models was performed. The first, included biologically associated variables (metformin use, T2DM), and the second, stablished risk factors (PSA, Gleason score (GS)). Results: We identified 352 PC cases. In 190 a TMA was done, and 73 were optimal for PTP-1B expression evaluation and were included for analysis. Patient´s mean age was 62 ± 7 yo. Twenty nine (40%) without APF, and 44 (60%) with APF. Median PTP-1B score was 5 [3-8] in patients without APF vs 8 [5-9] in patients with APF (p = 0.026). PTP-1B score correlated with GS (r = 0.24, p = 0.042) and PSA (r = 0.24, p = 0.046). PTP-1B was a risk factor for the presence of APF even adjusted for the presence of metformin use and T2DM (OR 1.21; 95% CI 1.01-1.45; p = 0.037). However, PTP-1B score was not an independent risk factor for APF when PSA and GS were included (OR 1.68; 95% CI 0.97-1.41; p = 0.11). The addition of PTP-1B score to the prediction model for APF, which includes GS and PSA, only provided a slight increase in accuracy (AUC 0.73; 95% CI 0.61-0.84 vs AUC 0.71; 95% CI 0.59-0.82). Conclusions: Patients with PC and APF have an increased expression of PTP-1B.
Serial next generation sequencing (NGS) of cell free DNA (cfDNA) and clonal evolution of <i>AKT1</i> E17K mutant tumors: Analyses from patients (pts) enrolled on a phase I basket study of an AKT inhibitor (AZD5363).
Authors: Lillian Mary Smyth, Jonathan B Reichel, Jiabin Tang, Juber Ahamad A Patel, Fanli Meng, S Duygu Selcuklu, Daoqi You, Aliaksandra Samoila, Gaia Schiavon, Bob T. Li, Pedram Razavi, Salvatore Piscuoglio, Jorge S. Reis-Filho, Clifford A. Hudis, Jose Baselga, David B. Solit, Barry S. Taylor, David Michael Hyman, Michael F. Berger, Sarat Chandarlapaty
Journal: Journal of Clinical Oncology (2016)

11500 Background: E17K mutation of AKT1 is a recurrent, oncogenic event in solid tumors where treatment (Tx) with AKT inhibition has shown promise. Little is known about the significance of genomic alterations that coexist with AKT1or become acquired in these tumors. To investigate these alterations, we sought tumor genotypes and their evolution before, during, and after Tx with an AKT inhibitor (AKTi). Here we report interim results from this ongoing study. Methods: Eligible pts at MSKCC had AKT1 E17K mutation (mut) positive (+) solid tumors and were enrolled to the multi-centre basket study (NCT01226316) of AZD5363, an oral catalytic pan-AKTi. AKT mut status was prospectively confirmed on archival or fresh tumor samples prior to enrollment. Serial plasma samples were collected for detection and tracking of the AKT1 E17K mut (expressed as the mutant allele fraction [MAFAKT ]) in cfDNA by allele-specific droplet digital PCR (ddPCR) and exon capture NGS analysis of 410 genes (MSK-IMPACT). Tumor NGS was also performed on available pre-Tx and progression biopsy specimens. Results: From October 2014 to December 2015, 24 pts had cfDNA extracted from 82 plasma samples for NGS. Mean sequencing coverage was 436. cfDNA was AKT1 E17K mut +ve in 22/24 (92%) pts by ddPCR and NGS. MAFAKT by NGS and ddPCR was highly concordant (r= 0.98; p<2.2e-16). MAFAKT by ddPCR could be correlated with tumor response, with durable RECIST responses seen in 5/5 (100%) pts with persistent (>21 days) cfDNA clearance. The most frequently mutated genes in addition to AKT1 were ESR1 (27%), TP53 (23%) and GATA3 (18%) with an average of 4 muts per pt. Pre-Tx cfDNA NGS revealed muts not observed in the archival specimen in 4/9 (44%) pts. 7 muts emerged on NGS of on-study and progression cfDNA, which were not observed or found at low abundance in pre-Tx cfDNA, including muts in GRIN2A, TP53 and CEBPA, among others. Second site muts in AKT1 were not observed. Conclusions: Serial NGS of cfDNA is feasible and highly concordant with ddPCR. Throughout therapy with an AKTi, the AKT1 E17K alteration appears to be clonal, however, serial NGS can identify emergent genomic alterations. Clinical trial information: NCT01226316.
Poorly differentiated malignant salivary gland tumors (MSGTs) amenable to resection and their association with higher stage, higher prevalence in males, and poor prognosis.
Authors: Mohammad Razaq, Tyler Gutschenritter, Sara Vesely, Michael Machiorlatti, Wajeeha Razaq
Journal: Journal of Clinical Oncology (2016)

e17563 Background: Outcome data on MSGTs is limited with most coming from retrospective single institution experiences. We present a retrospective outcome of patients with resectable MSGTs treated at our institute between 2002 & 2014 Methods: 108 patients with stage I-IVB, resectable tumor were identified, 89 meeting inclusion criteria were included in analysis. Patients with squamous histology, missing data and not treated in standard fashion were excluded. We evaluated association of stage with age, grade (G) and resection margins using Chi-Square analysis. We estimated survival rates for sex and grade groups using Kaplan-Meier curves. A Cox Proportional Hazard model was used to assess the association of treatment groups with OS adjusting for age, resection margins and stage. Results: A total of 89 patients were assessed. Median age was 58 years. The sample was 55% male and 88% white. G1,G2, G3 were 28, 21, and 29% respectively. 21% had undetermined G. Early stage (ES-stage 1 &2) were 49% and late stage (LS- stage 3&4) were 51%. Histologies were; 40% mucoepidermoid histology, 19% acinar, 12% adenoid cystic, 11% adenocarcinoma and 18% other.75% had R0 resection. LS had significantly higher G3 tumors (49% LS vs 9% ES, p = .0002) and significantly higher R1 resection (35% LS vs 14% ES, p = 0.0172). There was no significant association between stage and age or sex. Males had more G3 tumor compared to females (41% vs 15%, p = 0.026). 75th percentile survival for female was 8.39 & male 3.05 years (p = .00002). Adjusting for age, margins, and stage the hazard ratio (HR) of death for G2 was 3.30 times higher than G1 (p = 0.33) and for G3 17.74 times higher than G1 (p = 0.013). After adjustment HR of death for males was 3.84 higher than females (p = 0.058). Conclusions: In localized MSGT treated with surgery ± radiation± chemo, tumors with higher grade present with advanced stage and have poor prognosis.G3 tumors are more common in males than females. Males have poorer OS than females but not in multivariate analysis. Further studies should be carried out to optimize treatment in higher grade tumors and role of chemotherapy should be explored.
A comparative study of ALK and ROS genes rearrangements among IHC/FISH/CLART in NSCLC.
Authors: Maria Cortes-Sempere, Maria Jesus Sanz, Nuria Manjon, Marta Sanchez-Muñoz, Rosa Somoza, Yolanda Ruano, Irene Sansano, Javier Hernandez-Losa, Jose Luis Rodriguez-Peralto, Maria Luisa Villahermosa
Journal: Journal of Clinical Oncology (2018)

e21152 Background: With the launching of the new GENOMICA’s kit for the detection of ALK and ROS1 genes rearrangements in non-small cell lung cancer (NSCLC), a comparative study with the current two routine diagnosis techniques, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) was performed. CLART CMA ALK-ROS.1 detects the main chromosomal translocations of ALK gene with EML.4 and ROS1 gene with SDC4, CD74 and SLC34A2 in patients with lung cancer. Starting material is extracted RNA from lung biopsies in the form of formalin-fixed paraffin-embedded tumor tissue (FFPE). Detection is based on our CLART® technology: End-point Multiplex PCR amplification, followed by visualization in low-density microarray. The objective of this study is to determine the diagnostic validity of the GENOMICA CLART system as a routine technique in the detection of these rearrangements in clinical practice. Methods: Two Spanish hospitals participated in this clinical study: Hospital Universitario 12 de Octubre from Madrid and Hospital Vall d’Hebron from Barcelona. 86 FFPE tissue samples from NSCLC were obtained by surgery, bronchoscopy or biopsy-puncture. They were assessed with IHC or/and FISH and with CLART system in parallel. The discrepancies were analysed by NGS with the Oncomine™ Focus Assay panel from Thermo Fisher Scientific. Results: 6 out of 86 samples were positive with the routine techniques, 1 positive for ROS1 and 5 for ALK rearrangements. Out of these 6 samples, 3 were positive and 3 were negative with CLART system. The 3 discrepancies were analysed by NGS and 1 resulted positive for a ROS1 variant that GENOMICA kit does not detect and the other 2 discrepancies were WT. Conclusions: Comparing the results obtained from CLART system and IHC/FISH we have a 96.5% of concordance, but after the discrepancies analysis by NGS we could observe that the results of the routine techniques had 3 false negatives and that CLART system have a 100% of sensitivity and specificity. CLARTCMA ALK-ROS.1 may provide an effective and accurate alternative to FISH/IHC testing for the detection of known EML4-ALK and ROS1 rearrangements in clinical diagnostic settings, being a method easy to perform and to be integrated into clinical routine.
Global trends in phase I trials: Changes in cancer types of enrolled patients in 1991-2015.
Authors: Kota Itahashi, Toshio Shimizu, Takafumi Koyama, Shunsuke Kondo, Yutaka Fujiwara, Noboru Yamamoto
Journal: Journal of Clinical Oncology (2017)

e14037 Background: Detailed information on cancer types of enrolled patients in phase I oncology trials is scarce. Global distribution, time-dependent change, and regional differences were evaluated. Methods: A systematic search of the PubMed database was performed and all single-agent phase I clinical trials permitting enrollment of all-comer patients (i.e. patients with any type of solid tumor) published between Jan 1991 and Dec 2015 were included. The trials expected to enroll specific patient populations were excluded per the criteria developed for this study. Results: A total of 10,596 articles were reviewed by three researchers. We identified 866 eligible clinical trials, which enrolled a total of 28,751 patients with advanced solid tumors. The extracted trials were performed mainly in North America (55.5%), Europe (27.8%), and Asia (10.5%). Colorectal (n = 7,483; 26.0%) and lung (n = 3,211; 11.2%) cancers were the most prevalent solid tumors, followed by sarcoma (n = 1,739, 6.0%), breast cancer (n = 1,625, 5.7%), and renal cancer (n = 1,547, 5.4%). The proportion of patients with either colorectal or lung cancer tended to decrease with time: 28.0% and 16.3% in 1991-1995; 31.9% and 12.4% in 1996-2000; 27.1% and 10.8% in 2001-2005; 23.9% and 10.7% in 2006-2010; and 23.4% and 9.9% in 2011-2015. In the same years, the proportion of trials, in which patients with either of these two cancers accounted for ≥50% of the total number of patients in each trial, also decreased: 33 of 67 trials (33/67) (49.3%), 59/142 (41.5%), 62/223 (27.8%), 38/189 (20.1%), and 40/245 (16.3%), respectively. This tendency was consistent in the three main regions. Instead, the proportion of patients with various types of cancer increased, leading to diversification of enrolled patients in phase I trials. Conclusions: The distribution of cancer types among enrolled patients in all-comer phase I trials has changed. Patients with common forms of cancer, whose general condition is likely to be deteriorated after many lines of standard chemotherapy or other approved drugs, tend to not participate in these trials. Diversification of enrolled patients will increase the chances of assessing the preliminary efficacy of new treatments against various types of cancer.
Secondary prophylaxis with romiplostim for temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma.
Authors: Emilie Le Rhun, Patrick Devos, Caroline Houillier, Stéphanie Cartalat-Carel, Olivier L. Chinot, Anna Luisa Di Stefano, Malek Dib, Nicolas Reyns, François Dubois, Michael Weller
Journal: Journal of Clinical Oncology (2018)

2042 Background: Thrombocytopenia is a major adverse event of temozolomide (TMZ) chemotherapy. It may lead to dose reduction/interruption or bleeding. Platum (NCT 02227576) was a phase II open label, multicenter single arm trial evaluating the thrombopoetin receptor agonist, romiplostim, for secondary prevention of TMZ-induced thrombocytopenia in patients with newly diagnosed glioblastoma. Methods: Patients diagnosed with CTCAE grade 3/4 thrombocytopenia during standard treatment of glioblastoma received weekly subcutaneous injections of romiplostim at a starting dose of 750 µg. Dose adjustments were based on weekly platelets counts. The study aimed at demonstrating that the percentage of thrombopenic patients treated with romiplostim able to complete 6 cycles of maintenance TMZ chemotherapy exceeded 10% (p0 = 0.10; pA = 0.35) (Gerber et al., 2007). Using type I error equal to 0.05 and 95% power, 31 patients had to be recruited. According to a Fleming's two step design, an interim analysis was planned after recruitment of 20 evaluable patients. Three scenarios were pre-defined: (1) ≤2 patients meeting the endpoint: termination for futility (p < P0), (2) ≥6 patients meeting the endpoint: termination for success (p > P0), (3) 3 to 5 patients meeting the endpoint: enrollment of 11 more evaluable patients. Results: 20 patients were enrolled in step 1 between July 2014 and December 2016. Median age was 61 (range: 33-73 years). Surgery included biopsy (n = 8), partial (n = 5), subtotal (n = 1) or gross total resection (n = 6). Isocitrate dehydrogenase 1R132H mutations were noted in 2 cases. 12 patients enrolled in step 1 received the 6 planned maintenance TMZ cycles, corresponding to a success rate of 60% (95% confidence interval 36-81). Three of 8 patients discontinued TMZ because they did not respond to romiplostim, 3 for progression and 1 for clinical deterioration prior to completion of six cycles, 1 due to an adverse event. Romipostim was well tolerated. The trial was terminated early for success. Conclusions: Thrombopoetin receptor agonists such as romiplostin allow to assure adequate exposure to chemotherapy in glioblastoma patients experiencing early, severe chemotherapy-induced thrombocytopenia. Clinical trial information: NCT 02227576.
Prognostic value of CEA mRNA in the peritoneal lavage of patients undergoing curative surgery for gastric cancer.
Authors: Yan Yang, Yang Yang, Jia Wei, Juan Du, Hui Yang, Quanan Zhang, Baorui Liu
Journal: Journal of Clinical Oncology (2018)

e16090 Background: Most patients have peritoneal metastasis over the course of gastric cancer. The prognosis of these patients with peritoneal metastasis is extremely poor. The aim of this study is to elevate the clinic significant of the expression of Carcinoembryonic Antigen mRNA (CEA mRNA) in peritoneal lavage in stage III gastric cancer. Methods: From 2013 to 2016, RT PCR were used to test CEA mRNA in peritoneal lavage in 100 patients after surgery with pathological stage III gastric cancer in Drum Tower Hospital, Medical School of Nanjing University and The Affiliated Jiangning hospital with Nanjing Medical School. According to the result of CEA mRNA in peritoneal lavage, patients were divided into CEA-positive group and CEA-negative group. All the patients received postoperative adjuvant chemotherapy, 1-year disease-free survival rate was compared between the two groups of patients. Results: Of 100 patients, 45 were positive for peritoneal lavage CEA mRNA. The higher positive CEA mRNA rate was associated with higher T stage, or higher N stage. The 1-year diease-free survival rate for patients with negative CEA mRNA was statistically significant higher than that for patients with positive CEA mRNA (84% vs 57%, p < 0.05). Conclusions: Peritoneal lavage CEA mRNA can predict the prognosis of patients with stage III gastric cancer. Patients with positive CEA mRNA in peritoneal lavage should consider a more positive treatment including intraperitoneal therapy.
Clinical outcomes by nephrectomy status in METEOR, a randomized phase 3 trial of cabozantinib (cabo) vs everolimus (eve) in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Nizar M. Tannir, Thomas Powles, Bernard J. Escudier, Frede Donskov, Viktor Grünwald, Cora N. Sternberg, Manuela Schmidinger, Patrick Schoffski, Cezary Szczylik, Katriina Johanna Peltola, Dmitry Nosov, Bohuslav Melichar, Douglas O. Clary, Christian Scheffold, Robert J. Motzer, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

4570 Background: Most pts with advanced RCC undergo nephrectomy (Nx) as curative or palliative therapy. In a retrospective analysis of pts treated with targeted therapy, pts who were older and had more comorbidities and higher tumor grade were less likely to have had Nx. Pts without Nx had shorter overall survival (OS) than pts with Nx (Hanna, J Clin Oncol 2016). Here we report outcomes for cabo vs eve in pts with advanced RCC with or without prior Nx in the phase 3 METEOR trial (NCT01865747). Methods: 658 pts with clear cell RCC and ≥1 prior VEGFR TKI were randomized 1:1 to receive cabo at 60 mg qd or eve at 10 mg qd. Stratification was by MSKCC risk group and number of prior VEGFR TKIs. Endpoints included progression-free survival (PFS), OS, and objective response rate (ORR). Results: 85% of enrolled pts had prior Nx of which 7% were partial; 15% had no prior nephrectomy (NoNx). Baseline characteristics, including Karnofsky performance status (KPS), MSKCC risk group, time from diagnosis to randomization, and median sum of diameters (SoD) for tumor target lesions, were less favorable for the NoNx subgroup (Table). Improved PFS and OS with cabo vs eve were observed regardless of Nx status. For the Nx subgroup, the hazard ratio (HR) was 0.51 (95% CI 0.41-0.64) for PFS and 0.66 (95% CI 0.52-0.84) for OS; for the NoNx subgroup, the HR was 0.51 (95% CI 0.30-0.86) for PFS and 0.75 (95% CI 0.44-1.27) for OS. Median OS was longer in the Nx subgroup for both treatment arms (Table). ORR per independent radiology committee (IRC) for cabo vs eve was 17% vs 4% for Nx and 21% vs 2% for NoNx. Grade 3 or 4 adverse events for both subgroups were generally consistent with the safety profiles of cabo and eve in the overall population. Conclusions: Cabo improved PFS, ORR, and OS compared with eve in pts with advanced RCC irrespective of nephrectomy status. Clinical trial information: NCT01865747. [Table: see text]