tbuckley/cabot-search huggingface dataset:
Comparison of trends and outcomes of hematopoietic stem cell transplant in geriatric (≥ 65 years) and non-geriatric (50-64 years) patients with cancer.
Authors: Achuta Kumar Guddati, Gagan Kumar, Iuliana Shapira
Journal: Journal of Clinical Oncology (2016)

e18143 Background: Outcomes of hematopoietic stem cell transplant (HSCT) in the geriatric population have not been extensively studied and compared with younger patients. We have analyzed a database with nationwide representation for outcomes of HSCT in these patients over a 12 year period. Methods: Data regarding patients who underwent HSCT was extracted from the Nationwide Inpatient Sample (NIS) from 2000 to 2011 using ICD-9-CM codes. HSCT hospitalizations were classified into allogeneic transplantation, autologous transplantation, subsequent hospitalization (s/p transplant) with graft versus host disease (GVHD) and subsequent hospitalization with other complications. NIS variables were used to identify in-hospital mortality and the trend HSCT and associated mortality was studied from 2000 to 2011. Chi square test and Wilcoxon rank test were used to compare categorical and continuous variables respectively. Results: The proportion of elderly patients ( ≥ 65 years) receiving autologous and allogeneic transplants has increased over the past decade. Subsequent hospitalizations with GVHD or for other complications have also increased in elderly patients. Notably, a statistically significant decrease in mortality in all classes of hospitalization is noted in the younger age group but such an effect is seen only in the allogenic transplant group of the elderly population. The trends are summarized in the table below. Conclusions: The rate of HSCTs performed in the geriatric patient population has significantly increased in the past decade. However, transplant related mortality has not improved as much as it has in the younger population. Trend from 2000 to 2011 50 to 64 years ≥ 65 years Autogenic transplant 79.9% to 66.1%* 20.1% to 33.9%* Allogeneic transplant 91.3% to 78.6%* 8.7% to 21.4%* s/p transplant with GVHD 94.5% to 82.1%* 5.47% to 23.2%* s/p transplant with other complications 84% to 63%* 16% to 37%* Mortality trend from 2000 to 2011 Autogenic transplant 3.6% to 0.4%* 2.9% to 1.5% Allogeneic transplant 11.4% to 3.5%* 8.67% to 2.5%* s/p transplant with GVHD 19.1% to 9.7%* 10% to 12.7% s/p transplant with other complications 6.9% to 5.4%* 7.4% to 5.25% * p < 0.05
Vascular endothelial growth factor A as a marker of bevacizumab in glioblastoma.
Authors: Weir Chiang You, Jin-Ching Lin
Journal: Journal of Clinical Oncology (2018)

e14068 Background: Glioblastoma multiform is highly malignant and comes with worse survival. One of the hallmark of glioblastoma is angiogenesis. Bevacizumab is one of very limited treatment options after recurrence. This study evaluated the anti-angiogenesis effect of chemoradiation and investigated the circulating angiogenesis-related factors that may be prognostic on the survival in recurrent glioblastoma. Methods: Peripheral venous blood samples from recurrent glioblastoma patients who had completed temozolomide chemoradiation were prospectively collected. All patient received bevacizumab therapy after recurrence. We used proteome antibody array (R&D Co.) to analyze 55 human angiogenesis-related proteins simultaneously. Quantification of the expression intensity was measured by digital imaging system (Bio Pioneer Tech Co.). Averages differences across paired pre- and post-chemoradiation samples were calculated by ANOVA. Progression-free survival (PFS) is defined as the time from bevacizumab therapy to tumor progression. The predictive values on survival were estimated by Cox regression and Kaplan-Meier method. Results: From July 2015 to April 2017, twenty-three patients were prospectively enrolled in this study. Reduced expression intensity after chemoradiation was observed among fifty-five angiogenesis-related proteins in the array and sixteen of them were statistically significant. Further univariate analysis revealed that higher insulin-like growth factor binding protein-2 (IGFBP2) to vascular endothelial growth factor A (VEGFA) ratio (IVR) is associated with worse progression-free survival (PFS) after (p= 0.038 and p= 0.038 pre- and post-chemoradiation respectively). Using the cut-off value of 5, the patients after chemoradiation IVR ³5 have significant worse PFS (6.9±0.9 months vs. 16.1±3.2 months, p= 0.027). Conclusions: Our results imply the anti-angiogenesis effect of chemoradiation in glioblastoma. Post-chemoradiation IVR < 5 may serve as a marker to determine who will have survival benefit from bevacizumab. Clinical trial information: CT03225963.
An individual patient level data pooled analysis of T-DM1 cardiac safety in HER2-positive (HER2+) metastatic breast cancer (MBC) patients.
Authors: Noam Falbel Ponde, Lieveke Ameye, Matteo Lambertini, Marianne Paesmans, Evandro De Azambuja
Journal: Journal of Clinical Oncology (2018)

10068 Background: T-DM1 is approved for the treatment of HER2+ MBC and is currently under investigation for use in the early setting. Cardiac dysfunction is a known side effect of trastuzumab, an anti-HER2 antibody that is a component of T-DM1. However, individual studies were not large enough to permit an adequate understanding of cardiac events (CEs) associated with T-DM1 use. We have conducted a pooled analysis of T-DM1 trials in the advanced setting to understand its incidence, clinical presentation as well as to establish possible risk factors. Methods: we have conducted an individual patient-level pooled analysis of trials testing T-DM1 in HER2+ MBC patients. CEs were defined either as: (1) congestive heart failure (CHF) of any grade or grade 3/4 LVEF drop (symptomatic CHF); (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Logistic regression was used to assess possible risk factors (age, prior heart disease, prior hypertension, prior diabetes, prior anthracycline use, concomitant pertuzumab, among others) for CEs. Results: 7 trials with 1961 patients exposed to T-DM1 were obtained. Of these, 1544 received T-DM1 and 417 T-DM1 + Pertuzumab. Median age of patients was 53 years (25-89) and median LVEF at baseline was 63%. 63% of patients had received anthracyclines previously. Symptomatic CHF was reported in 0.7%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.7% and grade 1/2 LVEF drop in 2%, resulting in a total CE rate of 3.4% (95% CI, 2.6% to 4.3%). No cardiac deaths or cardiac event grade 4 were reported, and only one in five CEs was of grade 3. Multivariate analysis showed patient’s age (odds 5% increase per one-year increase, p < 0.001) and concomitant pertuzumab use (odds ratio 2.1 {95% CI, 1.2 to 3.5}, p 0.007) as significant risk factors for CEs. Further analysis will be presented at the conference. Conclusions: The incidence of CEs in patients receiving T-DM1 was low and most events were not symptomatic. As is the case for trastuzumab, the most common presentation was LVEF drop. Elderly patients receiving T-DM1 should be carefully evaluated for cardiac safety during treatment.
Perioperative radiotherapy in patients with synovial sarcoma: An NCDB analysis.
Authors: Alicia Gingrich, Sarah Bateni, Chin-Shang Li, Yu Liu, Amanda Kirane, Richard J. Bold, Robert J. Canter
Journal: Journal of Clinical Oncology (2018)

e23529 Background: Previous studies have demonstrated an association of perioperative radiotherapy (RT) with improved oncologic outcome among synovial sarcoma patients undergoing surgery. However, the impact of chemotherapy, surgical margin status, comorbidities, and facility type on this association is unknown. Therefore, we sought to further evaluate the impact of RT on synovial sarcoma outcomes using the National Cancer Database (NCDB). Methods: After excluding patients < 18 years old, those lacking pathologic diagnosis, with metastatic disease and who did not undergo surgical intervention, we identified 1,216 synovial sarcoma patients from 2004-2012. We used Kaplan-Meier and Cox proportional hazards methods to study the effect of predictor variables on overall survival (OS). Results: Mean age at diagnosis was 41.5 (range 18 – 90), 47.5% were lower extremity, 71.3% were high grade (III/IV). 22.9% underwent surgery alone, 59.6% received RT, 44.2% received chemotherapy and 26.3% received tri-modality therapy. 5-year survival was 62.2 months for surgery alone, 72.8 months for surgery and RT, 48.3 months for surgery and chemotherapy, and 66.7 months for trimodal therapy (P < 0.001, see Figure). On univariate analysis, RT was associated with superior OS with a hazard ratio (HR) of 0.660 (95% CI 0.540-0.809, P < 0.0001). A higher Charlson-Deyo score (HR 3.28, 95% CI 1.92-5.61, P < 0.0001) and positive surgical margins (HR 2.83, 95% CI 1.26-6.36, P = 0.012) were associated with worse survival on univariate analysis. Interestingly, neither facility type nor chemotherapy showed a survival benefit on univariate or multivariable analysis. On multivariable analysis, age, sex, grade, Charlson-Deyo score (HR 2.54, 95% CI1.37-4.71, P = 0.003) and RT (HR 0.676, 95% CI 0.519-0.880, P = 0.004) were predictors of OS. Conclusions: In patients with synovial sarcoma undergoing surgery, we observed that there was a significant effect of RT on OS when adjusting for comorbidity score, margin status, and receipt of chemotherapy. Routine implementation of RT in the multimodality treatment of synovial sarcoma patients appears indicated.
Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer
Authors: Simon R. Lord, Wei-Chen Cheng, Dan Liu, Edoardo Gaude, Syed Haider, Tom Metcalf, Neel Patel, Eugene J. Teoh, Fergus Gleeson, Kevin Bradley, Simon Wigfield, Christos Zois, Daniel R. McGowan, Mei-Lin Ah-See, Alastair M. Thompson, Anand Sharma, Luc Bidaut, Michael Pollak, Pankaj G. Roy, Fredrik Karpe, Tim James, Ruth English, Rosie F. Adams, Leticia Campo, Lisa Ayers, Cameron Snell, Ioannis Roxanis, Christian Frezza, John D. Fenwick, Francesca M. Buffa, Adrian L. Harris
Journal: Cell Metabolism (2018)

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.
Cost-effectiveness of single versus dual immune checkpoint blockade for chemotherapy-refractory esophageal, GE junction, and gastric cancers.
Authors: Sassan Ostvar, Jin G. Choi, Jacqueline N. Chu, Ryan David Nipp, Michael Lawrence Dougan, Kerry Lynn Reynolds, Justin F. Gainor, Chung Yin Kong, Chin Hur
Journal: Journal of Clinical Oncology (2018)

e16089 Background: Immune checkpoint inhibition has shown early promising results in patients with chemotherapy-refractory metastatic or advanced tumors of the esophagus, gastroesophageal junction, and stomach. We explore the cost-effectiveness of checkpoint inhibitors as second-line treatments for this group of patients using a decision analytic approach. Methods: A Markov model was developed to simulate a virtual cohort of patients treated by (i) nivolumab 3 mg/kg, (ii) combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg, and (iii) best supportive care (BSC). A patient in the hypothetical cohort was a 55-year-old with advanced/metastatic disease who had received at least one prior line of chemotherapy. Patients who remained stable in treatment were monitored for adverse events until death. Rates of cancer-related mortality, disease progression, and drug-related toxicity were estimated using results from the CheckMate-032 clinical trial. The primary endpoints were survival, measured in life-years (LY), quality adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER). Cost-effectiveness of each strategy was evaluated from a US-payer perspective considering costs of drugs, treatment, and management of drug-related toxicity. Cost-effectiveness was defined using a willingness to pay threshold of $100,000/QALY. Results: Combination therapy with nivolumab and ipilimumab yielded the highest effectiveness (QALYs = 0.47, LYs = 1.09) in our base case modeling results, compared with nivolumab (QALYs = 0.43, LYs = 1.03), and BSC (QALYs = 0.19, LYs = 0.42). Nivolumab had an incremental cost of $84,555/QALY compared with BSC, while nivolumab with ipilimumab resulted in an incremental cost of $1.1M/QALY compared with nivolumab alone. The cost gap between the two was due to the higher price of ipilimumab, and costs of managing increased toxicity Conclusions: Our modeling analysis finds that combination therapy of ipilimumab and nivolumab is the most effective, but is expensive from a cost-effectiveness perspective, making nivolumab monotherapy the cost-effective option. Additional clinical data are needed to confirm our modeling results.
A randomized phase III trial between adjuvant docetaxel and surveillance after radical prostatectomy for high risk prostate cancer: Results of SPCG12.
Authors: Goran Ahlgren, Per Flodgren, Teuvo L. J. Tammela, Pirkko Kellokumpu-Lehtinen, Michael Borre, Anders Angelsen, Jon Reidar Iversen, Asgerdur Sverrisdottir, Eirikur Jonsson, Lisa Sengelov
Journal: Journal of Clinical Oncology (2016)

5001 Background: Docetaxel has proved to prolong survival in advanced castrate resistant prostate cancer (PCa) and we therefore started this trial to evaluate if six courses of docetaxel improves biochemical disease free survival (BDFS) after radical prostatectomy for high risk PCa. Methods: A total of 459 patients were randomised in 2005-2010 in this multinational openlabeled phase III study, to receive either 6 cycles of adjuvant docetaxel 75mg/m2 q 3 weeks (Arm A) or Surveillance (Arm B). Primary end-point was a rising PSA >0.5ng/ml. High risk prostate cancer was defined as pT2 with a positive margin if Gleasonscore (GS) 4+3 or higher, pT3b >GS 3+4, any lymph node positive disease with >GS 3+4, patients were followed for 5 years with PSA every 3 months. The study was powered to show a 15% difference at 5 years follow up. Results: All six cycles were completed by 79.1% of the patients. Salvage radiotherapy before the primary end-point was reached was given to 8% in Arm A and 10% in Arm B. Mean age was 62.2 years, mean baseline PSA 0.156, 83.7% had pT3 disease and 37.5% had GS 8-10 at randomisation. Of the 308 patients that had a lymph node dissection, 55 (17.5%) had metastasis. Median follow up was 56.8 months. The endpoint was reached in 43.2% of patients; 47.9% in Arm A and 38.9% in Arm B. In a Kaplan-Meier analysis there was no significant difference between the BDFS curves (p=0.078), but the curve of Arm A crossed the curve of Arm B at 15 months and it was parallel at a 10% lower level beyond 24 months. There were 6 deaths from prostate cancer in Arm A and only 3 in Arm B. Febrile neutropenia occurred in 18.7% of the patients in Arm A. No deaths were related to treatment. In a Cox multivariate analysis excluding lymph node status, GS (p<0.001), pT-stage (p=0.002) and positive surgical margin (p=0.009) were significant predictors of progression while randomisation arm (p=0.09) did not reach significance. Conclusions: Adjuvant docetaxel without hormonal therapy did not improve BDFS after radical prostatectomy for high risk prostate cancer. Instead, docetaxel as monotherapy seems to generate a more rapid biochemical progression in a subgroup of patients. Further analysis of this subgroup is warranted. Clinical trial information: NCT00376792.
Utility of liquid biopsies to assess circulating tumor DNA in patients with lung adenocarcinoma.
Authors: Maria Clemence Schwaederle, Sandip Pravin Patel, Hatim Husain, Megumi Ikeda, Richard Burnham Lanman, Kimberly C. Banks, AmirAli Talasaz, Lyudmila Bazhenova, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

e23097 Background: Liquid biopsies were used to assess genomic alterations in plasma circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC), and therapeutic outcomes analyzed. Methods: ctDNA testing (digital next-generation sequencing (NGS)) was performed in 88 patients with advanced NSCLC; (54 or 68 gene panel; 40 and 48 patients, respectively (Guardant Health, Inc. (Guardant360 test))) (Clinical Laboratory Improvement Amendment (CLIA) laboratory). Fifty-five patients (62.5%) also had some tissue molecular testing, 37 of whom had a consistent tissue NGS panel ( ≥ 182-genes). Results: Eighty-two percent of patients (72/88) had ≥ 1 ctDNA alteration(s) (median = 2 alterations), most frequently TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%). Retrospective analysis showed that 25 of 88 patients (28.4%) had received a therapy matching at least one ctDNA alteration(s) (most frequently an inhibitor of EGFR (N = 18), ALK, BRAF, other). Sixty-five percent of evaluable (N = 5 patients, too early) matched patients (N = 13/20) achieved stable disease (SD) ≥ 6 months or partial response (PR). The median progression-free survival for the 25 matched patients was 13.9 months. For the 37 patients who had both the tissue NGS panel and the ctDNA test (median 1.3 months (range, 0.1 to 20.9) between tissue biopsy and blood draw), the concordance rate for EGFR ctDNA alterations with tissue NGS was 70.3% (k = 0.361), with higher concordance when time interval between tissue and blood tests was ≤ 1.3 months. When we only considered patients in whom ctDNA confirmed present (N = 27), the EGFR concordance was 77.8% (k = 0.526). Fifty-one patients (58%) did not have the tissue NGS test performed, including 33 (37.5%) who had no other tissue molecular testing, usually because of inadequate tissue or potential morbidity for repeat biopsy. Conclusions: ctDNA frequently revealed genomic alterations in NSCLC adenocarcinoma, including in difficult-to-biopsy patients. Patients who received cognate therapies demonstrated a high rate of SD ≥ 6months/PR, suggesting clinical utility.
OS outcomes to anlotinib in patients (pts) with refractory NSCLC of both wild-type (WT) and mutant EGFR.
Authors: Kai Li, Baohui Han, Qiming Wang, Li Zhang, Jianhua Shi, Zhehai Wang, Ying Cheng, Jianxing He, Yuankai Shi, Weiqiang Chen, Xiuwen Wang, Yi Luo, Kejun Nan, Faguang Jin, Baolan Li, Jing Wang
Journal: Journal of Clinical Oncology (2018)

e21013 Background: Anlotinib, a novel multi-targeted TKI targeting VEGFR, FGFR, PDGFR and c-Kit, significantly prolonged OS and PFS in ALTER0303 trial (NCT02388919) Here we report the efficacy of anlotinib on pts with different EGFR status. Methods: 437 pts progressed after at least 2 lines of prior therapies were randomized 2:1 to receive anlotinib or placebo till progression or intolerable toxicity. Pts harboring driven gene mutations must had received previous TKI therapies. EGFR status was determined as a pre-stratified factor. Results: Of 437 pts, 138 (31%) exhibited EGFR mutations and 299 (69%) presented WT. Anlotinib provided more benefit in OS on mutant EGFR pts than WT pts (table 1). Of 138 EGFR mutant pts, in anlotinib arm and placebo arm pre-treated by one EGFR-TKI were 91/93 (97.85%) and 42/45 (93.33%) (P= 0.33), respectively; pre-treated by two TKIs were 13 /93 (13.97%) and 8/45 (17.78%) (P= 0.86), respectively; pervious EGFR-TKI treatment in two arms was statistically equivalent. In 18 pts with T790 mutation, mPFS of 10 pts in anlotinib and 8 pts in placebo group were 3.27 vs. 0.83 month (P< 0.0001, HR = 0.044), and 1 pts received previous osimertinib (osim) therapy. For 3rd-generation TKI, 7/93 in anlotinib arm and 3/45 in placebo arm underwent osim treatment revealed statistically equivalent at baseline (P= 0.40). The PFS of 7 pts in anlotinib and 3 pts in placebo arm with previous osim treatment were 4.00 vs. 0.40 month (P= 0.0076, HR = 0.108), and OS were 10.10 vs. 2.20 month (P= 0.03, HR = 0.071), respectively. In EGFR mutant pts, 21/93 (22.60%) in anlotinib arm and 12/45 (26.70%) in placebo arm received osim treatment after the end of ALTER 0303 trial and mean duration of treatment were 13.0 vs. 12.0 month, respectively (P= 0.7219). Conclusions: (1) Anlotinib presented significant improvement in OS on pts with refractory disease (resistant to 1st-generation TKI) of mutant EGFR comparing WT EGFR. (2) Anlotinib revealed an optimistical trend in PFS than placebo in pts with T790 mutation or resistance to osim. Clinical trial information: NCT02388919.EGFR Arm N(%) mOS Statistic HR Wild Anlotinib 201(31.34%) 8.87 Chisq = 5.38 P = 0.0204 HR = 0.685 (0.50, 0.95) Mutatant 93(45.16%) 10.70
PDL-1 and immunohistochemistry markers in esophageal adenocarcinoma.
Authors: Dawn E. Jaroszewski, Joanne Xiu, Zoran Gatalica, Staci Beamer, Melissa Stanton, Rish Pai, Murli Krishna, Mathew Thomas, Helen J. Ross, Thai Huu Ho
Journal: Journal of Clinical Oncology (2017)

e15567 Background: Esophageal adenocarcinoma (EAC) prognosis is poor and there is a need to identify patients that benefit most from neoadjuvant therapy. To examine the association of various biomarkers with clinical outcomes in neoadjuvant treatment of EAC, we retrospectively evaluated the biomarker expression (TS, ERCC1, TOPO1, PD-L1, PD-1) in patient matched formalin-fixed paraffin-embedded (FFPE) tumor samples. Methods: Immunohistochemistry of TS (TS106/4H4B1) , ERCC1 (Ab. 8F1), TOPO1 (1D6), PD-L1 (both 22c3 and SP142), PD-1 (NAT105), and chromogenic in-situ hybridization (CISH) of Her2 were performed on FFPE samples from 35 patients across 2 institutions at time of EAC diagnosis and after treatment when available. Retrospective clinical data and survival (5/2006-1/2016) was analyzed with a mean follow up of 110 months (range 22-306). Results: Overexpression (pre/post-treatment) of TS (60%/54%), ERCC1 (69%/16%), TOPO1 (74%/50%), PD-1 (54%/63%), PD-L1 (SP142) (2.9%/4%), PD-L1 (22c3) (0%/4%) and amplification of Her2 (18%/23%) were observed. Pretreatment observed PD-L1 levels were lower in our study (3%) when compared to other studies in EAC specimens (35%). Immunohistochemistry and changes observed after chemoradiation are reviewed in Table. No markers had significant correlation with prognosis however TS negative expression showed a non-significant (p=0.15) trend towards improved survival. Conclusions: Analyzing biomarkers in our neoadjuvant EAC cohort demonstrated a lower than expected PD-L1 positivity. In the largest cohort, to our knowledge, of patient matched FFPE tumor samples, we did not observe a statistically significant association between TS, ERCC1, TOPO1, PD-L1, or PD-1 with improved clinical outcomes. [Table: see text]