tbuckley/cabot-search huggingface dataset:
Genetic variations in semaphorin/neuropilin signaling to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab-based chemotherapy.
Authors: Yuji Miyamoto, Fotios Loupakis, Wu Zhang, Shu Cao, Satoshi Okazaki, Martin D. Berger, Mitsukuni Suenaga, Marta Schirripa, Shivani Soni, Satoshi Matsusaka, Yan Ning, Dongyun Yang, Roel Gopez, Elizabeth Melendez, Diana L. Hanna, Afsaneh Barzi, Hideo Baba, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

11608 Background: Neuropilin ( NRP) is known to be an important VEGF co-receptor that acts as a key mediator of angiogenesis. Its ligands, semaphorins ( SEMA), compete with VEGF for NRP binding and can themselves have angiogenic activity. Plexins are also receptors of SEMAs, and have the GTPase activating proteins (GAPs) domain for RAS. NRPs are shown to signal through RAS pathways. We aimed to evaluate whether single nucleotide polymorphisms (SNPs) of genes involved in the SEMA/NRPpathways predict clinical outcome in bevacizumab-treated mCRC pts. Methods: Associations between nine SNPs in 7 genes ( SEMA3A, SEMA3D, SEMA3F, NRP1, NRP2, PLXNA1 and PLXND1) and clinical outcomes were evaluated in mCRC patients receiving first-line FOLFIRI-bevacizumab in a phase III trial: TRIBE ( N= 228). Associations between genotype and RAS mutation status with clinical outcomes was also examined. Main characteristics were the following: male/female = 138/90; median age = 60; RAS-wildtype/mutant = 55/116; median PFS = 9.7 months; median OS = 26.1 months, median follow-up time = 49.3 months. Results: NRP1 rs2228638 Any A ( N= 40) showed a significantly longer PFS compared to G/G variant ( N= 188) in the univariate (11.6 months (M) vs. 9.5 M, HR = 0.64, 95%CI = 0.43-0.95, p = 0.022) and the multivariate analysis (HR = 0.59, 95%CI = 0.38-0.90, p = 0.016). SEMA3F rs12632110 A/A ( N= 20) showed a significantly shorter PFS compared to any G variant (N = 205) in the multivariate analysis (HR = 1.89, 95%CI = 1.02-3.49, p = 0.043). Among RAS-mutant pts, SEMA3F rs12632110, SEMA3F rs1046956, SEMA3D rs7800072, NRP1 rs228638, PLXNA1 rs4679323 and PLXND1 rs2255703 polymorphisms were significantly associated with PFS in the univariate and multivariate analysis. PLXNA1 rs4679323 was also significantly associated with OS in the univariate and multivariate analysis. There was no association between these polymorphisms and outcome in patients with RASwildtype tumors. Conclusions: Genetic variants within SEMA/NRP pathways may be prognostic markers in RAS mutant mCRC patients treated with bevacizumab-based chemotherapy.
Clinical and radiological characteristics of metastatic prostate cancer (mPCa) patients (pts) with liver metastases (LM) and association with overall survival (OS).
Authors: Diletta Bianchini, Nuria Porta, Nina Tunariu, Raquel Perez, Zafeiris Zafeiriou, Pasquale Rescigno, Michael Kolinsky, Semini Sumanasuriya, Joaquin Mateo, Niven Mehra, Anurhada Jayaram, Adam Sharp, Daniel Nava Rodrigues, Spyridon Sideris, Roberta Ferraldeschi, Gunther Boysen, Suzanne Carreira, David Lorente, Gerhardt Attard, Johann S. De Bono
Journal: Journal of Clinical Oncology (2016)

5043 Background: The diagnosis (Dx) of LM in PCa pts carries a poor prognosis and its incidence is increasing. We conducted a retrospective analysis to identify clinical and radiological factors associated with OS in these pts. Methods: Pts with computed tomography (CT) radiologically confirmed LM referred to our institution between June/2003 and May/2015 were selected for this analysis. Clinical data were retrospectively collected and imaging performed at the time of Dx of LM was assessed by a radiologist. OS was measured from LM diagnosis until death or last follow-up. Descriptive summaries and Kaplan-Meier estimates were used to explore the data. The association of radiological features at the time of LM Dx and other known prognostic factors with OS were evaluated through univariate (UV) and multivariate (MV) Cox regression analyses. Results: We identified 126 mPCa pts with LM from a total of 632 pts (19.9%) of which 122 were evaluable. Four pts were excluded due to lack of adequate imaging. We observed 110 deaths (90.2%) and median OS time from LM diagnosis was 7.2 months (mo) (3.4-13.3 mo). In the MV, the onset of LM in relation to castration resistant (CR) status (p = 0.003), the ratio neutrophils/lymphocytes (NLR) (p = 0.005) and the size of the largest lesion (LL) (p = 0.018) remained significant. Conclusions: These data show the association of NLR with OS in this pts population and suggest other potential prognostic variables in mPCa pts with LM. UV MV N HR 95% CI p-value N HR 95% CI p-value Time being CR No CR or < 12mo 32 1.0 < 0.001 21 1 0.003 12-36mo 42 2.9 1.8 4.8 39 2.8 1.5 5.4 > 36mo 48 2.4 1.4 4.0 46 1.3 0.7 2.6 Radiological pattern < = 3 L and LL > 25 mm OR 4-10 L and LL > 50 mm 25 1.0 0.01 19 1.0 0.079 < = 3 L and LL < 25 mm OR 4-10 L and LL 25-50 mm 30 1.5 0.9 2.8 25 1.6 0.6 3.9 4-10 L and LL < 25 mm OR > 10 L 67 2.2 1.3 3.6 62 2.5 1.0 5.9 Largest L, mm 122 1.0 1.0 1.0 0.727 106 1.0 1.0 1.0 0.018 Smallest L, mm 122 1.0 1.0 1.0 0.156 106 1.0 1.0 1.1 0.488 Bone mets 0-4 42 1.0 0.9 3.0 < 0.001 32 1.0 0.052 5-20 21 1.7 2.6 6.9 18 2.1 1.0 4.6 > 20 59 4.3 56 2.2 1.1 4.4 Lung mets No 94 1.0 0.318 85 1.0 0.981 Yes 26 0.8 0.5 1.3 21 1.0 0.6 1.8 NLR 106 1.0 1.0 1.1 0.155 106 1.1 1.0 1.1 0.005
Tumor profiling of liver metastases (LM) from CRC, NSCLC, pancreatic (PC), breast (BC) and gastroesophageal (GE) tumors to reveal differences versus primary tumors including in cMET, MYC, CDK4, Her2, b-catenin and PD1.
Authors: Wafik S. El-Deiry, Joanne Xiu, Elias Obeid, Ranee Mehra, Igor A. Astsaturov, Jessica Wagner, Avital Lev, Marie Baumeister, Anthony Frank Shields, Mohamed E. Salem, Jimmy J. Hwang, Namrata Vijayvergia, Crystal Shereen Denlinger, Efrat Dotan, Hossein Borghaei, Michael J. Pishvaian, Philip Agop Philip, John Marshall, Steven J. Cohen
Journal: Journal of Clinical Oncology (2016)

11604 Background: Liver is the most common metastatic site for various tumors and associates with poor prognosis. To understand LM as distinct molecularly from other origins such as CRC, NSCLC, BC and GE, we compared a large cohort of LM with local disease (LD) and other metastases (OM). Methods: Tumors from LD or metastatic site submitted to Caris Life Sciences for IHC (protein expression), ISH (gene amplification) and NGS sequencing (mutation, MT, CNV) between 2009 and 2015 were studied. A total of 9818 NSCLC (6289 LD, 420 LM, 3109 OM), 3486 PC (1453 LD, 1111 LM, 922 OM), 9739 BC (4413 LD, 1232 LM, 4094 OM), 1656 GE (1456 LD, 200 LM, 3937 OM) and 6368 CRC (4842 LD, 1526 LM, 3069 OM) were included. Tumors (metastases and primary) were not paired. Chi-square tests were used for statistics. Results: TOPO1 expression (Table) was highest in LM vs OM and LD, p < 0.01, suggesting a difference in DNA replication activity. Similar observations were made for TOP2A and TLE3. PD-L1 varied, and PD-1 on TILs was consistently the lowest in LM, and highest in LD (p < 0.02). Additionally, in CRC LM, OM and LD, Her2 ISH (5%, 2%, 3%), cMET IHC (56%, 51%, 48%) and APC (71%, 48%, 65%) MT were the highest in LM. In NSCLC, cMET ISH was higher in LM than LD (6.1% vs. 2.2%). MYC mutation was 11% in LM, 0.9% in OM and 0 in LD. In PC, cMET IHC was highest in LM (64%), followed by OM (57%) and LD (48%). In BC, CDK4 CNV was seen in 15% of LM, but not in OM or LD. In GE, CTNNB1 mutation was seen in 8% of LM, 2% in OM and 1% in LD. (p < 0.05). Conclusions: Molecular alterations shared by LM in 5 tumor types may warrant investigation in clinical trials of cMETi, BETi, CDKi, Her2, b-catenin and immune checkpoint inhibitors. Further research into alterations seen in LM may identify molecular drivers responsible for liver metastases. Differences between LM, OM, and LD support use of fresh biopsies from dominant metastatic site for molecular profiling. % TOPO1 TOP2A TLE3 PD-L1 PD-1 NSCLC LM 76 78 40 19 40 OM 55 77 40 30 56 LD 49 61 39 22 63 PC LM 70 69 42 11 32 OM 56 53 31 7 29 LD 35 37 30 5 41 GE LM 78 91 49 13 43 OM 59 74 31 8 45 LD 61 82 34 9 63 CRC LM 60 86 30 2 35 OM 53 74 25 3 38 LD 39 85 26 2 48 BC LM 79 67 64 4 30 OM 65 64 53 9 47 LD 55 57 54 10 52
Pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors.
Authors: Bin Fan, Lipika Goyal, Maeve Aine Lowery, Shuchi Sumant Pandya, Erika Manyak, Kha Le, Liewen Jiang, Julia Auer, David Dai
Journal: Journal of Clinical Oncology (2017)

4082 Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) produce the oncometabolite D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class selective inhibitor of mutant IDH1 (mIDH1) under evaluation in an ongoing phase 1 study in patients with mIDH1 advanced solid tumors, including cholangiocarcinoma (CC) (NCT02073994). Objectives for this abstract were to 1) characterize the PK profile of AG-120 and the relationship between AG-120 exposure and 2-HG suppression, and 2) evaluate the influence of intrinsic patient factors on AG-120 clearance, in patients with mIDH1 CC. Methods: AG-120 was administered orally once daily (QD) or twice daily (BID) in continuous 28-day cycles. As of Dec 5, 2016, 60 of 73 patients enrolled with mIDH1 CC had PK/PD samples available for analysis at 100 mg BID, 300 mg QD, 400 mg QD, 500 mg QD, 800 mg QD, and 1200 mg QD in dose escalation (n = 24) and 500 mg QD (n = 36) in dose expansion. Blood (n = 60) and fresh tumor biopsy samples (n = 14) were collected to assess AG-120 and 2-HG using qualified liquid chromatography-tandem mass spectrometry methods. Results: Following both single and multiple doses, AG-120 plasma exposure increased less than dose proportionally from 100 to 1200 mg. Mean terminal half-life was 38.4–85.8 h, supporting a QD dosing regimen. Following multiple doses, steady state was reached within 15 days, with approximately 2-fold accumulation in plasma AG-120 exposure. No patient-specific factors were identified as clinically significant covariates affecting AG-120 plasma clearance. After multiple doses, plasma 2-HG levels were reduced (up to 98.4% inhibition, achieving levels similar to those in healthy volunteers) and tumor biopsy 2-HG levels were also substantially reduced (by up to 99.9%) at all dose levels tested. The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition vs. other dose levels. Conclusions: AG-120 demonstrated a long half-life in patients with mIDH1 CC and robustly inhibited 2-HG in plasma and tumor samples. These PK/PD data, along with emerging safety and clinical activity data, support the selection of 500 mg QD for future clinical investigation. Clinical trial information: NCT02073994.
Physician experience and attitudes toward addressing the cost of cancer care.
Authors: Ivy Altomare, Blair Billings Irwin, Yousuf Zafar, Kevin Houck, Bailey Maloney, Rachel Adams Greenup, Jeffrey M. Peppercorn
Journal: Journal of Clinical Oncology (2014)

6561 Background: ASCO recommends that patient-physician treatment discussions include addressing costs of cancer care; when and how these conversations should optimally take place is unclear. We sought to determine contemporary attitudes of US cancer physicians toward discussing treatment costs as a part of medical decision-making. Methods: A 15-question, self-administered, anonymous, electronic survey was distributed to US ASCO physician members after conducting 10 pilot interviews to improve usability and face validity. Differences in answers among groups were compared using simple logistic regression with 2-sided p-values. Results: 333 of 2290 physicians responded (RR=15%; 35% medical oncologists, 35% radiation oncologists, and 31% surgeons; 45% academic, 55% community practice). Overall, 67% agreed that doctors should discuss costs of care with patients; 33% disagreed. 60% reported addressing costs frequently/always and 40% rarely/never in their own practice. Medical oncologists were more likely than radiation or surgical oncologists to discuss costs with patients (OR 3.14 and 3.75, p≤.00001). Compared to community physicians, academic physicians were less likely to discuss costs (OR 0.41, p=.00012), and felt less prepared for such discussions (OR 0.492, p=.005), but were more likely to consider costs to the patient (OR 2.68, p=.02) and to society (OR 1.822, p=.02) when planning treatment. Physicians who reported frequent discussions were significantly more likely to prioritize treatments in terms of cost, have a sense of their patients' financial well-being, feel their patients were well-informed about costs and believe doctors should explain both out of pocket and societal costs of care to their patients. Surgeons were most likely to refer patients to financial counselors (p=.01). The most common reported barriers were lack of resources to guide cost discussions (58%) and lack of time (44%). Conclusions: Though a majority of oncology physicians believe it is important to discuss costs of care, practice is inconsistent and there is no consensus on when and how to discuss costs. There is a need to define the goals and content of cost discussions and to address perceived barriers that limit this aspect of quality cancer care.
P01.057 Effects of tumor treating fields on health-related quality of life (HRQoL) in newly diagnosed glioblastoma: An exploratory analysis of the EF-14 randomized phase III trial
Authors: T Walbert, G Lavy-Shahaf
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are a novel treatment modality that continuously delivers alternating electric fields to the tumor region. TTFields interfere with the assembly of the mitotic spindle leading to apoptosis. In the EF-14 phase III study in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) showed significant increase in overall and 5-year survival rates compared to temozolomide. TTFields/TMZ did not negatively impact nine prespecified HRQoL scales (global health, physical, cognitive, role, social and emotional functioning, itchy skin, pain, and leg weakness) except for increased itchy skin. We present an exploratory analysis of the remaining 17 EORTC QLQ C-30 and BN-20 HRQoL scales. HRQoL was measured by the EORTC QLQ-C30 and BN20 questionnaires at baseline and every 3 months thereafter. Mean changes from baseline as well as significant changes in scores over time (>10 points) were evaluated using a repeated measures test. Deterioration-free survival and time-to-deterioration in HRQoL were assessed for each scale, as well as % patients with stable/improved HRQoL versus baseline. No statistically or clinically significant decline in any of the exploratory HRQoL scales was seen in the repeated measures analysis or in time to deterioration. Significantly more patients treated with TTFields/TMZ versus TMZ reported stable/improved bladder control (63.6% versus 46.8%, p=0.001) and diarrhea (60.6% versus 43.7%, p=0.001) compared to baseline. The deterioration-free survival for diarrhea, future uncertainty and headaches was significantly delayed in TTFields/TMZ treated patients compared to TMZ alone (HR 0.68, 0.71 and 0.67, respectively, p<0.001). No negative impact of HRQoL was seen in any of the exploratory scales between patients treated with temozolomide only or TTFields and TMZ. Adding TTFields to standard therapy in newly diagnosed glioblastoma does not appear to negatively impact QoL.
Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Final efficacy and safety analysis.
Authors: María-Victoria Mateos, Robert Z. Orlowski, David Samuel DiCapua Siegel, Donna Ellen Reece, Philippe Moreau, Enrique M. Ocio, Jatin J. Shah, Paula Rodríguez-Otero, Nikhil C. Munshi, David Avigan, Joy Yang Ge, Patricia Maria Marinello, Jesus San Miguel
Journal: Journal of Clinical Oncology (2016)

8010 Background: Pembrolizumab (pembro) is a monoclonal antibody against PD-1 that helps to restore antitumor immune surveillance. KEYNOTE-023 (NCT02036502) is a phase 1 dose-escalation study evaluating safety and efficacy of pembro in combination with lenalidomide (len) and low-dose dexamethasone (dex) in patients with RRMM. Methods: Patients with RRMM who failed ≥ 2 prior therapies enrolled. Modified 3 + 3 design was used for dose determination with cohorts of 3-6 patients treated with pembro 2 mg/kg Q2W + len 10 mg or 25 mg on days 1-21 and dex 40 mg weekly, repeated every 28 days. After preliminary MTD/MAD identification, additional patients received pembro 200 mg Q2W + len and dex for dose confirmation. Upon final MTD, patients enrolled in the dose expansion phase. Treatment continued for 24 mo or until confirmed disease progression or unacceptable toxicity. Response evaluated monthly using IMWG 2006. Results: 3 DLTs from the pembro 2 mg/kg, 25-mg len cohort were observed in 17 patients in the dose determination/confirmation phase: grade 3/grade 4 neutropenia, grade 3 pneumonia, and grade 3 tumor lysis syndrome with grade 4 hyperuricemia. Based on dose confirmation phase, pembro 200 mg + len 25 mg and dex 40 mg was the MTD/MAD. As of Sep 22, 2015, an additional 33 patients were enrolled in the expansion phase. Median age for the total population was 62 y, 72% had ≥ 3 prior therapies, 76% were refractory to len, and 30% had double refractory disease. 36 patients (72%) experienced treatment-related AEs, most commonly thrombocytopenia (28%) and neutropenia (24%). With a median follow-up of 9.7 mo (range, 4.3-18.4), 13/17 (76%) patients evaluated for efficacy in dose determination/confirmation responded to treatment, including 4 VGPRs (2 in len-refractory) and 9 PRs (3 in len-refractory), with median duration of response 9.7 mo (range, 0+-16.7+). 3 patients (18%) had stable disease. 94% had a reduction in M protein or free light chains. Updated efficacy data for all 50 patients will be presented. Conclusions: Pembro in combination with len and dex was associated with a tolerable safety profile and promising antimyeloma activity in heavily pretreated patients with RRMM. Clinical trial information: NCT02036502.
Determinants of receipt of hematopoietic cell transplantation (HCT) in younger patients with acute myeloid leukemia (AML).
Authors: Vijaya Raj Bhatt, Baojiang Chen, Stephanie Lee
Journal: Journal of Clinical Oncology (2016)

e18027 Background: HCT can improve overall survival (OS) in AML with high or intermediate-risk cytogenetics, however, the use of HCT is low even in younger patients. Methods: We utilized the National Cancer Database to identify factors associated with receipt of HCT in younger patients (≤60 years) with AML reported between 1998-2012. Subjects with complete data for the variables sex, age, race, education, income, distance traveled for health care, hospital type, facility location, Charlson co-morbidity score, chemotherapy use, time to treatment initiation, use of HCT and vital status were included. We included only those patients, who had all of the first course treatment or a decision not to treat made at the reporting facility. Multivariate logistic regression model was used to determine factors associated with receipt of HCT. Results: 13.7% of patients (n=39,805) underwent HCT. Median OS for all patients was 21.1 months (95% CI 20.6-21.8). Factors associated with a lower likelihood of receiving HCT included initial care in a non-academic hospital, male, black or other race, Charlson comorbidity score of ≥1, uninsured status, Medicaid or Medicare insurance, lower educational and income status (Table 1). Conclusions: HCT may be underutilized in younger patients with AML in the US. Several health care system and socioeconomic factors may contribute to a lower receipt of HCT. Factors associated with non-use of HCT. Variable Odds ratio 95% confidence interval P value Academic 1 Non-Academic 3.0 2.7-3.3 <0.01 Male 1 Female 0.9 0.8-0.9 <0.01 White 1 Black 1.6 1.4-1.9 <0.01 Others 1.2 1.0-1.4 0.04 Percentage without high school diploma <7% 1 7-12.9% 1.1 1.0-1.2 0.18 13-20% 1.2 1.02-1.3 0.02 >21% 1.4 1.2-1.6 <0.01 Median Household Income <$38,000 1 $38,000-47,999 1.0 0.9-1.2 0.5 48,000-62,999 0.9 0.8-1.0 0.1 ≥63,000 0.8 0.7-0.9 <0.01 Primary Payor Private insurance 1 Medicaid 1.5 1.3-1.7 <0.01 Medicare 1.9 1.6-2.3 <0.01 Uninsured 3.3 2.6-4.3 <0.01 Other government 1.2 0.8-1.6 0.3 Unknown insurance status 5.8 4.2-8.1 <0.01 Charlson co-morbidity score 0 1 1 1.3 1.2-1.5 <0.01 ≥2 1.9 1.5-2.4 <0.01
Randomized, single-blind, crossover study to assess the pharmacokinetic and pharmacodynamic bioequivalence of CHS-1701 to pegfilgrastim in healthy subjects.
Authors: John A. Glaspy, Paula G. O'Connor, Hong Tang, Barbara Finck
Journal: Journal of Clinical Oncology (2017)

e21693 Background: CHS-1701 is a proposed biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony stimulating factor approved for decreasing infection in patients receiving myelosuppressive anticancer drugs associated with febrile neutropenia. This multi-center, randomized, single-blind, 3-sequence, crossover study in healthy subjects assessed bioequivalence of CHS-1701 to pegfilgrastim with regard to pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Subjects were randomized to 1 of 3 treatment sequences; each included 1 dose of CHS-1701 (6-mg) and 2 doses of pegfilgrastim (6-mg) separated by ≥28 days. Primary PK endpoints were area under the curve from 0 to infinity (AUC 0-∞ ) and maximum concentration (C max ). PD endpoints were maximum absolute neutrophil count (ANC max ) and ANC area under the curve (ANC AUCs). Bioequivalence was demonstrated if the 90% confidence interval (CI) for the geometric mean ratio (GMR) of CHS-1701 to pegfilgrastim was within 80-125% for the endpoints. Results: 122 subjects were randomized and treated. Baseline characteristics were comparable between treatment groups. Median age was 29.5 (range 18-45). PK bioequivalence criteria were met for C max (GMR = 105.0; 90% CI 95.5, 115.4) and AUC 0–∞ (GMR = 97.5; 90% CI 88.6, 107.2). PD bioequivalence criteria were met for ANC max (GMR = 99.6; 90% CI: 96.2, 103.2), ANC AUC 0–last (GMR = 96.7; 90% CI: 92.2, 101.4), and ANC AUC 0–480 (GMR = 99.8; 90% CI: 97.7, 102.0). Adverse events (AEs) occurred in 76.0%, 76.6%, and 73.1% of subjects during the CHS-1701, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigator-designated treatment-related AEs occurred in 71.9%, 71.2%, and 62.8% of subjects, respectively, and most commonly included back pain (47.9%, 42.3%, 33.3%) and headache (33.3%, 41.4%, 34.6%). There were no treatment-related serious AEs. Conclusions: This study established the bioequivalence of CHS-1701 to pegfilgrastim with respect to PK and PD. There were no unexpected safety findings, and the two treatments displayed similar safety profiles. Clinical trial information: NCT02650973.