tbuckley/cabot-search huggingface dataset:
Survival outcomes in plasmacytoid urothelial carcinoma: Results with contemporary systemic therapy.
Authors: Neda Hashemi-Sadraei, Carmen M Perrino, M. Francesca Monn, Elhaam Bandali, Liang Cheng, Muhammad Idrees, Richard Bihrle, Michael O. Koch, John Eble, Chia-Sui Kao, Nabil Adra, Roberto Pili, David A. Grignon, Hristos Z. Kaimakliotis, Costantine Albany
Journal: Journal of Clinical Oncology (2018)

e16525 Background: Plasmacytoid urothelial carcinoma (PUC) is a rare variant histology where malignant cells resemble those of plasmacytoma. Majority of the patients (pts) are upstaged at the time of cystectomy and prognosis is extremely poor. Management remains controversial. Methods: We retrospectively reviewed treatments and outcomes in pts with PUC seen at our institution between 1996 and 2017. The Kaplan-Meier method was used to calculate overall survival. Results: A total of 72 pts (59 male, 13 female) with a median age of 67 (range, 36-90) were identified. Six pts presented with metastatic disease, whereas 66 were diagnosed with clinically localized PUC. Forty-five pts had upfront radical cystectomy (RC), 16 had neoadjuvant chemotherapy followed by RC (NAC-RC), and 11 elected for bladder preservation approaches. Upstaging was seen on post-op pathology in 13 (81%) of pts who received NAC-RC. Only one pt had a pathologic complete response with pT0N0. Seventeen pts received adjuvant chemotherapy, 2 of which received NAC as well. Median overall survival (OS) for all pts from time of initial diagnosis was 17.7 months (mo), (stage I-III vs stage IV: 21.0 vs 10.4 mo, p = 0.053). Median OS was 12.6 mo from time of cystectomy for patients undergoing RC. Median OS for pts who received NAC was 15.9 mo, compared to 82.8 mo in pts who received adjuvant chemotherapy and 10.1 mo in pts undergoing cystectomy alone (p = 0.086). Median recurrence free survival (RFS) was 13.9 mo. Median RFS for pts who received NAC was 12.9 mo, compared to 15.7 mo in pts who received adjuvant chemotherapy and 13.9 mo in pts undergoing cystectomy alone (p = 0.073). Median OS in 9 pts with pure (100%) PUC compared to mixed plasmacytoid variants (PCV) was 46.1 vs 15.9 mo (p = 0.503). Median RFS in pts with pure PUC compared to mixed PCV was 34.3 vs 13.8 mo (p = 0.0102). Pts with < 75% PCV morphology had an OS of 11.6 mo compared to 21.4 mo in pts with ≥75% PCV morphology (p = 0.312). Conclusions: PUC is an aggressive variant with overall poor outcomes. NAC-RC appeared to result in poor outcome while adjuvant chemotherapy appeared to trend toward better clinical outcome. The amount of PCV morphology did not appear to have an effect on outcome.
Can chemoradiotherapy improve survival after an R1 resection for gastric cancer: A retrospective study of a Chinese cohort.
Authors: Menglong Zhou, Guichao Li, Ran Hu, Wang Yang, Yan Wang, Zhen Zhang
Journal: Journal of Clinical Oncology (2018)

e16092 Background: The aim of this study was to compare the efficacy of postoperative chemoradiotherapy (CRT) and chemotherapy (ChT) on survival of non-metastatic gastric cancer (GC) patients who had undergone an R1 resection. Methods: We retrospectively compared the survival of patients after an R1 resection of GC who only received postoperative chemotherapy (ChT group) with the survival of resected patients who had been treated with postoperative CRT (CRT group) at our center. Patients who had a resection between 2004 and 2016 were included. CRT consisted of radiotherapy (45Gy) combined with concurrent 5-fluorouracil-based chemotherapy. The impact of CRT treatment on overall survival (OS) was evaluated using multivariable Cox regression and stratified by propensity score. Results: A total of 116 GC patients who had undergone an R1 resection were studied (ChT, N = 83; CRT, N = 33). There were no significant differences in baseline characteristics and pathological T- and N-classification between the two groups. The median overall survival was significantly better in the CRT group (28 vs. 13 months; p = 0.007). In a multivariable analysis, CRT was an independent prognostic factor for improved OS (hazard ratio 0.67; 95 % confidence interval 0.43–0.94). This effect of CRT was further supported by propensity score analysis. Conclusions: Postoperative CRT was associated with improved OS in patients who had undergone an R1 resection for GC.
Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression and effects of mutations in the FGFR signaling pathway.
Authors: Markus Joerger, Philippe Alexandre Cassier, Nicolas Penel, Richard Cathomas, Heike Richly, Martin Schostak, Andreas Janitzky, Martin Wermke, Lucia Nogova, David Wai-Meng Tai, Cyrus Sayehli, Carsten Grüllich, Enrique Grande, Alejandro Navarro, Se Hoon Park, Hendrik Nogai, Sebastian Bender, Peter Ellinghaus, Martin H. Schuler
Journal: Journal of Clinical Oncology (2018)

4513 Background: Activation of FGFR signaling is involved in a variety of malignancies including advanced urothelial cancer (UC). Rogaratinib is an oral pan-FGFR kinase inhibitor. We report here the results from a phase I expansion cohort in UC patients prescreened for FGFR1-3 mRNA expression levels with particular attention to activity in patients (pts) with evidence of activating mutations in potential resistance genes, including PIK3CA and RAS. (NCT01976741) Methods: Pts with advanced urothelial carcinomas were selected based on high FGFR1-3 mRNA expression in biopsy specimens. Somatic mutations in FGFR downstream signaling genes were detected by PCR array. Pts were treated with rogaratinib 800mg twice daily until tumor progression, intolerable toxicity, or withdrawal. Tumor response was assessed by RECIST, v1.1. Adverse events were reported using CTCAE v4.03 criteria. Results: A total of 219 UC pts were prescreened for FGFR1-3 mRNA expression levels and FGFR3 activating mutations, with 99 samples (45%) found to be FGFR-positive. Of those, 87% of samples were positive for FGFR3 mRNA, 5% for FGFR1 mRNA and 8% were double FGFR mRNA-positive (FGFR1/2, 1/3 or 2/3). Frequency of FGFR3 activating mutations in UC samples was 7%, all of which also had high FGFR3 mRNA. Fifty one pts were evaluable for response. Overall objective response rate (ORR) was 24% (12/51; all PRs) and disease control rate (DCR) was 73% (37/51). Interestingly, 0/12 pts with a PR had a hotspot mutation in either PIK3CA or RAS-encoding genes whereas 7/14 pts with PD revealed such a mutation. ORR in PIK3CA/RAS wild type UC pts is 30.6 %. Ten FGFR-positive UC pts had prior immuno-oncology (I/O) treatment, 9 of whom had progressive disease as best response. For these 10 pts the ORR was 30% and the DCR 80%. Conclusions: Selection of pts for treatment with rogaratinib based on FGFR mRNA expression levels was feasible and identified drug-sensitive pts with and without underlying FGFR gene alterations. Rogaratinib had a favorable safety profile and showed promising anti-tumor activity in UC pts, with an ORR of 24%, including pts refractory to prior I/O treatment but not with PIK3CA or RAS mutations. Clinical trial information: NCT01976741.
Blastic transformation in Mexican population with chronic myelomonocytic leukemia treated in a tertiary referral center.
Authors: Alfonso Alfredo Rivera Duarte, Alejandra Armengol Alonso, Elena Tuna-Aguilar
Journal: Journal of Clinical Oncology (2017)

e18566 Background: Chronic myelomonocytic leukemia (CMML) is the most aggressive of chronic leukemias, with a short overall survival and a high transformation rate to acute leukemia. We investigated factors related to blastic transformation in Mexican population treated in a tertiary referral center Methods: Records of patients diagnosed with CMML between 2000-2015 were reviewed; patients with incomplete data were excluded. IBM SPSS Statics 21.0 software was used to perform statistical analysis. Results: 54 patients were included, with a median age of 71 years and an overall survival of 16 months. The rate of blastic transformation found was 33% (18 patients), with a time to progression of 9 (0-87) months. Comparing patients who didn’t underwent blastic transformation to those who did, those who progress to acute leukemia tend to be younger (58 vs. 71 years, p = 0.001), have a higher peripheral blood blast count (2% vs. 0%, p = 0.003), where more likely to have immature myeloid precursors circulating in peripheral blood (94% vs. 64%, p = 0.02). In multivariate analysis, age continued to be statistically significant (HR 0.97, 95% IC = 0.929-0.987). There where no statistical difference in the two groups regarding hemoglobin levels (8.2g/dL vs. 10.1g/dL) platelets count (115 X 10 9 vs. 93 X 10 9 ), absolute neutrophil count (5.83 X 10 9 vs. 5.18 X 10 9 ), absolute monocyte count (3.09 X 10 9 vs. 2.680 X 10 9 ), and bone marrow blast count (0 vs. 2%). Cytogenetic considered as high risk was not predictor of blastic progression. Intensive chemotherapy was offered to 7(38.9%) patients, with a complete response rate of 0%, the overall survival was 1.4 months (0-9). Conclusions: Contrary to other reported series;Mexican patients with CMML that progresses to overt acute leukemia were considerably younger, with a higher tumor burden and a very short overall survival. In this population, it is important to consider more aggressive treatments at diagnosis, focusing in high dose chemotherapy and hematopoietic stem cell transplantation in a short term ratter than watching and waiting or using agents that do not impact in disease natural history.
A phase I, first-in-human, dose escalation study of intravenous TK216 in patients with relapsed or refractory Ewing sarcoma.
Authors: Noah Federman, Paul A. Meyers, Najat C. Daw, Jeffrey Toretsky, James Bradley Breitmeyer, Arun S. Singh, Langdon L. Miller, Tilman Oltersdorf, Deborah Jezior, Katayoun A. Jessen, Brian Lannutti, Joseph A. Ludwig
Journal: Journal of Clinical Oncology (2017)

TPS11626 Background: Ewing sarcoma (ES) is a rare cancer that affects children and young adults. Patients with recurrent/refractory ES have a poor prognosis (5-year survival 10-15%) with no improvement despite advances in cytotoxic and targeted therapies. Genomic rearrangements resulting in fusion proteins and over-expression of ets family transcription factors occur in 95% of ES. In particular, the EWS-FLI1 oncogenic fusion creates a constitutively active transcription factor that drives the malignant ES phenotype. Strategies to target the EWS-FLI1 fusion protein have been limited by lack of specificity. A promising approach is to target the interaction of the ets transcription factor with its critical protein partner, RNA helicase A (RHA). TK216 is a novel small-molecule that directly binds to EWS-FLI1 and inhibits its function by blocking binding to RHA. TK216 demonstrates potent anti-proliferative effects on ES cell lines and xenografts. Methods: We initiated a Phase 1, first-in-human, open-label, multi-center, dose-escalation/dose-expansion trial of TK216 in patients with recurrent/refractory ES who are ≥12 years of age (ClinicalTrials.gov: NCT02657005). TK216 is dosed based on body surface area and administered as a continuous intravenous infusion for 7 days followed by 14 days rest every 21 days. Treatment may continue in the absence of disease progression. One intrapatient dose escalation is allowed. Enrollment of 6 to 8 cohorts using a 3+3 dose-escalation design is anticipated. During dose expansion, a total of 18 patients with ES will be accrued at the recommended Phase 2 dose (RP2D). The primary objective of the study is to determine the maximum tolerated dose and RP2D of TK216. Secondary objectives are to assess the safety profile, pharmacokinetics, pharmacodynamics, and antitumor activity of TK216. Molecular assays will be performed to characterize EWS-FLI or EWS-ets abnormalities in archival tumor tissue. The overall response rate, duration of response, progression-free survival, and overall survival will be determined in the expansion cohort. Nine patients have been enrolled since June 2016. Accrual to cohorts 1, 2, and 3 completed and cohort 4 opened in January 2017. Clinical trial information: NCT02657005.
A basal gene expression signature to predict for synergy of combined EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.
Authors: Jennifer Kimberly Lue, Sathyen Alwin Prabhu, Yuxuan Liu, Yulissa Gonzalez, Akanksha Verma, Nebiyu Abshiru, Emily Chen, Changhong Qiao, Renu Nandakumar, Serge Cremers, Neil Kelleher, Olivier Elemento, Jennifer Effie Amengual
Journal: Journal of Clinical Oncology (2018)

7546 Background: EZH2 is the catalytic subunit of PRC2, and induces methylation of H3K27. Activating mutations and overexpression of EZH2 are found in NHL. Inactivating mutations in histone acetyltransferases (HATs) are also common in germinal center (GC) B-cell lymphomas and together with EZH2 mutations enforce a condensed chromatin state. Given the dysregulation of EZH2 and HATs in GC-B cell lymphomas, we hypothesized that dual inhibition of EZH2 and HDAC would be synergistic. Methods: Lymphoma cell lines (n = 21) were exposed to the EZH2 inhibitor GSK126 (G) and HDAC inhibitor romidepsin (R). Cell viability was assessed via Celltiter-Glo assay. Synergy was assessed by Excess over Bliss (EOB), where EOB > 10 defines synergy. A cutoff of > 20 was used. Western blot, mass spec and Co-IP were performed after exposure to G+R. Mice xenografts were enrolled in: 1. Control; 2. G (100mg/kg); 3. R (2mg/kg); 4. G+R. GSEA and differential gene expression of synergistic vs. non-synergistic cell lines was performed. Results: EZH2 mutation is associated with increased sensitivity to G (p = 0.02). HAT mutations do not predict sensitivity to R (p = 0.2). G+R treatment was highly synergistic in cell lines with EZH2 dysfunction. G+R led to increase acetylation and decrease methylation of H3K27 as well as decreased protein expression of PRC2 members as compared to single agent. Exposure to R or G+R led to dissociation of EZH2 from other PRC2 members as well as HDAC2 and DNMT3L, which is secondary to RbAP46/48 acetylation. A selective HDAC1/2 inhibitor, ACY957, was combined with G and showed synergy. G+R led to significant tumor growth delay compared to single agents (p < 0.05), and led to improved OS (Median OS G = 16 d; R = 16 d; G+R = 24 d; p < 0.001). Synergistic cells lines share a common basal gene expression signature which was validated in DLBCL via the TCGA database. Synergistic cell lines are enriched in pathways involved in chromatin silencing and remodeling, including epigenetic pathways (FDR < 0.2). Conclusions: G+R is highly synergistic. Responses are predicted by the presence of EZH2 dysregulation and a shared basal gene expression signature. G+R may serve as a targeted approach for NHL dependent upon EZH2 dysfunction.
Atezolizumab Treatment Beyond Progression in Advanced NSCLC: Results From the Randomized, Phase III OAK Study
Authors: David R. Gandara, Joachim von Pawel, Julien Mazieres, Richard Sullivan, Åslaug Helland, Ji-Youn Han, Santiago Ponce Aix, Achim Rittmeyer, Fabrice Barlesi, Toshio Kubo, Keunchil Park, Jerome Goldschmidt, Mayank Gandhi, Cindy Yun, Wei Yu, Christina Matheny, Pei He, Alan Sandler, Marcus Ballinger, Louis Fehrenbacher
Journal: Journal of Thoracic Oncology (2018)
Detection and measurement of HER2+ breast cancer cells using tumor-targeted iron oxide nanoparticles and magnetic relaxometry.
Authors: Farideh Z. Bischoff, Kelsey Boitnott Mathieu, Lan Pang, Adam Kulp, Zhen Lu, Dale Huber, John D. Hazle, Robert C. Bast, Giulio Paciotti
Journal: Journal of Clinical Oncology (2018)

e13019 Background: Lymph node assessment following a primary HER2 positive breast cancer diagnosis often requires biopsy for pathologic evaluation to determine patients’ risk for metastatic disease and treatment selection. However, in the absence of tumor-specific image-based guidance, unnecessary lymph node resection and testing cannot be avoided. Furthermore, due to tumor heterogeneity and tissue sampling, HER2+ cases may go undetected. The MagSense Clinical Diagnostic System (MagSense System) is a system that may be used for in-vivo detection of HER2+ tumor cells within the entire lymph node, thus enabling a noninvasive approach for staging and selection of therapy for patients diagnosed with HER2 responsive primary breast cancer. We present the development of a model system to be used in demonstrating feasibility and potential sensitivity of the MagSense System in HER2+ breast cancer. Methods: Spleen from NGS mice were processed to a single cell suspension of spleenocytes. Pellets of 1x10-6 and 2x10-6 BT-474 or MCF7 cells mixed in 10-7 spleenocytes were prepared to model lymph node preparations containing tumor cells expressing high or low levels of cell membrane HER2 antigen, respectively. Anti-HER2-conjugated nanoparticles were incubated with the spleenocyte/tumor cells for 3 and 24 hrs. As control, each test point was matched with a competition replicate using Herceptin to compete for the HER2 sites in both cell lines. All spiked cell pellets were then evaluated for relaxation signal using ultra-sensitive SQUID sensors. Results: After 3hr and 24hr incubation, HER2+ BT-474 cells spiked into spleencytes yielded a significantly higher SQUID relaxometry signal relative to the competed matched sample. For the MCF7 HER2- cells, we detected a slight relaxometry signal but only after 24hr, suggesting non-specific signal detection that was not observed after 3hrs. Conclusions: These preliminary results demonstrate feasibility of an ex-vivo model for highly sensitive detection of HER2+ tumor cells using the Mag Sense System. Current studies are ongoing to further establish magnetic relaxometry signal cut-off levels for classification of HER2+ status using clinical specimens.
Efficacy of epirubicin-paclitaxel (EPI-TAX) prior to high-dose chemotherapy (HDCT) in germ cell tumors (GCTs): A 17-year experience.
Authors: Jean-Pierre Lotz, Daniele Grazziotin Soares, Stephane Culine, Benjamin Laverdant, Anne Kieffer, Yohann Dabi, Joseph Gligorov, Frederic Selle
Journal: Journal of Clinical Oncology (2017)

4557 Background: GCTs patients (pts) relapsing after conventional-dose salvage chemotherapy (CDCT) are candidates to receive HDCT with hematopoietic stem cell (SC) support. We have previously reported (Ann Oncol 2014; 25:1775-82) that non-refractory pts can benefit from HDCT. We here analyzed the efficacy of the induction regimen EPI-TAX. Methods: All male GCTs pts treated by EPI-TAX between 1998 and 2015 were identified from clinical records at Tenon Hospital. Primary aim was response rate after EPI-TAX. Secondary aims were efficacy of SC harvest, Beyer score, toxicities and overall survival (OS) after HDCT. Kaplan-Meier methods were used for analysis. Results: Of the 170 pts treated (EPI 100 mg/m2, TAX 250 mg/m2, days 1-15), 142 (83.5%) had received &gt; 2 previous lines of CDCT. 79 (46.5%) had disease progression at the time of treatment and 44 were absolutely refractory to cisplatin. The other pts were in remission (65) or had stable disease (SD, 26). Most of pts (75.3%) had Beyer score &gt; 1. Following EPI-TAX, favorable responses were achieved in 140 pts (82.4%,CI95% 79.8-85.0; 21 complete responses, 68 partial responses and 51 SD). EPI-TAX was able to control disease in 56 (70.9%, CI95% 61.0-80.8) out of 79 pts who were in progression. Beyer score after EPI-TAX resulted 0 in 70.6% of pts. Successful harvested of SC was achieved in 146 (85.8%, CI95% 80.5-91.1) pts. EPI-TAX was well tolerated with peripheral neuropathy as the main non-hematopoietic toxicity. Treatment discontinuation was needed in 3 (1.8%) pts and 2 (1.2%) related deaths were observed. Following EPI-TAX, 155 (91.2%) pts received HDCT. HDCT was given in consolidation, once progressive disease was controlled by EPI-TAX or for progressive pts. With a median follow-up of 31 months (0.5-223) the 2- and 10-years OS for the subgroup consolidation were 78.2% (95%CI 69.1-87.4) and 66.9% (95%CI 55.4-78.6). Disease control by EPI-TAX resulted in 55.8% (95%CI 42.4-69.2) and 38.2% (95%CI 24.9-51.4) 2- and 10-y OS compared to 14.6% (95%CI 0-33.2, logrank p = 0.006) 2-y OS for progressive pts. Conclusions: EPI-TAX is effective to collect SC and to control disease of pts who were in progression after CDCT allowing them to receive HDCT.
P01.148 Intra-tumor heterogeneity analysis of low-grade gliomas. A POLA Network study
Authors: A Alentorn, K Labreche, C Dehais, C Carpentier, F Ducray, K Mokhtari, D Figarella-Branger, M Sanson, J Delattre, A Idbaih
Journal: Neuro-Oncology (2018)

Low-grade gliomas (LGG) are divided into three histo-molecular groups: i) IDHwt, ii) IDHmut and 1p19q intact and iii) 1p19q co-deleted with IDH1 mutation. The current classification has improved the clinical stratification and its reproducibility. However, LGGs are still associated with an important degree of clinical heterogeneity.We sough to analyze the genomic and genetic heterogeneity by re-analyzing next-generation sequencing data of two different cohorts of LGG to dissect the potential role of clonal architecture on the clinical evolution of LGG. We have re-analyzed whole-exome sequencing (WES) using LGG TCGA dataset and a cohort of 40 LGG analyzed by WES from the POLA Network. We have obtained the clonal architecture, the mutation burden, the number of clones, the clonal and subclonal distribution of genetic and genomic alterations and the distribution of the somatic signatures. In addition, we have also analyzed 5 1p19q co-deleted samples at different timepoints to further dissect the clonal evolution of this entity. As expected, the mutation burden of LGG is low (median somatic mutation per sample 34). Surprisingly, the number the subclones was higher in the 1p19q co-deleted subgroup.LGG were enriched in somatic signatures associated with hydrolytic deamination of methylated CpG and with deficiency of mismatch repair. Interestingly, only within 1p19q co-deleted gliomas, the number of subclones, the mutant-allele tumor heterogeneity (MATH) score and the signature associated with hydrolytic deamination of methylated CpGwere associated with poorer outcome in univariate analysis. Finally, only the enrichment of the mutational signature associated with hydrolytic deamination of methylated CpG had prognostic impact in 1p19q co-deleted LGG in Cox multivariate analysis afteradjusting by age, mutational clones number, MATH score and loss of CDKN2A loss. The clonal architecture of LGG may provide additional clinical relevant data within 1p19q co-deleted tumors. The enrichment of a somatic signature associated with hydrolytic deamination of methylated CpG is independently associated with poor overall survival.