tbuckley/cabot-search huggingface dataset:
Influence of genetic variations of the angiopoietin and pericyte pathways in resected colorectal liver metastases.
Authors: Stefan Stremitzer, Wu Zhang, Dongyun Yang, Yan Ning, Sebastian Stintzing, Ana Sebio, Yu Sunakawa, Shinichi Yamauchi, Satoshi Matsusaka, Rita Elie El-Khoueiry, Judith Stift, Friedrich Wrba, Thomas Gruenberger, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

3564 Background: Liver resection in patients with colorectal liver metastases (CLM) offers the chance of cure and long-term survival. Angiogenesis is essential for tumor growth and progression. Genes involved in angiopoietin and pericyte pathways may be escape mechanisms for anti-vascular endothelial growth factor (VEGF) therapy. Therefore, we investigated whether genes of the angiopoietin and pericyte pathways have an influence on recurrence and outcome in patients with CLM treated with bevacizumab based chemotherapy. Methods: Genomic DNA was extracted from resected bevacizumab-pretreated CLM (FFPE) from 149 patients [median age 62 years (range 30-80), 58.4% male, median follow-up 3.9 years (range 0.02-7.7)]. Single nucleotide polymorphisms (SNP) in nine genes (ANGPT1, ANGPT2, TIE2, PDGF-B, PDGFR-B, IGF-1, TGF-B1, RALBP1, RGS5) were analyzed by direct Sanger DNA sequencing and evaluated for association with response, recurrence-free survival (RFS) and overall survival (OS). Results: In univariate analysis, rs329007 (RALBP1) showed a significant difference in RFS (A/A 14.0 months, A/G or G/G 9.2 months; HR 1.60, P=0.024) and rs1800818 (PDGF-B) in three-year OS rate (A/A 78%, A/G 69%, G/G 53%; HR 1.37 and 2.12, P=0.048). In multivariate analysis adjusted for age, number of metastases, size of metastases and time since diagnosis of colorectal cancer, rs329007 remained significant (HR 1.99, P=0.002). With respect to radiological response, rs1800818 and rs329007 showed a significant difference [(G/G 71%, A/G or A/A 86%, P=0.042) and (A/A 78%, A/G or G/G 94%, P=0.018), respectively]. With respect to histological response, rs329007 showed significant different rates between the groups (A/A 36% major histological response (MjHR), 34% partial histological response (PHR), 30% no histological response (NHR); A/G or G/G 46% MjHR, 13% PHR, 41% NHR, P=0.029). Recursive partitioning analyses revealed that rs329007 and rs1800818 were the dominant SNPs predicting histological response and OS, respectively. Conclusions: Our data suggest that genetic variations in genes involved in the angiopoietin and pericyte pathways may be predictive and/or prognostic biomarkers in patients with resected CLM treated with bevacizumab based chemotherapy.
Prostate cancer inhibitory activity of a novel dual inhibitor, EL102, in combination with docetaxel, and its effects on MDR1-mediated drug resistance in vitro.
Authors: Sharon A. Glynn, Aidan Toner, Joe Lewis, Frank Sullivan, Laura Breen, Martin Clynes, Francis J. Giles
Journal: Journal of Clinical Oncology (2012)

e15126 Background: EL102 is a dual-action drug promoting apoptosis and inhibiting angiogenesis. It exerts its action though the inhibition of Hif1a induced hypoxic signalling and induction of the Caspase 3/7 apoptotic cascade. The drug has equal activity in normoxia and hypoxia indicating it may be equally active in these different tumor compartments. We tested its ability to circumvent chemotherapeutic drug resistance. Methods: We assessed the ability of EL102 to inhibit prostate cancer cell proliferation and motility in vitro, calculating IC50s for CWR22, 22Rv2, PC3 and DU145 prostate cancer cell lines, comparing sensitivity between androgen dependent, androgen independent and metastatic prostate cancer. Additionally we assessed the activity of EL102 in combination with docetaxel in vitro and in murine CWR22 xenografts. The ability to overcome MDR1 and BCRP mediated drug resistance was also tested using DLKP drug resistant variants which exhibit 200 fold resistance to doxorubicin, docetaxel, paclitaxel and vincristine. Results: We found that prostate cancer cell lines are sensitive to EL102 with IC50s in the region of 10-50nM. Of particular interest was the identical sensitivity of the androgen independent 22Rv1 and its androgen dependent parent CWR22, suggesting ability to overcome hormone refractory prostate cancer. Additionally we demonstrate dose response for inhibition of cell motility in metastatic DU145. In CWR22 murine mouse models treatment with EL102 resulted in decreased tumor volume compared to control. A docetaxel and EL102 combination arm demonstrated the greater inhibition of tumor growth than EL102 or docetaxel alone. The lung cancer cell line DLKP, its drug resistant variants DLKPA (MDR1 overexpressing) and DLKPMitox (BCRP overexpressing) were equally sensitive to EL102 indicating that EL102 is not a substrate for MDR1 or BCRP. Conclusions: EL102 is a potential therapeutic for the treatment of prostate cancer, in particular in combination with docetaxel, and exhbibits the potential to overcome drug resistane. Future studies will include the efficacy of this drug in prostate cancer metastatic mouse models.
The quality of phase I trial (P1T) abstracts submitted to ASCO meetings
Authors: E. L. Strevel, N. Chau, G. R. Pond, A. J. Murgo, S. P. Ivy, L. L. Siu
Journal: Journal of Clinical Oncology (2007)

6532 Background: Conference abstracts of P1T communicate important information of anticancer drug development. Our objectives were to determine elements considered by experts as essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to ASCO meetings, and to propose guidelines for future reporting. Methods: Elements important for P1T abstract reporting were determined by a survey of experts in developmental therapeutics, and a scoring system for abstract quality was generated. All P1T abstracts published in ASCO Proceedings from 2002–2006 were reviewed, and a quality score was assigned. Results: An electronic survey was sent twice to 69 experts, with a response rate of 39% (27/69). Characteristics of the 27 experts were: average age = 48; male = 74%, USA:Europe:Canada = 78%:15%:7%; 89% had 10+ years experience in drug development; 93% from academic institutions versus 7% from governmental agencies; 56% currently involved in clinical research versus 44% in translational research. Experts were asked to rate each of 37 elements using a five-point Like rt scale, and elements with average expert ratings over 3.75 were included in the final quality score calculations. A total of 920 P1T abstracts over 5 years were reviewed. A positive and linear association was observed between average expert rating of the elements and proportion of P1T abstracts that included those elements (Spearman correlation coefficient, ρ=0.65). The median quality score for all 920 abstracts was 65% (range 26%–95%, SD 12.6%). Deficiencies existed in abstract reporting; for instance, dose-limiting toxicity was described in only 63% of abstracts, while recommended dose or maximum tolerated dose was reported in only 38%. A significant association between year of presentation was found (ρ=0.36, P&lt;0.001), with later years possessing better quality scores. The quality score was also statistically significant as a predictor of type of presentation (odds ratio 0.20, 95% CI 0.08–0.54, P=0.002), with oral presentations having the highest scores. Conclusion: The quality of P1T abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus. No significant financial relationships to disclose.
Mechanisms mediating the negative interaction between oxaliplatin (Ox) and epidermal growth factor receptor (EGFR) inhibitors in patients (pts) with <i>KRAS</i> mutant (MT) colorectal cancer (CRC).
Authors: Daniel J. Freeman, Selam Ogbagabriel, Jiansong Xie, Gloria Juan, Nicholas Potter, Josh Dekeyser, Robert Radinsky
Journal: Journal of Clinical Oncology (2012)

3580 Background: Phase 3 trials have shown that pts with MT KRAS tumors have shorter progression-free survival and overall survival when an EGFR inhibitor is added to Ox-containing chemotherapy (CT) (Bokemeyer et al 2011, Douillard et al 2010). However, KRAS status alone is not predictive of pt outcomes in this setting. The negative interaction has not been observed in pts with wild-type (WT) KRAS tumors receiving an EGFR inhibitor and platinum-CT or with MT KRAS tumors receiving an EGFR inhibitor with irinotecan (Peeters et al 2010, Van Cutsem et al 2009). Our goal was to understand the pharmacodynamic interaction between EGFR inhibitors and Ox in KRAS MT CRC cells. Methods: Isogenic MT and WT KRAS-expressing HCT116 CRC cells were treated with Ox, SN-38 (the active metabolite of irinotecan), panitumumab, gefitinib, or inhibitors of MEK, PI3K or Src as single agents or in combination. Viability was measured using an ATPlite assay. Cellular distribution of EGFR was visualized by a confocal microscopy. Downstream activation of MAPK and PI3K was detected by Western blotting. Results: Treatment (tx) with gefitinib, but not panitumumab, reversed the anti-proliferative effects of Ox in the MT KRAS-expressing CRC cells vs Ox alone (p&lt;0.0005) despite no differences in the number of platinum-DNA adducts. Neither tx reversed the anti-proliferative effects of Ox observed in the WT KRAS-expressing cells or SN-38 in either the MT or WT KRAS-expressing cells. EGFR was predominantly expressed in the cytoplasm of KRAS MT cells vs on the cell surface in the KRAS WT cells, which may explain the inability of panitumumab to reverse the anti-proliferative effects of Ox in the CRC cells. Combination tx of MT KRAS CRC cells with Ox and gefitinib increased pAKT which was not observed with Ox alone. Tx of the MT KRAS-expressing cells with a MEK, PI3K or Src inhibitor reversed the negative interaction between Ox and gefitinib (p&lt;0.0005). Conclusions: Feedback though AKT may contribute to the increased resistance to Ox in KRAS MT cells. Inhibitors of MEK, PI3K, or Src reversed the negative interaction between the EGFR inhibitors and Ox in a MT-KRAS genetic background.
A randomized, double-blind, placebo-controlled phase II study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naive metastatic/unresectable non-small cell lung cancer (NSCLC).
Authors: Joachim Von Pawel, Dietrich Hadler, Tara Fox, Qiang Wang, Jonathan Greenberg, Robert A. Beckman, Maciej Jerzy Krzakowski, Martin Reck
Journal: Journal of Clinical Oncology (2012)

7536 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist induces apoptosis in human cancer cell lines and has shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 were enrolled at 15 European sites. Pts received T or placebo (PL) IV + carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. In the case of complete response (CR)/partial response (PR) or stable disease, T or PL was given as maintenance therapy. The dosage regimen was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks thereafter; P: 175 mg/m 2 every 3 wks; C: AUC 6 every 3 wks. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS) and objective response rate (ORR) (CR + PR), safety. Efficacy was assessed in both the full population and a prospectively-defined FCGR genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR = 0.96; 95% CI: 0.6, 1.6. Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 14.5) for PL (HR = 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts (n = 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a non-significant trend towards increased PFS with T vs PL (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% with PL). The number of treatment cycles was similar in both treatment arms. Conclusions: T does not improve the efficacy of C/P as treatment for systemic therapy-naïve, unselected advanced NSCLC pts. T was well tolerated and is being investigated in other settings.
The plasma level of soluble epidermal growth factor Receptor (EGFR) and overall survival (OS) in non-small-cell lung cancer (NSCLC) patients.
Authors: Ping Ye, Jing Zhao, Shulian Wang, Feng Ming Kong
Journal: Journal of Clinical Oncology (2015)

e19091 Background: Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignant tumors including lung cancer. A soluble fragment of the EGFR extracellular domain can be detected in the blood of patients who have non–small-cell lung cancer (NSCLC), but its prognostic role to the overall survival (OS) of these patients should be further elucidated. Methods: PlasmaEGFR concentration was retrospectively determined using a commercial enzyme-linked immunoassay (BosterBio Inc. Pleasanton, CA). Plasma samples of 62 NSCLC patients before radiotherapy were obtained from University of Michigan and VA Ann Arbor Health System. Patients were seen in follow-up by a single physician every 3 months for the first 2 post-radiotherapy years, then every 6 months for 3 years and annually thereafter. Results: A total of 62 patients (median age 63.6 years old; 41 male and 21 female) with stage I-III NSCLC were eligible. Median follow-up for surviving patient is 14 months. The plasma concentration of EGFR was 27.4 ± 0.72 ng/ml (mean ± standard error of mean) in 62 NSCLC patients (95% confidence interval [CI], 26-28.8). The median OS of 62 patients is 14 months (95% confidence interval [CI], 16.6-25.4). There was a significant correlation between plasma EGFR concentration and overall survival (OS) of these patients (R2 = 0.14, p = 0.0028). After the dichotomization of EGFR using an arbitrary cutoff concentration of 27.24 ng/ml (median), survival analysis showed that patients with lower plasma EGFR concentrations (< 27.24 ng/ml) had a significant shorter OS compared with the patients who had higher plasma EGFR concentrations (> 27.24 ng/ml) (18.2 m vs 33.4 m, p = 0.021). Conclusion: This study suggests that baseline plasma EGFR, if validated by an external study, may be used to predict survival in patients with NSCLC. Further study is ongoing to correlate the plasma level of EGFR with mutations in the tumor tissue.
Tumor biomarker evaluation of 6,785 patients for combination treatment strategies in NSCLC.
Authors: Joanne Xiu, Rebecca Feldman, Ryan P. Bender, Ravi Salgia
Journal: Journal of Clinical Oncology (2014)

e19012 Background: Non-small cell lung cancer (NSCLC) exhibits activation of multiple tumor pathways. Presence of multiple aberrations may account for drug resistance as well as strategies for combination therapies. We examined concurrent aberrations of biomarkers in NSCLC to present an overview of potential patient cohorts who may benefit from such combinations. Methods: 6,785 NSCLC cases were evaluated. Specific testing was performed and included a multiplatform approach: sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: The EGFR mutation (MT) rate in this population was 12.7% (135/1059), of which 57% (55/96) overexpressed EGFR (IHC) and 61% (169/277) had EGFR gene amplification (FISH). This demonstrates the dependence on the EGFR pathway and potential importance of dual inhibition with cetuximab and EGFR TKIs. 66% (63/96) and 7% (6/90) of EGFR MT patients were MET high (IHC) and amplified (CISH), respectively, suggesting potential benefit from dual targeting of EGFR and MET. Interestingly, TP53 mutations were observed in 54% (70/129) of EGFR MT which has important implications for resistance to EGFR TKIs and possible cross-resistance to radiotherapy. ALK translocations were observed in 101 of 3611 (2.8%) patients, among which 19% (7/36), 3% (1/29) and 2% (1/48) carried concurrent EGFR, MET and HER2 amplification (ISH), respectively, suggesting the potential for combining crizotinib with agents such as cetuximab, onartuzumab or trastuzumab. A BRAF mutation was observed in 3.3% (34/1061), among which EGFR and MET expression was high by IHC (both have been implicated in resistance to BRAFi in other tumor types) in 58% (15/26) and 48% (12/25), respectively, indicating benefit from combination of newly approved dabrafenib with cetuximab or onartuzumab. Conclusions: This is one of the largest analyses in the United States of biomarkers in NSCLC.Our study shows the non-exclusive activation of multiple pathways. These results also show the importance of multiplatform testing as both protein, gene copy number and genetic alterations were detected.
Oral chemotherapy performance indicators: Early results from three rounds of Quality Oncology Practice Initiative (QOPI) data.
Authors: Jessica A. Zerillo, Trang Pham, Pamela Kadlubek, Jane Alcyne Severson, Emily Mackler, Joseph O Jacobson, Douglas W Blayney
Journal: Journal of Clinical Oncology (2014)

6532 Background: While use of oral chemotherapy is becoming more and more prevalent, little is known about the quality of care patients currently receive when these agents are prescribed. Moreover, few practice-level systems are in place to ensure safe utilization of oral chemotherapy. Methods: We analyzed results from 151 practices that voluntarily provided data to the American Society of Clinical Oncology’s (ASCO’s) QOPI program on 17 test measures of oral chemotherapy administration and management in at least one of three collection periods: spring or fall 2012, or spring 2013. The 17 test measures cover three domains—treatment plan documentation, patient education, and adherence/toxicity monitoring. We defined composite scores for each of the three domains. We analyzed the individual measures and composite scores by secular trend and tested the difference in composite scores for the three domains, excluding practices that had fewer than five charts for each analysis. Additionally, we tested change in scores over time among practices that participated at least twice. Results: The majority of data was provided by QOPI-certified practices. Overall, mean practice scores ranged from 66-68% for treatment plan documentation, 51-57% for patient education and 75-81% for adherence/toxicity monitoring (p<.0001 for all collection periods). Composite scores for practices that participated more than once did not improve significantly. Conclusions: The collection of oral chemotherapy test measures was feasible. Practices generally scored better on adherence/toxicity monitoring compared to plan documentation and patient education. Participation in subsequent rounds was not associated with an improvement in scores. These findings highlight opportunities for improvement in care for patients taking oral chemotherapy. Composite measures by collection round. Spring 2012 Mean (SD) Fall 2012 Mean (SD) Spring 2013 Mean (SD) Trend P value Plan documentation 65.80 (19.95) 65.85 (19.20) 68.47 (18.36) .3938 Patient education 50.63 (25.10) 54.02 (26.52) 56.64 (24.87) .5237 Adherence/toxicity monitoring 75.16 (17.15) 78.00 (14.09) 81.07 (14.01) .2015 P value <.0001 <.0001 <.0001
Outcome evolution of matched molecular targeted agents (MTAs) in metastatic colorectal cancer (CRC) patients (pts): VHIO experience.
Authors: Guillem Argilés, Elena Élez, Carolina Ortiz, Enrique Sanz-Garcia, Teresa Macarulla, Maria Alsina, Jaume Capdevila, Analia Azaro, Cristina Cruz, Cinta Hierro, Marta Vilaro, Debora Moreno, Rodrigo Dienstmann, Stefania Landolfi, Paolo Nuciforo, Ana Vivancos, Jordi Rodón, Josep Tabernero
Journal: Journal of Clinical Oncology (2015)

3602 Background: Biomarker-driven selection of new MTAs has not been widely successful in CRC as we reported in 2012. New screening platforms and drugs have reached early drug development. We aimed to evaluate outcome evolution between 2012 and 2014 Methods: MTAs given to CRC pts based on molecular tumor profiling (MTP) from Jan/2012 to Dec/2014 were compared to the reported in 2012. MTP included mutations (mt) detected by Sequenom (Sq), VHIO-Card Amplicon panel, cMET amplifications (amp), PTEN and PDL1 expression. Benefit was calculated comparing treatment failure of prior line (TTF1) to the MTAs’ one (TTF2). TTF2/TTF1≥1.3 supposed MTAs benefit. Relevant MTAs-biomarker pairs were analyzed. Results: A total of 174 MTAs were given. Pairs biomarker-MTAs were: KRASmt: MEK inhibitors (i)+PI3Ki or MEKi + anti-receptor tyrosine kinase (RTK) mAbs; PIK3CAmt or PTEN loss: PI3Ki, MTORi, dual PI3K-MTORi, MTORi + anti-RTK mAbs; cMET path activation: METi [mAbs or RTKi]; BRAF V600mt: BRAFi, BRAFi + MEKi +/- CDK4i, BRAFi + anti-EGFR mAbs +/- PI3Ki; RAS wild-type (wt): 2nd generation anti-EGFR mAbs. Median (m)TTF1 was 21.9 weeks (w) (18.9-24.8), mTTF2 8.3w (7.7-8.9), with 17.2% of pts benefiting from MTA (i.e. TTF2/TTF1≥1.3). Derived benefit was not higher to the reported in 2012 mTTF1 16.3w (14-18.5), mTTF2 7.9w (7.2-8.5) with 14.3% pts benefiting from MTAs (p=0.47). BRAF V600E mt pts receiving BRAFi combos was the group with more benefit from MTAs (30%) Conclusions: Recent evolution with MTAs in CRC does not widely correlate with better outcome in overall population. However, significant benefit is observed when there is a mechanistic rationale for MTA (BRAF V600E). Further CRC molecular subtyping is needed to improve outcomes. MatchedMTAs pts mTTF1 w mTTF2 w % clinical benefit BRAF V600Emt(BRAFi combos) 23 21.8 (12-31.7) 10.9 (7.3-14.4) 30.4% RASmt(MEKi + PI3Ki) 51 18.1 (11.4-24.9) 7.9 (7.1-8.6) 11.8% RASmt (MEKi + anti- RTKsmAbs) 22 25.4 (21.5-29.4) 6 (4.2-7.8) 18.2% RASwt (2ndgeneration anti-EGFR mAbs) 38 21.6 (14.8-28.3) 12.6 (7-18.2) 21.1% PIK3CAmt/PTEN loss (s/a PI3K-path i) 40 15 (10.8-19.3) 8.4 (7.5-9.3) 20% PIK3CAmt/PTEN loss (combos PI3K-path i) 24 24.4 (9.8-39.9) 8 (7.9-8.1) 17.2%