tbuckley/cabot-search huggingface dataset:
Initial validation of a highly sensitive RT-qPCR assay for detecting all fusions and wild-type upregulation of ALK.
Authors: D. Hout, J. Nickols, L. Xue, M. Skokan, X. Tang, S. Morris, M. Varella-Garcia, I. I. Wistuba
Journal: Journal of Clinical Oncology (2011)

e21070 Background: Anaplastic lymphoma kinase (ALK) fusions cause a variety of malignancies (e.g. NSCLC and NHL). Patients with ALK fusion-driven cancers treated with the ALK inhibitor crizotinib, currently in clinical trials, have had marked antitumor responses. There are 15+ ALK fusions reported in NSCLC and other cancers, and testing by fluorescence in situ hybridization (FISH) has shown ALK gene amplification in cancers as well. The clinical significance of amplification is currently undetermined. We report results from a novel RT-qPCR assay (Insight ALK Screen) that is unbiased toward fusion partners and also detects wild-type upregulation. Results were compared to FISH and immunohistochemistry (IHC) to assess the accuracy of the qPCR assay and to correlate mRNA expression with gene amplification. Methods: Twenty-three NSCLC FFPE specimens were blinded and analyzed by the qPCR assay. ALK mutation status was independently determined by FISH and IHC. FISH studies used the ALK break-apart probes (Abbott); IHC used the D5F3 antibody (Cell Signaling). The qPCR method amplifies two regions corresponding to the ALK extracellular and intracellular kinase domains. EML4-ALK and other ALK fusion events result in a change in threshold cycle increase in transcripts encoding the ALK kinase domain over wild-type ALK expression levels. Results: The qPCR assay was positive for 11 samples from the enriched NSCLC cohort. The assay was 100% concordant with FISH in detecting the 4 samples with ALK fusions. The qPCR assay was also positive for 3 cases that were below (13%, 10% and 8%) the widely accepted criterion for being FISH-positive (>15% of tumor cells with split ALK 5’ and 3’ probe signals or with isolated 3’ signals) for fusions. Four other samples were both positive by qPCR and showed some level of gene amplification by FISH. Conclusions: Insight ALK Screen is a highly sensitive assay for detecting any ALK fusion regardless of the fusion partner. Detecting ALK mRNA expression by qPCR in cases below the FISH criterion for fusion positivity or that showed gene amplification suggests that more NSCLC patients could potentially qualify as candidates for ALK inhibitor therapy; further work is investigating this possibility.
Validation of TPX2 as a novel prognostic marker for malignant progression and metastasis of colon cancer.
Authors: Ping Wei, Dawei Li, Ye Xu, Sanjun Cai
Journal: Journal of Clinical Oncology (2013)

442 Background: We previously identified aberrant overexpression of TPX2 in colon cancer by using a genome-wide gene expression profiling analysis. Here, we aimed to investigate its expression pattern, clinical significance, and biological function in colon cancer. Methods: The expression of TPX2 was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis and metastasis was examined in vitro and in vivo. Results: Overexpression of TPX2 was found in metastatic lesion of colon cancer, significantly higher than primary cancererous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with the clinical staging, vessel invasion and metastasis. In survival analyses, patients with TPX2 expression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistently, Silencing TPX2 inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT mediated MMP9 activity. Conclusions: These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer and may represent a novel prognostic biomarker and therapeutic target for the disease.
Gene expression changes in buccal mucosa tissue 2 days post-chemotherapy in acute myelogenous leukemia (AML) patients
Authors: M. T. Brennan, M. L. Kent, Z. Mostafavi, G. P. Frenette, P. C. Fox, P. B. Lockhart
Journal: Journal of Clinical Oncology (2005)

8041 Background: The pathophysiology of alimentary mucositis associated with cancer chemotherapy is poorly understood, but the identification of genes up- and down-regulated in mucosal tissue following chemotherapy may lead to a better understanding of the mechanisms of mucositis. Methods: 3 mm punch biopsies of buccal mucosa were collected pre-chemotherapy and 2 days post-chemotherapy in 5 AML patients. In addition, buccal mucosa biopsies were collected from 3 healthy controls. RNA was isolated from the tissue and gene expression analysis was completed with Affymetrix Human Genome U133 Plus 2.0 microarray. Differences in gene expression were quantified as the fold change in gene expression between pre- and post-chemotherapy samples and between pre-chemotherapy AML and healthy controls. Results: 26 genes were consistently over-expressed, and 14 genes under-expressed at least 3-fold post-chemotherapy. Genes over-expressed included: Chemokine, CXC motif, ligand 9 (CXCL9); CXCL10; CXCL11; Keratin 2A; Epiplakin 1; Interferon alpha-inducible protein 27; Heat-shock protein, and 75kd. Genes under-expressed included: Fatty acid desaturase 1(FADS1); FADS2; Galanin; Human transforming growth factor-beta-2 mRNA; Sterol O-acyltransferase 1; and I factor. A comparison of pre-chemotherapy AML and healthy control tissue demonstrated 49 genes consistently overexpressed and 7 genes under-expressed at least 3-fold in the AML patients. Some genes over-expressed included v-fos FBJ murine osteosarcoma viral oncogene homolog; carcinoembryonic antigen-related cell adhesion molecule 7; S100 calcium-binding protein P; placenta-specific gene 8; Phospholipase A2, group IIA; Prostate cancer overexpressed gene 1; and Mucin 1, transmembrane. Under-expressed genes included Sarcomeric muscle protein; Secreted frizzled-related protein 4; and Periostin. Conclusions: The genes up-regulated following chemotherapy appear to reflect an inflammatory and epithelial response. AML mucosa tissue demonstrated specific cancer-related genes compared to mucosa from healthy controls. Validation by immunohistochemistry and Real-Time PCR analysis is planned to confirm these findings. No significant financial relationships to disclose.
Time trends in survival in young women with breast cancer in a population-based study: Are there estrogen receptor status differentials?
Authors: Foluso Olabisi Ademuyiwa, Adrienne Groman, Chi-Chen Hong, Shicha Kumar, Ellis Glenn Levine, Austin Miller, Christine B. Ambrosone
Journal: Journal of Clinical Oncology (2012)

85 Background: As mammography is not generally recommended to women under 40, it is reasonable to conclude that documented outcome improvements over time are attributable to treatment advances with screening playing a less important role. In order to determine the contribution of screening and treatment to improvements, we evaluated the odds of presenting with more advanced disease by time-period and examined the time-trends in outcome in a population-based cohort ≤50. We evaluated whether any outcomes differentials existed by ER status. Methods: Patients in SEER diagnosed with breast cancer were divided into 4 by year of diagnosis (1990-1994, 1995-1999, 2000-2004, 2005-2008). Patients were categorized into 2 age-groups: &lt;40 and 40-50 years. Odds ratios for presenting with more advanced disease over the 4 time-periods were calculated for the 2 age-groups. Multivariate analysis was done to investigate the association of survival with time-period for the 2 age-groups by ER status. Results: 110,629 patient records were included. Patients 40-50 who were diagnosed in the 3 later time-periods (1995-1999, 2000-2004, 2005-2008) were more likely to have small tumors (≤2cm) compared with patients diagnosed in 1990-1994. Similarly, these patients were less likely to have larger tumors (≥3cm) comparing the 3 time-periods relative to 1990-1994. Conversely, patients &lt;40 years had a higher odds of presenting with larger tumors (≥3cm) when the 3 later time-periods were compared to 1990-1994. In the ER positive patients, multivariate analysis showed that being diagnosed in the 3 later time-periods relative to 1990-1994 was associated with improved survival irrespective of age. In the ER negative cohort, those 40-50 years had a higher risk of death in the 3 later time-periods relative to 1990-1994; while there was a no effect of time-period on mortality for the younger age group of &lt;40. Conclusions: Patients who are ER positive and between 40-50 years have had time-trend changes with improvements in breast cancer outcome and smaller tumors likely attributable to both screening and hormonal therapies. Patients who are &lt;40 years and/or ER negative have not had improvements in breast cancer outcome.
Comparing MicroRNA Expression In Aggressive and Indolent Non-Hodgkin Lymphomas Identifies a Prognostic Signature for Mantle Cell Lymphoma
Authors: Rashmi S. Goswami, Levi Waldron, Patricia P Reis, Yali Xuan, Wei Xu, John Kuruvilla, David Good, Denis Bailey, Alanna Church, Tara Baetz, David LeBrun, Raymond Lai, Laurie Sehn, Pedro Farinha, Randy D. Gascoyne, Michael Crump, Igor Jurisica, Suzanne Kamel-Reid
Journal: Blood (2010)
Analysis of p16 expression by AQUA in non-small cell lung cancer (NSCLC) among non-smokers.
Authors: R. Mehra, K. Q. Cai, B. Egleston, J. Weaver, C. Dubyk, H. Borghaei, W. J. Scott, R. B. Cohen, G. R. Simon
Journal: Journal of Clinical Oncology (2011)

e21173 Background: The tumor suppressor p16 is a biomarker for HPV-related head and neck squamous cell cancer, especially in patients (pts) without prior tobacco use. Retrospective analyses of NSCLC from unselected pts provide limited data regarding the role of p16 and incidence of HPV, but suggest that p16 expression is associated with a favorable prognosis. Our goal is to estimate the proportion of never/light smoking (< 10 pack years) pts with NSCLC with p16+ tumors and correlate these data with outcomes. We hypothesize that p16+ tumors will be HPV related. Methods: A tissue microarray was constructed with NSCLC surgical specimens from never/light smokers (1995-2009) available in the Fox Chase Cancer Center Biosample Repository. Slides were incubated with anti-p16 antibody (E6H4, MTM Laboratories) and wide-spectrum screening rabbit cytokeratin antibody (Dako Z0622). DAPI was used to define tissue nuclei. p16 levels were measured with fluorescent immunohistochemistry (IHC) on the HistoRx PM-2000 platform (AQUA). After image validation, scores from two nonoverlapping images were obtained per case. p16 AQUA score was analyzed as a dichotomous variable (positive/negative) based on a naturally occurring cutpoint. We used Wilcoxon rank-sum tests, Fisher's exact tests, and Kaplan-Meier estimators with log-rank tests for analyses. Results: 33 pts were included (25 female, ages 47-84). Histology: adenocarcinoma (28), adenosquamous (3), squamous (2). TNM Stage: T1 (4), T2 (26), T3 (1), N0 (15), N1 (8), N2 (8), N3 (1), M1 (2). Perioperative treatment: chemotherapy (9), radiation (5). AQUA score range: 91-7733. A natural cutpoint occurred at 3000 with 25 low (p16-) and 8 high (p16+) expressors. AQUA score correlated with standard IHC H score (p=0.0005). There was no significant relationship between p16 level and gender, T or N stage. When controlling for N stage and p16 level, p16+ was associated with inferior survival (HR 2.68, p=0.03). Conclusions: In NSCLC among never/light smokers, p16 expression can be quantified with a natural cutpoint (high vs. low). p16+ is associated with inferior survival. Analysis of HPV status and EGFR/KRAS mutations in these tumors is ongoing and will be presented at the meeting. Funded by ACS-IRG grant.
Evaluation of a novel irreversible pan-HER inhibitor in bladder cancer models.
Authors: Petros Grivas, Andreas Karatsinides, Kathleen C. Day, Priya Kunju, Alyssa Paul, Nazia Shakir, Evan T. Keller, Maha Hussain, Mark L. Day
Journal: Journal of Clinical Oncology (2013)

253 Background: Human epidermal receptors (HER) are overexpressed and HER signaling is biologically relevant in bladder cancer and may mediate chemotherapy resistance. Dacomitinib is a novel, potent, irreversible pan-HER inhibitor with activity against several solid tumors, currently in a phase III clinical trial in NSCLC. We hypothesized that dacomitinib has antitumor activity in bladder cancer models. Methods: Expression level of EGFR and HER2 protein was measured semi-quantitatively in 8 bladder cancer cell lines. We treated UM-UC-3, UM-UC-6, UM-UC-9 cell lines with dacomitinib (1nM-10uM) for 24-72 hours, and measured cell viability, proliferation, apoptosis, and cell cycle effects. Correlations between dose and cell viability were measured by two-way ANOVA (GraphPad Prism 5.0). We injected age-matched male NOD/SCID mice SC with 1x106 UM-UC-6 and UM-UC-9 cells, respectively, generating xenografts. Mice were randomized and treated with dacomitinib, 6mg/kg p.o. daily, starting 1 day or 1 week after cell injection; controls were treated with vehicle. Mice were monitored daily, weighed weekly, sacrificed at 4 weeks and tumors weighed. Results: In vitro, significant cytostatic effect was noted with as low as 50nM in UM-UC6 cells and 100nM in UM-UC9 cells. UM-UC3 cells did not exhibit cytostatic effect even with 1000nM, corresponding to differential target protein (HER) expression. Dacomitinib (2uM) induced apoptosis (UM-UC-6), and G1 cell cycle arrest in both cell lines. These effects corresponded to dacomitinib-mediated inhibition of EGFR, ERK, AKT phosphorylation. In vivo, xenograft weights in both cell lines were significantly lower in dacomitinib-treated mice vs control (p<0.001), corresponding to pharmacodynamic effects (decreased E-cadherin, p-EGFR, p-ERK, mitotic count). Dacomitinib 6mg/kg p.o. daily resulted in significantly lower tumor weights vs lapatinib 50 mg/kg p.o. daily in UM-UC-9 xenograft model (p=0.0052). Conclusions: Dacomitinib demonstrated single-agent activity in bladder cancer cell lines and xenografts. Induction of apoptosis and G1 phase arrest are the suggested mechanisms for anti-tumor activity. Further investigation of this inhibitor in bladder cancer models is being pursued.
A phase I/II study of S-1 plus cisplatin (CDDP) in patients with head and neck cancer (HNC)
Authors: M. Fujii, S. Endo, K. Tomita, W. Nishijima, M. Tsukuda, Y. Hasegawa, J. Ishitoya, H. Yamane, H. Fujii, A. Honma, T. Tomita
Journal: Journal of Clinical Oncology (2005)

5552 Background: S-1 is an active anticancer drug for HNC with a response rate of 28.8% as single agent treatment in phase II study (#1526, 2001ASCO). It has also shown synergistic effects with CDDP in a preclinical study. The aims of this study was to determine the maximum tolerated dose (MTD) and recommend dose (RD) in the combination treatment with S-1 and CDDP (Phase I part), and evaluate the response and safety using defined RD (Phase II part). Methods: Eligible patients were defined as histologically or cytological confirmed advanced/recurrent HNC with evaluable lesions, adequate organ function, Performance Status 0–1, age < 80. S-1 was administered orally at 40mg/sqm twice a day for 14 consecutive days, and CDDP (Level.1–2:60–70mg/sqm, within approved dose in JPN) was infused over 2 hours on day 8. Each course was repeated every 3–4 weeks. Dose limiting toxicities (DLT) were determined as grade 4 hematological and grade 3 non-hematological. Results: A total of 38 patients, 10 patients for Phase I and additional 28 patients for Phase II part, were registered. Although DLT was not observed in Level.1 (n=4), fatigue and diarrhea of grade 3 (DLT) occurred in Level 2(DLT:2/6). MTD was not achieved in Phase I part. Level 2 (70mg/sqm of CDDP) was considered as recommend dose for phase II part. The median number of courses was 2 (range 1–3) in 34 patients. Among these 34 patients, response rate was 67.6% (CR:6, PR:17) at the termination of treatment. Conformed responses with adequate duration time (d28) were 2 complete response and 13 partial responses with an overall response rate of 44.1% (95%CI:27.4–60.8). The degree of toxicity was generally mild to moderate. Hematological toxicities of grades 3 and 4 included neutropenia (11.8%), thrombocytopenia (11.8%) and anemia (8.8%). Non-hematological toxicity of grades 3 and 4 included anorexia (26.5%), nausea (14.7%), fatigue (8.8%) or diarrhea (2.9%).Since the observation period is short the median survival time and the 1-year survival rate is not obtained so far. Conclusions: S-1 plus CDDP combination chemotherapy demonstrated a promising effectiveness for not only advanced but recurrent HNC patients with acceptable toxicity rates. These results warrant further investigations of this regimen. No significant financial relationships to disclose.
Deep vein thrombosis (DVT) and pulmonary embolism (PE): Awareness and prophylaxis practices reported by patients with cancer.
Authors: F. R. Rickles, E. Varga, A. Brownstein, R. J. Friedman, G. A. Maynard, J. Ansell
Journal: Journal of Clinical Oncology (2011)

9101 Background: The goals of this study were to measure DVT/PE awareness among patients with cancer and to identify gaps in evidence-based prophylaxis reported by these patients. Methods: A survey was conducted among 500 adults, screened from an online research panel, diagnosed with cancer within 12 months of sampling. Responses from patients who required a hospital stay for treatment (n=206) were compared to responses of patients who were exclusively treated as outpatients (n=294). Results: Of the 500 patients surveyed, mean age was 58 (range 20-80+), 64% female, and cancer diagnoses included: breast 34%, prostate 10%, lung 9%, skin 8%, colon 5%. Among all respondents, 76% had not heard of a medical condition called DVT and 85% had not heard of PE. Significantly more outpatient respondents were unfamiliar with the terms DVT (85%; p=<.05) and PE (91%; p=<.05) compared to inpatient respondents. Among 155 respondents who said they could name DVT risk factors, 8% named surgery and 4% named chemo/radiation or some cancer treatments. Among 86 respondents who said they could name PE signs/symptoms, 69% cited breathing difficulties, 28% chest tightness, 5% coughing up blood. Less than one-third (27%) of all respondents said their doctor/healthcare professional (HCP) told them about blood clot risks due to cancer. When compared to inpatient responses, significantly fewer outpatient respondents (14%; p=<.05) said their doctor/HCP told them about blood clot risks due to cancer. About half (48%) of all respondents said they were told to get out of bed and walk around. DVT prophylaxis reported by all respondents included: compression stockings 35%, mechanical compression 31%, aspirin 28%, anticoagulant pill 21%, anticoagulant injection 16%. Compared to inpatient respondents, outpatients reported significantly lower utilization of DVT prophylaxis, including: compression stockings 22% (p=<.05), mechanical compression 16% (p=<.05), aspirin 20% (p=<.10), anticoagulant pill 9% (p=<.05), anticoagulant injection 6% (p=<.05). Conclusions: Oncology patient awareness of DVT/PE is low. Effective interventions are needed to optimize patient/physician dialogue about DVT/PE and prophylaxis.
Evaluation of neutrophil gelatinase-associated lipocalin (NGAL) as predictor of response to neoadjuvant chemotherapy (NACT) in primary breast cancer.
Authors: A. S. Wenners, K. Mehta, S. Loibl, H. Park, N. Arnold, S. Hamann, J. Weimer, B. Ataseven, C. Schem, F. Khandan, C. Thomssen, W. Jonat, H. Holzhausen, G. Von Minckwitz, C. Denkert, M. Bauer
Journal: Journal of Clinical Oncology (2011)

595 Background: In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In NACT pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Methods: Immunhistochemistry was performed on tissue microarrays from 855 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression was evaluated according to the Allred score. Primary endpoints were pCR, disease-free survival (DFS) and overall survival (OS). For statistical analysis Pearson’s and Fisher’s exact test as well as Kaplan-Meier analysis and Cox proportional hazard models were used. Results: NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status (p = 0.038). NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status (p = 0.033). In addition, strong NGAL expression correlated with higher pCR rates in node negative patients (p = 0.038), patients with histological grade 1 or 2 (p = 0.036) tumors and a tumor size < 40 mm (p = 0.031). In univariate survival analysis, positive NGAL expression as well as strong staining intensity correlated with decreased DFS (HR = 1.818; CI = 1.294 – 2.556) in the entire cohort (p = 0.0005) and different subgroups, including HR, estrogen and progesterone receptor positive patients (p = 0.0019; p = 0.0019; p = 0.0027). Similar results were shown for intense staining and decreased OS. In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS (HR = 1.886; CI = 1.249 – 2.848). Conclusions: In low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.