tbuckley/cabot-search huggingface dataset:
Lymphopenia as a predictive factor of responsiveness to preoperative treatment in patients with locally advanced breast cancer.
Authors: C. R. Desposorio, F. Hurtado de Mendoza, S. G. Falcon, A. R. Capellino, R. Lujan, D. Morales, J. J. Castillo, B. E. Beltran
Journal: Journal of Clinical Oncology (2011)

e21096 Background: It has been suggested that lymphopenia is an important prognostic factor for survival in patients with advanced breast cancer. The aim of this study was to evaluate if lymphopenia could be a predictive factor of responsiveness to preoperative treatment in patients with locally advanced breast cancer. Methods: We retrospectively evaluated 163 consecutive locally advanced (T3-4, N0-3, M0) breast cancers patients who received preoperative treatment in our hospital from January 2003 to December 2005. We classified them according to the subtypes: Luminal A, Luminal B, HER2 and Triple Negative (TN). The absolute lymphocyte count (ALC) was recorded at the time of diagnosis and a cutoff value of 1500/mm3 was used to define lymphopenia. Kaplan Meier, log-rank and pairwise comparisons were used to compared overall survival (OS) and time to treatment failure (TTP) between subtypes and to look for predictive factors of progression during preoperative treatment. Results: Of the 163 patients, 101 (62%) were Luminal A, 35 (21%) were TN, 18 (11%) were Luminal B and 9 (6%) were HER-2. OS and TTP were significantly lower for TN and HER2 subtypes compared to Luminal A. Only 33 patients (20.2%) progressed during preoperative treatment. 34% of TN patients progressed during preoperative treatment; 28% of Luminal B; 15% of Luminal A; and 11% of HER2 patients. Based on lab data 28 (17.2%) patients had an ALC <1500/mm3. Of these, 43% progressed during preoperative treatment. On the other hand 16% of the patients with an ALC ≥1500/mm3 progressed (p=0.001). Other variables such as age, clinical T, clinical N, histological grade, HER-2 status, ER status and breast cancer subtypes did not predict failure to preoperative treatment significantly. Conclusions: Lymphopenia at the time of diagnosis could predict progression during preoperative treatment in patients with locally advanced breast cancer. These results suggest that the host immune response could play an important role in the response of chemotherapy. Studies with larger numbers of patients are needed to validate these results.
An evaluation of siRNA screening in identification of targets in PTEN deficient tumor cells.
Authors: N. McCabe, S. M. Walker, K. Wikstrom, C. Greenan, E. McLean, T. Delaney, M. McCarthy, D. Cochrane, C. Wilson, T. S. Davison, F. A. McDyer, G. L. Jellema, N. Goffard, I. James, T. Harrison, P. B. Mullan, D. P. Harkin, R. D. Kennedy
Journal: Journal of Clinical Oncology (2011)

e13569 Background: PTEN is frequently lost in cancer cells through genetic mutation or epigenetic silencing. Loss of PTEN function has been widely reported to result in up-regulation of PI3K and consequently AKT signalling, therefore promoting cell survival and proliferation. More recently a role for PTEN in maintaining genomic integrity was suggested by the finding that PTEN deficient cells demonstrate chromosomal instability and are sensitive to ionising radiation induced DNA damage. Methods: We utilised a siRNA screening approach with a human ‘druggable’ genome siRNA library to identify novel drug targets for PTEN associated cancers. The library contained 2 individual siRNAs directed against 6,961 druggable targets of the human genome, including 691 kinases, 206 phosphatases, 230 DNA repair genes. Bioinformatics analysis identified 981 genes as being synthetically lethal with loss of PTEN. The Ingenuity knowledgebase tool was then used to define the biological processes which were represented by these genes. Results: Twenty-one statistically significant processes were identified as being synthetically lethal with loss of PTEN, including the response to cellular stress. We show that PTEN deficient cells have an increase in endogenous DNA damage due to elevated ROS Furthermore we identify a specific requirement for the DNA damage response kinase ataxia telangiectasia mutated in response to ROS in PTEN deficient cells. Inhibition of ATM caused DNA damage, cell cycle arrest and apoptosis. The dependence on ATM was shown to be the result of a loss of a nuclear function for PTEN and independent of AKT deregulation. Conclusions: This study highlights the utility of siRNA screening in target identification and in uncovering novel biological functions. Furthermore, these observations suggest that ATM may represent a therapeutic target in PTEN deficient tumours.
Final results of a randomized phase II trial of pemetrexed (P) + carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) + Cb as first-line treatment of patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: C. K. Obasaju, R. N. Raju, T. Stinchcombe, L. S. Couch, R. Jotte, D. M. Kocs, Y. Wang, J. Bromund, J. Treat, M. A. Socinski
Journal: Journal of Clinical Oncology (2009)

8037 Background: E is a selective, oral serine/threonine kinase inhibitor. The combination of PCb has shown clinical activity in two phase 2 trials of advanced NSCLC. A phase 3 trial among pts with stage IIIB/IV NSCLC showed that P + cisplatin provides similar efficacy with better tolerability than gemcitabine + cisplatin (Scagliotti, JCO, 2008). The toxicity profile observed with P + platinum doublets makes these regimens attractive for the integration of novel agents with different mechanisms of action. In the TAX 326 trial, D + cisplatin was associated with a median survival of 11.3 mos vs. 10.1 mos for vinorelbine + cisplatin (P=.04). The current open-label three- arm trial was designed to assess PCb ± E versus a control arm of DCb. Methods: Between 3/06 and 5/08, pts with stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to 3 arms: (A) P 500 mg/m 2 and Cb AUC 6 every 3 wks × 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m 2 and Cb AUC 6 every 3 wks × 6 cycles. Pts receiving P were administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. Results: See table . Conclusions: First-line treatment with PCb was associated with a significantly longer overall survival than DCb in advanced or metastatic NSCLC. E did not add to the activity of the PCb doublet. PCbE, PCb, and DCb appeared to be well tolerated. Complete results for all patients in the study will be available at the time of the meeting. [Table: see text] [Table: see text]
Quality of life (QoL) assessment in patients (pts) with <i>K-RAS </i>wild-type (WT) chemotherapy refractory metastatic colorectal cancer (mCRC) treated with cetuximab (CET) plus brivanib alaninate (BRIV) or placebo: Results of the NCIC Clinical Trials Group and AGITG CO.20 trial.
Authors: Jolie Ringash, Heather-Jane Au, Lillian L. Siu, Jeremy D. Shapiro, Derek J. Jonker, John Raymond Zalcberg, Malcolm J. Moore, Andrew H. Strickland, Rami Kotb, Mark Jeffery, Thierry Alcindor, Siobhan Ng, Muhammad Salim, Sabe S. Sabesan, Jacob C. Easaw, Jennifer Anne Shannon, Fabyolla El-Tahche, Ian B. Walters, Dongsheng Tu, Christopher J. O'Callaghan
Journal: Journal of Clinical Oncology (2012)

542 Background: The CO.20 trial randomized pts with K-RAS WT chemotherapy refractory mCRC to receive CET + BRIV (Arm A) or CET + placebo (Arm B). Although overall survival (primary endpoint) was not significantly improved (HR=0.88, p=0.12) in this heavily pre-treated population, progression free survival (PFS) favoured Arm A (HR=0.72 p&lt;0.0001). Methods: Patients with K-RAS WT mCRC previously treated with or with contraindications to a fluoropyrimidine, irinotecan, and oxaliplatin were randomized to a loading dose of IV CET followed by weekly IV CET + BRIV 800 mg PO daily or CET + placebo daily. QoL, a secondary endpoint, was assessed using the EORTC QLQ-C30 at baseline and at 2, 4, 6, 8, 12, 16 and 24 weeks until progression or clinical deterioration. Co-primary QoL endpoints were defined a priori as definitive deterioration (first worsening from baseline of ≥10 points) on the physical function (PF) and Global scales. Time to QoL deterioration (DET) was measured from randomization using the Hochberg procedure to adjust for multiple testing. Results: 721 (358 Arm A) of 750 randomized pts were assessable for QoL. QoL compliance did not differ by arm and declined in follow-up from 87% to 47% over time. Baseline Global and PF scores did not differ by arm. Median time to QoL DET was 1.6 vs 1.1 mo for Global (p=0.02) and 5.6 vs 1.7 mo. for PF (p&lt;0.0001) in Arm B vs A, respectively. Secondary QoL response evaluation showed a greater proportion of patients on Arm A to have worsening on the PF (31 vs 17% at 6 wks) and cognitive functioning scales, and on the fatigue, nausea, appetite and diarrhea symptom scales. Clinical adverse events ≥ Grade 3 were more common on Arm A than B including fatigue (25 vs 10%), hypertension, rash, diarrhea, abdominal pain, dehydration and anorexia. Conclusions: Despite a PFS benefit, the combination of CET + BRIV worsened time to QoL DET on the PF and Global scales of EORTC QLQ-C30 in pts with chemotherapy refractory K-RAS WT mCRC. This result may be due to higher rates of fatigue and gastrointestinal adverse events observed with the combination.
HIF-1a and target genes as metabolic biomarkers in Mexican women with breast cancer.
Authors: S. Rodriguez-Enriquez, J. L. Aguilar, C. M. Villarreal-Garza, R. Moreno, E. Ruiz, J. C. Gallardo, C. Arce, A. Marin, P. Villarreal
Journal: Journal of Clinical Oncology (2011)

e21063 Background: Breast cancer is the principal malignancy in Mexican women. Breast neoplasias develop chaotic and fragile neovasculature originating intermittent hypoxia which in turn, leads to an adaptive response coordinated by the transcriptional factor HIF-1a (hypoxia-inducible factor-1a). In the present work the expression of HIF-1a was analyzed in different female breast cancer biopsies in order to determine the relationship between HIF-1a expression and cancer prognosis. To determine the functional role of HIF-1a, proteomic and kinetic analysis of several well-established HIF-1 targets such as the glycolytic proteins glucose transporters (GLUT1), hexokinase (HKII), and lactate dehydrogenase (LDH-A) were also determined. In addition, to evaluate the role of HIF-1a expression on mitochondrial function, content of mitochondrial enzymes were also assayed. Methods: Twenty tru-cut biopsies were obtained from female patients (30-45 years old) without previous clinical treatment. After patho-histological assessment of breast cancer incidence, samples were processed by Western-blot analysis (for proteomic analysis) and for enzyme activity determination. Results: Significant increased content of HIF-1a was determined in all human solid tumor biopsies analyzed. In consequence, enhanced GLUT1, HKII and LDH-A contents and activities (12 and 314 mU/mg protein for HK and LDH, respectively) were also detected. On the contrary, mitochondrial enzymes (cytochrome c oxidase, ATP/ADP translocator, glutaminase-K and 2-oxoglutarate dehydrogenase) were not detected, whereas ATP synthase content significantly increased in all analyzed samples. Conclusions: These results clearly indicated that HIF-1a, together with their target glycolytic genes and possibly the mitochondrial enzyme ATP synthase, may be useful to depict a breast cancer metabolic marker pattern.
Utility of invasive staging procedures in patients (pts) with localized esophageal cancer (EC).
Authors: Thomas A. Giever, Arjun Ranade, James P. Thomas, Paul S. Ritch, George Haasler, Mario Gasparri, David Johnstone, Elizabeth Gore, Candice Aitken Johnstone, Kulwinder Dua, Abdul Khan, Young Oh, Ben George
Journal: Journal of Clinical Oncology (2015)

54 Background: Definitive treatment for localized EC involves surgery alone or tri-modality therapy (TMT-chemotherapy, radiation, and surgery). TMT is administered to pts with clinical T2 or higher and lymph node (LN) positive ECs. Standard staging includes Computerized Tomography (CT)/Positron Emission Tomography (PET) imaging and Endoscopic Ultrasound (EUS). We investigated whether performing an EUS altered treatment decision in localized EC pts where a combination of imaging and clinical symptoms suggested the need for TMT. Methods: We performed a retrospective review to identify pts with localized EC who had their staging work up and treatment at the Medical College of Wisconsin between 2003 and 2012. Relevant clinical information was collected through review of the electronic medical record. Results: We identified 65 pts; median age at diagnosis was 62 years, 49 (75%) were male, and 56 (86%) were Caucasian. Histology was adenocarcinoma in 48 (74%) pts with 21 (44%) having background Barrett’s esophagus. Common presenting symptoms included dysphagia (83%), weight loss (73%), and odynophagia (25%). Staging evaluation included CT, PET, and EUS in 100%, 98%, and 89% of pts respectively. EUS staging results are in the table below. Dysphagia was reported by 67% of T1, 80% of T2, 84% of T3, 50% of T4, and 100% of Tx pts; 70% of pts with dysphagia were node positive by EUS. PET positive primary tumors/LNs were found in 89%/29% of all pts and 89%/33% of pts with dysphagia. Of the pts with PET positive LNs, 68% had node positive disease on EUS. Eighteen (28%) pts had both dysphagia and PET positive LNs, none with T1-2N0 staging by EUS; 36 pts had dysphagia and PET negative LNs, 7 (19%) with T1-2N0 staging by EUS. Among those 7 pts, 4 underwent surgery (1 pt-pT3N1aMx; 3pts-pT1bN0Mx). Conclusions: Localized EC pts with both dysphagia and PET positive LNs are candidates for TMT even in the absence of EUS staging. The role of EUS in this population may be limited to investigating adjacent organ invasion or confirmation of LN involvement. With improving PET capabilities, the role of EUS in this pt population needs to be studied prospectively. [Table: see text]
Ephrins/eph as novel synthetic lethal targets in <i>K</i><i>ras-</i>mutant colorectal cancer.
Authors: S. Van Schaeybroeck, W. L. Allen, P. Dunne, P. Jithesh, D. Longley, P. G. Johnston
Journal: Journal of Clinical Oncology (2011)

e13578 Background: Mutations in the Kras proto-oncogene are found in 40%-45% of colorectal cancer (CRC) patients and occur mainly in codon 12 and 13. Kras mutant (MT) CRC tumours are resistant to EGFR mAb therapies. Clear understanding of the biology of KrasMT CRC is important, and identification of druggable targets uniquely required by KrasMT CRC tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. The aim of this study was to identify novel targets whose knock-down is synthetically lethal with Kras mutation in CRC models. Methods: Transcriptional profiling (Almac Diagnostics CRC DSA) of primary KrasMT and WT CRC tissues and paired KrasMT and WT CRC xenografts models was performed and Metacore pathway analysis was used to identify individual genes from novel Kras-dependent pathways for incorporation into a primary RNAi screen. Results: Using clinical and in vivo KrasMT/WT CRC samples and public available Kras signatures, we identified 30 signalling pathways and 160 genes associated with KrasMT CRC cancer. The primary Kras siRNA screen identified a number of novel Kras synthetic lethal target genes with a critical role in EMT and cell adhesion/migration. In particular, down-regulation of members of the EpH/Ephrin family was found to be lethal in KrasMT but not KrasWT cells. These results were confirmed in secondary and tertiary siRNA screens using a panel of KrasMT/WT CRC cell lines and multiple siRNA sequences. In addition, EpHA1, EpHA2 and EpHA4 silencing resulted in strong increase in apoptosis in KrasMT cells and this was further synergistically enhanced in the presence of chemotherapy (5-FU, CPT-11) treatment. Interestingly, EpHA1, EpHA2 and EpHA4 silencing also inhibited migration of KrasMT cells. Conclusions: This study demonstrates the utility of microarray expression data, Metacore and siRNA screens to identify novel Kras synthetic lethal targets and pathways. In addition, we found that EpHA1, EpHA2 and EpHA4 are important novel targets for KrasMT CRC tumours.
ERCC1 and RRM1 expression in resected pancreatic adenocarcinoma.
Authors: M. A. Tejani, K. Q. Cai, F. Zhu, C. Dubyk, Y. S. Chun, S. J. Cohen, J. P. Hoffman, B. Burtness
Journal: Journal of Clinical Oncology (2011)

e14606 Background: Excision repair cross-complementing group 1 (ERCC1) plays a critical role in DNA repair and is associated with resistance to radiation and platinum-based therapy. RRM1 encodes the regulatory subunit of ribonucleotide reductase and is the molecular target of gemcitabine. We hypothesized that ERCC1 and RRM1 expression would predict for outcome and response in pancreatic adenocarcinoma. Methods: We determined ERCC1 and RRM1 expression levels in 89 pancreatic cancer specimens from patients who underwent resection, using automated quantitative analysis (AQUA), a fluorescence-based immunohistochemical method. The relationship between protein expression and patient characteristics was determined using box plots and Pearson’s correlation coefficient. The relationship between protein expression and outcomes was measured using Kaplan-Meier curves, log-rank test and Cox regression. Results: The average expression score of duplicate tissue cores from each patient was used for analysis. Tumor expression scores for ERCC1 and RRM1 ranged from 89 to 1016 (median 323) and 327 to 2,171 (median 1,066) respectively. Median values of ERCC1 and RRM1 expression were used to divide patients into high and low groups. Mean age was 67 years and median overall survival was 20.7 months. There were no significant differences between high and low ERCC1 and RRM1 groups with respect to age, gender, grade, tumor size (T) and lymph node metastases (N) except that T was negatively correlated with ERCC1 expression level (p=0.02). There was no significant correlation between ERCC1 expression and DFS or OS. DFS was significantly better for patients with low RRM1 expression (p=0.026, HR=2.92, 95% CI 1.14 – 7.5) with no significant correlation for OS. For the 21 patients who received gemcitabine at recurrence, low RRM1 expression was associated with improved PFS (p=0.034) and OS (p=0.022). Conclusions: ERCC1 expression did not correlate with outcome in this series. Low RRM1 expression was associated with an improved DFS. Low RRM1 expression also correlated to benefit in patients receiving gemcitabine at disease recurrence. With increasing treatment options for advanced pancreatic cancer, further study of pharmacogenomic-based selection strategies is warranted.
Effect of bevacizumab on the risk of chemotherapy-associated anemia in cancer patients: A meta-analysis.
Authors: A. F. Sher, S. Wu
Journal: Journal of Clinical Oncology (2010)

9136 Background: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is used extensively in the treatment of malignancies when combined with chemotherapy. While chemotherapeutic agents are known to cause dose-limiting bone marrow suppression including anemia, the role of VEGF and its inhibition by bevacizumab in this process is not known. Therefore, we conducted a meta- analysis of randomized controlled trials (RCT) to determine the effect of bevacizumab on severe anemia induced by chemotherapy. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until July, 2009 were searched to identify relevant studies. Eligible studies included prospective RCTs in which standard anti-neoplastic therapy was administered with and without the use of bevacizumab with available data of anemia. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated employing fixed- or random-effect models based upon the heterogeneity of the included studies. Results: A total of 6,445 patients with a variety of solid tumors from 11 RCTs were included for analysis. Among patients receiving chemotherapy and bevacizumab, the incidence of high grade (grade 3 and above) anemia was 2.8% (95% CI: 1.6–5.0%). In comparison with chemotherapy alone, bevacizumab significantly reduced high-grade anemia with an RR of 0.72 (95% CI 0.57-0.90, p=0.005). The risk was reduced similarly for bevacizumab at 5 mg/kg/week (RR, 0.71; 95% CI: 0.54–0.94) and 2.5 mg/kg/week (RR, 0.74; 95% CI: 0.53–1.03). The risk reduction may not vary significantly with different tumor types, with RRs ranging from 0.26 (95% CI: 0.06-1.17) for mesothelioma to 1.1 (95% CI: 0.18-7.0) for breast cancer. Conclusions: Bevacizumab significantly reduced the risk of severe anemia associated with chemotherapy in cancer patients. No significant financial relationships to disclose.
Prevalence and correlates of patient symptom burden at initiation of curative chemotherapy.
Authors: Caitlin McCarty, Lara Traeger, Joseph A. Greer, Jennifer S. Temel, Theresa Margaret McDonnell
Journal: Journal of Clinical Oncology (2014)

176 Background: Side effects of curative chemotherapy regimens are highly prevalent and can lead to unplanned oncology clinic visits or hospital-level care. The current study aim was to examine physical symptoms among patients at their first chemotherapy visit, even prior to receiving their first infusion, in order to characterize symptom burden and unmet needs at this early stage of care. Methods: The current study utilized baseline data from a larger health services research trial for consecutive patients initiating chemotherapy for non-metastatic breast (48.0%), colorectal (28.0%), or lung (24.0%) cancer (n=75). Patients were invited to complete a self-report survey at their first chemotherapy visit, including demographics and measures of physical symptoms (Memorial Symptom Assessment Scale) and psychological distress (Patient Health Questionnaire-4; score ≥ 3 indicates positive anxiety or depression screen). Results: Among participants (M age=55.3 [SD=13.3]; female=70.7%), more than half (54.7%) endorsed at least one physical symptom -- primarily fatigue (34.7%) and constipation (29.3%). Additionally, one-fourth (25.3%) screened positive for anxiety (22.7%) and/or depression (9.3%). There were no differences in physical symptom bother or likelihood of fatigue or constipation, by factors including patient age, gender, marital status, work status, disease type, recent surgery, or concurrent radiotherapy. However, patients with positive anxiety and/or depression screens reported greater symptom bother and were more likely to endorse fatigue relative to those with negative screens (Mbother=4.5 vs. 1.3; fatigue=78.9% vs. 19.6%, p’s&lt;.01). There was no difference in constipation between these groups. Conclusions: Symptom frequency was markedly high among patients initiating curative chemotherapy, with at least half reporting physical symptoms prior to their first infusion, and psychological distress clustered with general symptom bother and fatigue. Future work should explore 1) the extent to which physical and psychological symptoms at chemotherapy initiation may be associated with longitudinal symptom profiles, and 2) strategies for addressing symptom burden early on in outpatient care.