tbuckley/cabot-search huggingface dataset:
Genomic comparison of matched primary and metastatic germ cell tumors (GCT).
Authors: Francois Audenet, Mark Donoghue, Eugene J. Pietzak, Sumit Isharwal, Michael L. Cheng, Gopa Iyer, Samuel Funt, Dean F. Bajorin, Hikmat Al-Ahmadie, Victor E. Reuter, Jana Eng, Jonathan B Reichel, Maria E. Arcila, Dana Tsui, Maha Shady, Michael F. Berger, George J. Bosl, Joel Sheinfeld, David B. Solit, Darren R. Feldman
Journal: Journal of Clinical Oncology (2017)

4556 Background: Tumor genomic analysis may be useful in patients with GCT as a means of identifying potentially actionable genomic alterations or mutations such as TP53 that confer resistance to chemotherapy. As GCTs often exhibit significant morphologic heterogeneity, we evaluated the level of concordance between genomic alterations in matched primary and metastatic GCT samples. Methods: GCT patients enrolled on an institutional prospective sequencing protocol with available primary and metastatic tumor tissue were eligible. Each tumor was subjected to MSK-IMPACT, an exon capture sequencing assay, which detects copy number alterations (CNAs) and mutations in 410 cancer-related genes. For each primary-metastasis pair, concordance and clonality was assessed using the FACETS algorithm. Results: Matched primary-metastasis tumor pairs were available for 36 patients (78% nonseminoma, 22% seminoma, median age 33.5 years). All patients received chemotherapy, with 25 (69%) receiving treatment prior to analysis of the metastatic samples. The frequency of genetic alterations was low with a median of 3 mutations (1-7), 7 amplifications (1-26) and 1 deletion (1-9) detected per sample, with no significant difference in mutational/CNA burden between primaries and metastases. Of 109 unique mutations across patients, only 44 (40%) were concordant between the primary and matched metastasis, including 5 of 9 hotspot mutations. For CNAs, 184 (81%) of 226 were concordant. Only 24 of 109 (22%) mutations were clonal (defined as predicted to be present in all cancer cells) in either the primary or metastatic matched samples; of these, only 4 were clonal in both the primary and metastatic samples, including 2 hotspots. However, 4 of 5 alterations in TP53/MDM2 were shared by both the primary and metastasis pairs. In a separate exploratory cohort, 4 TP53 mutations were identified in 3 primary tumors and 1 metastasis, and all 4 mutations were also detected by cell-free DNA profiling. Conclusions: Genomic concordance, particularly for mutations, is poor between primary and metastatic GCT samples. Cell-free DNA analysis may help overcome this limitation by identifying alterations in progressive tumors without need for a new biopsy.
A phase II study of abemaciclib as a monotherapy and in combination with other agents in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: E. Gabriela Chiorean, Howard S. Hochster, Shivani Nanda, Donald Thornton, Suzanne Klise
Journal: Journal of Clinical Oncology (2017)

TPS4150 Background: PDAC is a lethal tumor with unusual resistance to cytotoxic and targeted therapies, and pathogenesis frequently associated with hyperactive CDK 4&amp;6 signaling. Pre-clinical models have demonstrated anti-proliferative activity with CDK 4&amp;6 inhibitors alone, however, synergistic effects have been observed when combined with a PI3K/mTOR or TGF- βR1 inhibitor. Abemaciclib is a selective inhibitor of CDK 4&amp;6 with an acceptable safety profile in clinical studies.This study will evaluate the safety and efficacy of abemaciclib alone or in combination with LY3023414, a PI3K/mTOR dual inhibitor, or galunisertib, a TGF-βR1 inhibitor, versus standard of care (SOC) in pateints (pts) with metastatic PDAC. Methods: Design: Study JPCJ is an adaptive, open-label, randomized, Phase 2 study in pts with previously treated metastatic PDAC. Pts will be stratified based on number of prior systemic therapies (1 or 2), and in Stage 1 (25 pts/arm) will be randomized in a 1:1:1:1 ratio to 4 treatment arms: abemaciclib; abemaciclib+LY3023414; abemaciclib + galunisertib; SOC treatment gemcitabine or capecitabine. Investigational arms demonstrating evidence of disease control rate (DCR) comparable to or better than the SOC will advance to Stage 2 (additional 50 pts/arm). Eligibility: Pts must have metastatic PDAC with disease progression following 1 or 2 prior lines of therapy, measurable disease, ECOG PS ≤1, no prior treatment with any CDK 4&amp;6, TGF-β, or PI3K and/or mTOR inhibitors, no severe cardiac disorders, and must not have insulin-dependent diabetes. Objectives: The primary endpoint is to evaluate the DCR (Stage 1) and progression-free survival (PFS [Stage 2]). Secondary objectives include response rate, overall survival, safety, pharmacokinetics, biomarkers related to the CDK 4&amp;6 pathway, and quality of life. Statistics: Assuming a hazard ratio of 0.65 in PFS (median PFS of 2.3 months in abemaciclib containing arms vs. 1.5 months in the SOC arm), the study has approximately 76% power to detect superiority of the abemaciclib-containing arm using a 2-sided log-rank test at 0.10 significance level. Accrual began on 01/12/2017. Clinical trial information: NCT02981342.
Autologous Haematopoietic Stem Cell Transplantation Is a Highly Effective Second Line of Treatment for Patients with Diffuse Large B-Cell Lymphoma
Authors: Malgorzata Krawczyk-Kulis, Anna Kopinska, Marek Seweryn, Malgorzata Sobczyk-Kruszelnicka, Slawomira Kyrcz-Krzemien
Journal: Blood (2011)
P04.85 Molecular characteristics of low grade glioma progression
Authors: M Łysiak, P Milos, A Malmström, A Dolot, C Bratthäll, M Strandéus, M Hallbeck, P Söderkvist
Journal: Neuro-Oncology (2018)

Low grade glioma (LGG), especially oligodendroglioma (ODG), are known for their usually good response to radio- and chemotherapy and relatively good prognosis amongst glioma. LGG can stay indolent after initial surgery for years, however many will eventually progress to higher grade tumor, although the pace of progression can differ greatly. Temozolomide administered after resection has been shown to promote a hypermutated recurrent tumor, however, not all patients receive postoperative chemotherapy. We investigated changes in the molecular profiles of genes involved in glioma development between primary and recurrent tumor. Eight pairs of tumors, from 6 males and 2 females diagnosed with LGG, were collected between 2008–2015. Three patients received chemo- or radiotherapy between surgeries. 1p19q co-deletion was assessed by droplet digital PCR and IDH mutations by Sanger sequencing. A glioma tailored HaloPlex NGS panel was created with 24 genes and 7 hotspot mutations (IDH1/2 TERT, ATRX, TP53, NF1/2, EGFR, CDKN2A/2B/2C, PTEN, PIK3CA, PIK3R1, CIC, FUBP1, RB1, MLH1/3, MSH2/3/5/6, PMS1/2, BRAF, H3F3A, LRIG1-3, NRAS). Library preparation was followed by Illumina sequencing on MiSeq. Variants were reported if missense or nonsense change was discovered and population allele frequency below 0.01. Transcriptome microarray data from the samples was used for hierarchical clustering and differential expression analysis. Three pairs of tumors did not show 1p19q co-deletion, out of which one was IDHwt and excluded. Tumors non-codeleted and IDH mutated were diffuse astrocytoma and IDHmut and codeleted tumors were ODG. The seven pairs of tumors were subjected to targeted resequencing and several variants were found. All IDH1mut were confirmed. SIFT and PolyPhen predicted damaging variants were found in FUBP1, CIC, TP53, EGFR, NF1, RB1, ATRX, TERT, CDKN2A, PIK3CA, MLH1 and MSH5. All variants were shared between primary and recurrent tumors, apart from 2 pairs. Mutations found in FUBP1 and CIC in the primary tumor of one ODG patient were absent at recurrence; both tumors were grade II. In an ODG that progressed from grade II to grade III a mutation in PIK3CA was detected at recurrence while a variant in NF1 was lost. Hierarchical clustering showed a good separation of primary and recurrent tumors and nearly 200 differentially expressed genes with 2-fold change were discovered, including up-regulation of the Rho family GTPase3, CHEK1, CDKN2C, CDKN3 and several others. LGG are relatively stable in their mutational profile at recurrence in the genes analyzed. Mutations in genes thought to be drivers in ODG, like CIC and FUBP1 are not always retained in the recurrent tumor. Differences in expression profiles of primary and relapsed tumors indicate common changes during progression, however an expanded cohort studies are needed for their elucidation.
A phase II-III, multicenter, randomized, open study evaluating the feasibility and efficacy of a supervised home-based standard physical exercise program for metastatic cancer patients receiving oral targeted therapy: The UNICANCER SdS 01 QUALIOR study (ID-RCB: 2015-A01922-47).
Authors: Florence Joly Lobbedez, Laurence Vanlemmens, Jean-Marc Descotes, Sophie Abadie-Lacourtoisie, Claude Boiron, Claire Garnier-Tixidre, Veronique Girre, Carole Helissey, Nadine Houede, Claudia Lefeuvre-Plesse, Benedicte Mastroianni, Nathalie Meneveau, Stephane Oudard, Valérie Plence, Frank Priou, S Bastien Salas, Laetitia Stefani, Alain Zannetti, Franck Bonnetain, Ivan Krakowski
Journal: Journal of Clinical Oncology (2017)

TPS10126 Background: Fatigue is a frequent side effect with oral targeted therapies (OTT). Physical activity has been reported to improve fatigue and quality of life (QoL). However, few studies focused on metastatic cancer patients and mainly among patients treated with chemotherapy. Furthermore, recent guidelines recommend evaluation and optimization of standardized exercise programs. The aim of our study is to evaluate home-based standard physical exercise program (SPEP) for metastatic cancer patients treated with OTT. Methods: This phase II-III study will randomize (2:1) patients starting first-line OTT for metastatic cancer between an individualized SPEP supervised by a personal coach, and recommended physical exercises via a booklet. Eligible patients will have received ≤2 lines of metastatic chemotherapy, ECOG PS ≤2, controlled pain (VAS &lt; 3/10), and life expectancy ≥3 months. The phase II part (120 patients) will evaluate the feasibility of a 3-month SPEP using the rate of patients performing ≥50% of SPEP (2-stage Fleming: one-sided α = 5%; β = 85%). An interim analysis is planned after the phase II. The phase III will compare the efficacy of an SPEP as opposed to recommendations to reduce fatigue and/or improve physical well-being (PWB) dimensions of QoL (evaluated with FACT-G and FACT-F questionnaires). To show a difference of ≥5 points in PWB and 2.5 for fatigue (α = 2.5%; β = 80%), 312 patients are required in the phase III trial. . Secondary objectives include: PFS, OS, other dimensions of QoL, tolerability and observance of OTT, change in body composition, physical benefits, and a medico-economic study. The SPEP was developed by specialized coaches involved in physical activity and cancer. The study has Ethic committee approval and accrual is planned in 18 French centers in April 2017, for 30 months. This is the first randomized trial dedicated to patients with metastatic cancer treated with OTT evaluating the feasibility and the efficacy of a well design home based SPEP on fatigue and physical well-being.
Phase II study of pembrolizumab in advanced, unresectable hepatocellular carcinoma.
Authors: Lynn G. Feun, Ying-Ying Li, Medhi Wangpaichitr, Patricia Denise Jones, Stephen P. Richman, Beatrice Madrazo, Deukwoo Kwon, Paul Martin, Peter Joel Hosein, Niramol Savaraj
Journal: Journal of Clinical Oncology (2018)

4086 Background: Recently, checkpoint inhibitors have shown modest activity in patients (pts) with advanced, unresectable hepatocellular carcinoma (HCC). In multicenter trials with nivolumab and pembrolizumab, the response rates have been reported to be 14% and 16%, respectively. We report a prospective single-institution investigator-initiated clinical/translational study of pembrolizumab in advanced HCC. Methods: A phase II trial is ongoing, with pembrolizumab administered at a fixed dose of 200 mg iv every 3 weeks for advanced HCC patients who may have progressed on, were intolerant of, or refused sorafenib. CT or MRI scans were performed after every 3 doses. RECIST 1.1 was used to assess response. Time to tumor progression (TTP) and overall survival (OS) were estimated by Kaplan-Meier method. Median TTP and median OS were estimated along with the corresponding 95% confidence interval. Results: Twenty six patients have been treated and 21 were evaluable for response at this time. Ten of the 21 patients had prior sorafenib. Seven had hepatitis C and 1 had hepatitis B. Sixteen had extrahepatic metastases. The median TTP was 3 months(95%CI:2-7) and median OS was 14 months(95%CI: 3- not estimable). In terms of response, one had complete response and 6 had partial response (PR) for overall response rate of 33%. Two others had stable disease. TTP for responding pts were 6+, 7, 8, 8,9, 9+, and 14 + months with 3 having ongoing responses. Five of these 7 had extrahepatic metastases which responded to treatment. Four of 7 had prior sorafenib. Drug-related toxicity included: hypothyroidism (4 patients) grade 4 neutropenia (1 ) and reversible, temporary elevation of liver function tests (grade 3 in 3 pts). Other grade 1-2 toxicities included: diarrhea (4 ), skin rash (5) and fatigue (2). Correlative studies including hepatitis B and C titers, IL1B, IL12, IL18, IL6, TGF beta, gamma interferon, and PD-L1/PD-1 staining are ongoing and will be presented. Conclusions: Pembrolizumab has activity in advanced HCC patients, including those with extrahepatic metastases. Toxicity was generally well tolerated and reversible. A set of immunological markers as well as PD-L1/PD-1 staining is being investigated as possible indicator for response. Clinical trial information: NCT02658019.
SM88/SMK non-hormonal therapy in recurrent or untreated prostate cancer.
Authors: Steve Hoffman, John Rothman, Giuseppe Del Priore, Jeanetta Stega
Journal: Journal of Clinical Oncology (2017)

e16540 Background: Prostate cancer (PC) has a poor prognosis. Androgen deprivation therapy is effective but has unacceptable short and long term side effects. SM88 (modulators of mTOR, mitochondrial stress, CYP3a4 and tyrosine isomers) is a novel combination of anti-cancer therapies with previously reported favorable results yet low toxicity in a heterogeneous group of 30 patients with cancer. We now report on a PC cohort treated with SM88. Methods: Retrospective chart review. Results: Between 2012 and 2014, 6 men with PC were treated with SM88, administered 5 days/week over a 6-week treatment cycle. SM88 consisted of daily oral and subcutaneous injection of the components. The average age was 54 years (range 32-66). Five (83.3%) were Caucasian, 1 (16.7%) was Hispanic. patients with prostate cancer were treated with SM88 daily, Monday-Friday, for between 6 to 31 wks (median 11). Four patients had castrate resistant disease, two declined ADT. One had failed prior chemotherapy (see Table). All subjects were not receiving other therapy. One subject died of disease complications approximately 3 months after starting treatment but only received approximately 20 days of therapy over a 6 week cycle. Three patients had PSA nadir responses of &gt;90% reduction over pretreatment peak levels (see table). Two others had radiographic SD for between 10-14 wks. There were no significant toxicity except cutaneous hyperpigmentation. The duration of responses ranged from 10-114 weeks. Best overall responses included 2 patients with complete biochemical response. Four subjects improved their ECOG score during treatment and 2 had no change. Conclusions: SM-88 appears to be well tolerated and to have anti-tumor activity in prostate cancer without androgen deprivation toxicity. Additional confirmatory prospective studies in prostate are ongoing and planned in other cancers. [Table: see text]
The relative clinical value of combined antiPD-1 and antiCTLA-4 treatment, the NNT values of immuno-therapy in metastatic melanoma patients.
Authors: Edit Porneczy, Imre Boncz
Journal: Journal of Clinical Oncology (2017)

e14595 Background: The PD-1 inhibitor Nivo and antiCTLA-4 Ipi in combination was registered by FDA and EMA for the treatment of metastatic melanoma.The accelerated approval of this indication was based on PFS data.OS data in previously untreated melanoma pts was reported only in the Phase II CheckMate 069 study.In the Nivo+Ipi group the 1YOS% was 73,4% and 63,8% at 2Y, in the Ipi group 1YOS% was 64,8%, 2YOS% was 53,6% at median follow up of 24,5 months.The median OS had not been reached, the outcome measures could not assess the long-term benefit of antitumor immun response. Methods: In order to measure the relative clinical values, we analyzed the 1Y, 2Y survival data and calculated the ARR (absolut risk reduction) and NNT values (the number of patients who need to be treated to prevent one death) of the Phase II CheckMate 069 trial Nivo+Ipi vs Ipi group, and the overall survival data in subgroup of pts who discontinued the immun-therapy due to treatment related AEs. We used GraphPad Software QuickCalcs/NNT for calculating the results of 95% CI. Results: In the CheckMate 069, the Nivo+Ipi group vs Ipi group ARR was 10,93, the NNT was 10(95%CI 3,6-17,8) at 1Y.The ARR was 13,19, the NNT value was 8(95%CI 3,3-24,1) at 2Y. 1 in every 8-10 pts will benefit from the Nivo+Ipi combined immuno-therapy in order to prevent one death. In the subgroup of patients (37%) who discontinued treatment, the ARR was 21,16 at 1Y and 21,76 at 2Y. Despite of discontinuation, 1 in every 5 pts will benefit from immuno-therapy at 1Y and 2Y, the NNT was 5 (95%CI 2,5-40,4) and 2Y (95%CI 2,3-127,2). Conclusions: These results of NNT 5-10 represent the exceptional survival benefit of combined immuno-therapy. The limitations of NNT bias the pts demographic parameters and the value depends on comparator drug. The risk reduction was not constant over the follow up time and the long term benefit of immuno-therapy is not linear.The NNT data provide measurement of relative clinical value and clinical impact.
Long-term survival after salvage SBRT for recurrent or secondary non-small cell lung cancer after prior surgery or radiation therapy.
Authors: Chunyu He, Yong-Mei Liu, Alberto Cerra-Franco, Kevin Shiue, Ru Liu, Mark P Langer, Karen Marie Rieger, DuyKhanh Ceppa, Thomas J Birdas, Kenneth Kesler, Richard C. Zellars, Lautenschlaeger Tim, Feng-Ming Spring Kong
Journal: Journal of Clinical Oncology (2018)

8558 Background: Patients with locally recurrent or newly diagnosed NSCLC after previous definitive radiotherapy (RT) or surgery pose a challenge in management. SBRT has been attempted as option of salvage treatment. The objective of this study is to report long-term outcome of SBRT in patients with recurrent or second primary NSCLC after previous local treatment. Methods: This single-institution retrospective study included patients with NSCLC who received thoracic SBRT for newly diagnosed or recurrent NSCLC. The primary and second endpoints were overall survival and radiation pneumonitis, respectively. Clinical factors analyzed included age, gender, race, tobacco history, respiratory/cardiovascular comorbidity, histology, modality of previous treatment, T stage, gross tumor volume (GTV), planning target volume (PTV), and prescription dose. Radiation pneumonitis was graded consistently per RTOG1106. Results: A total of 326 patients met the inclusion criteria, including 43, 40 and 243 patients with prior RT, surgery, and no prior treatment, respectively. The median follow-up was 59 (95% CI 48-68) months. The median survival were 23 (95% CI 15-31), 50 (95% CI 35-65), and 32 (95% CI 25-40) months, and the 5-year survival rates were 26.2%, 42.4%, and 24.7%, respectively (P= 0.077). In those treated with previous RT, there were no significant differences in overall survival between conventionally fractionated radiation therapy and SBRT (median survival 25.0 vs 13.4month, P= 0.280). In those treated with prior surgery, there was no significant difference in overall survival between pneumonectomy and lobectomy (56.0 vs 50.0 months, P= 0.576). The were significant differences in rates of grade 1+ (44.2%, 30.0%, 21.5%, P= 0.007), and 2+ RP (18.6%, 12.5%, 7.0%, P= 0.039), but no statistically significant differences in grade 3+ pneumonitis among these three groups. Conclusions: Salvage SBRT after previous radiation or surgery provides a chance of cure, with 5-year survival not significantly different from that of SBRT for newly diagnosed NSCLC, with significantly increased but acceptable risk of radiation pneumonitis.
Concurrent chemoradiotherapy (CRT) for bladder cancer: Practice patterns and outcomes in the general population.
Authors: Ketan Ghate, Kelly Brennan, Safiya Karim, William J. Mackillop, Christopher M. Booth
Journal: Journal of Clinical Oncology (2017)

e16025 Background: Clinical trials have shown that CRT improves survival compared to RT alone in muscle invasive bladder cancer. We describe uptake of CRT and outcomes in routine practice. Methods: Electronic treatment records were linked to the population-based Ontario Cancer Registry to identify all patients treated with curative intent RT for bladder cancer in Ontario 1999-2013. Practice patterns were described in three eras: 1999-2003, 2004-2008, 2009-2013. Modified Poisson regression was used to analyze factors associated with use of CRT. Cox model and propensity score analysis were used to explore the association between CRT and overall (OS) and cancer-specific survival (CSS). Results: 1398 patients underwent curative intent RT during 1999-2013; median age was 79 and 75% (1050/1398) were male. Use of CRT increased over time: 33% (135/409) in 1999-2003, 35% (170/482) in 2004-2008, 46% (232/507) in 2009-2013 (p &lt; 0.001). Among the 80% (431/537) of CRT cases with available drug details, the most common regimens were single-agent Cisplatin (57%, 245/431), single-agent Carboplatin (31%, 133/431) and 5-FU/Mitomycin (4%, 19/431). Factors associated with CRT include younger age (p &lt; 0.001), male sex (p = 0.027), and lower co-morbidity (p &lt; 0.001). There were large regional differences in use of CRT (range 14% to 85%, p &lt; 0.001). Five year OS, CSS, and cystectomy-free survival rates among CRT cases were 34% (95%CI 30%-39%), 45% (95%CI 40%-50%), and 30% (95%CI 26%-34%). On adjusted analyses CRT was associated with superior survival compared to RT alone (OS HR 0.68, 95%CI 0.60-0.70; CSS HR 0.64, 95%CI 0.54-0.76). These results were consistent on propensity score analysis. There was a non-significant trend towards improved survival among all treated cases in 2009-2013 compared to 1999-2003 irrespective of chemotherapy delivery (OS HR 0.86, 95%CI 0.74-1.01; CSS HR 0.82, 95%CI 0.67-1.01). Conclusions: Although there has been substantial uptake of CRT in routine practice, utilization rates vary widely by region. CRT is associated with superior survival compared to RT alone and its uptake corresponded to a temporal trend towards improved survival among all treated cases in the general population.