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  • American Association for Cancer Research (AACR)  (40)
  • 1
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    Abstract P3-04-01: Manual and digital detection of HER2 status of 2721 circulating tumour cells in patients with metastatic breast cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P3-04-01-P3-04-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P3-04-01-P3-04-01
    Abstract: Introduction: In metastatic breast cancer (MBC), discordant expression levels of the human epidermal growth factor receptor 2 (HER2) have been noted between primary tumours (PT) and matched metastatic lesions (Meta). Therefore reassessment of this predictive marker at time of metastatic disease might help to optimize treatment. Circulating tumour cells (CTCs) offer the potential to provide a repeatedly accessible source of tumour cells for the real-time assessment of actual tumour characteristics. Here we report on a retrospective study analysing over two and a half thousand CTCs in order to evaluate the inter-observer variability when using the semi-quantitative scale (0-3+) described by Riethdorf in 2010. Furthermore we designed a digital scoring system using 13 parameters selected by ImageJ. HER2 status in CTCs was compared to PT and/or Meta of patients with MBC. Materials and methods: 65 patients starting first or second line systemic therapy for MBC and harbouring more than 5 CTC/7.5 mL blood were selected. HER2 status of 2721 CTCs was determined by immunofluorescence using the CellSearch system. HER2 status of the solid lesions was determined by IHC or FISH. Inter-observer variability was calculated using the Kendalls tau tests. 284 CTCs were analysed with the digital scoring system using ImageJ 'plot profile' and 'analyse particles'. Selected parameters comprise cell size, mean and maximum intensity of the cell and its surrounding, and both ratio's and differences of the aforementioned. Dissimilarity matrix was calculated using Pearson Correlation-Distance. Results: Of 2721 CTCs, 1485 cells (55%) were scored 0+ and 2263 cells (83%) were found to be HER2- (0+ or 1+) by both observers. 458 cells (17%) were scored HER2+ (2+ or 3+) by at least one of the observers, however only 175 (6%) by both observers. Inter-observer variability was 0.703, but when omitting the usually undebatable 0+ cells, this variability showed to be 0.278. HER2 scoring of CTC by two observers. HER2- (0+/1+)HER2+ (2+/3+)HER2- (0+/1+)2263 (83%)131 (4.8%)HER2+ (2+/3+)152 (5.6%)175 (6.4%) 24 of 65 patients had at least 80% 0+ CTCs (≥96% HER2- cells). Of these patients, 5 were HER2+ based on their PT. Oppositely, 10 and 20 patients harboured at least 40% and 10% HER2+ CTCs respectively. From these 20 patients only 10 were diagnosed with HER2+ disease on PT or Meta and 1 was shifted form HER2- PT to HER2+ Meta. The digital scoring system was able to identify four groups with different HER2 expression levels. When comparing the identified clusters with the manually scored cells the two moderately related clusters showed to contain almost only 2+ and 3+ CTCs. A very isolated cluster contained almost solely 0+ CTCs. Discussion: The manual scoring system showed to be feasible, however we noticed that there are some discrepancies regarding the scoring of 1+ to 3+ cells. The digital scoring is able to predict the outcome and can by itself cluster CTCs into 4 groups. It strongly distinguishes between the HER2+ and HER2- cells. HER2+ status can change during disease progression, both with gain and loss of HER2 positivity. This can be monitored using CTCs. Citation Format: Brouwer A, van de Wiel M, Peeters B, van Dam P-J, Vermeulen P, Peeters M, Van Laere S, Peeters D, Dirix L. Manual and digital detection of HER2 status of 2721 circulating tumour cells in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-04-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P3-04-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
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    Abstract P3-02-10: Comparison of Circulating Tumour Cells in Peripheral and Central Venous Blood of Patients with Metastatic Breast Cancer: A Pilot Study
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 24_Supplement ( 2010-12-15), p. P3-02-10-P3-02-10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 24_Supplement ( 2010-12-15), p. P3-02-10-P3-02-10
    Abstract: Background: Enumeration of circulating tumour cells (CTC), as performed by the CellSearch System (Veridex, Raritan, NJ, USA), has prognostic significance in patients with metastatic breast cancer (MBC). Questions remain on how these cells - if all - are capable to survive in the circulation and ultimately give rise to distant metastases. Experiments in mouse models have shown that CTC only appear transiently in the circulation after injection in the tail vein or left ventricle. Data on the discrete localisation of CTC in the blood stream and CTC kinetics in human breast cancer is still limited. The aim of this pilot study was to directly compare the amount of CTC measured in peripheral and central venous blood samples of patients with MBC in order to reveal possible differences. Methods: So far, we have included 18 patients with MBC presenting at our hospital with either primary metastatic (N=2) or progressive disease (N=16). Most patients suffered from diffuse metastatic involvement and were extensively pretreated. Clinically evident lung metastases were documented in 4/18 patients. Peripheral venous blood (PVB) - obtained from an antecubital vein - and central venous blood (CVB) samples - obtained from the subcutaneous port catheter - were drawn into CellSave Preservative tubes (Immunicon, Huntingdon Valley, PA) and processed in parallel using the CellSearch Circulating Tumor Cell Test (Veridex, Raritan, NJ, USA). With this test, CTC captured from 7.5 mL whole blood, are defined as EpCAM+, nuclear cells (DAPI+), expressing cytokeratins 8/18/19 and lacking CD45 expression. Results: CTC were detected in both PVB and CVB samples of 16/18 patients. In 2 patients no CTC were detected, neither in PVB nor in CVB. In 16 patients with detectable CTC, the number of CTC was found to be significantly higher in CVB (median: 65; range: 3-4036) than in PVB (median: 45; range: 1-4013) samples (Wilcoxon Signed Ranks Test, P=0.001). When analyzing samples parewise, the number of CTC in CVB was higher than the number of CTC in PVB in 15/16 patients, although marginally in 4 of 15 patients (median ratio CVB/PVB: 1.8; range: 1.0-3.1). Only 1 patient showed a higher number of CTC in PVB (absolute value: 49 CTC/7.5 mL blood) as compared to CVB (absolute value: 41 CTC/7.5 mL blood). Conclusions: In this study, a substantial decrease in the number of CTC was observed between CVB and PVB of patients with MBC. This difference might be relevant in the clinical setting as a quantitative cut off in the number of CTC is used to distinguish between patients with good and worse prognosis. As hand metastases are most uncommon, the lungs are suggested to function as the main sieve, even in the absence of clinically overt lung metastases. However, further research in larger patient populations and - where feasible - including radial arterial blood sampling, is required in order to confirm these results and to investigate human CTC kinetics in depth. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS10-P3-02-10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
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    Abstract P1-01-10: Exome sequencing of circulating tumor cells in metastatic breast cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P1-01-10-P1-01-10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P1-01-10-P1-01-10
    Abstract: Aim: We interrogated whether Circulating Tumor Cells (CTCs) can complement metastatic biopsies for genomic analyses. Patients and Methods: We compared single nucleotide variants (SNVs) and copy number aberrations (CNAs) identified using whole exome sequencing (WES) of DNA from frozen tumor tissue (primary/metastasis), amplified DNA from CTCs and normal DNA from 3 metastatic breast cancer (BC) patients (pts). All samples of the same patient were collected at the same timepoint. CTC isolation was performed using CellSearch and DEPArray systems followed by whole genome amplification (Ampli1 kit). WES was performed using the Illumina HiSeq2000 with 200X targeted coverage. Reads were aligned using bwa. SNVs had to be called by both Haplotype Caller (vs. reference genome) and Strelka (vs. paired normal). CNAs were determined by counting reads in 1MB windows and by comparing tumor/CTC samples with normal DNA. Pairwise concordance of CNAs profiles of different samples from the same patient was assessed using Spearman correlation (ρ). Significance of ρ differences between pts was obtained by Kruskal-Wallis test. Orthogonal validation for selected SNVs was performed. Results: We studied 3 patients from the 3 major BC subtypes, patient (pt)1 with ER-/HER2+ BC (samples collected at diagnosis, initially metastatic disease), pt2 with triple-negative BC (samples collected 2 years from diagnosis) and pt3 with ER+/HER2- BC (samples collected 8 years from diagnosis). We first compared tumor tissue and CTCs for SNVs. For pt1, of the 77 SNVs identified in the tumor, 51 were found on at least one of 12 CTCs samples. For pt2, of the 62 SNVs identified in the tumor, 19 were found on at least 1 of 11 CTCs samples. For pt3, of the 225 SNVs identified in the tumor, 48 were found on at least 1 of 3 CTCs samples. Interestingly, by increasing the number of CTCs analyzed, we increased the % of identified SNVs from synchronous tumor tissue. SNVs with high variant allele fraction (VAF) in tumor tissue were detected significantly more often in CTCs: 22% of the SNVs with VAFs & lt;20% were found at least once, compared to 53% and 74% of SNVs with VAFs & gt;20% and & gt;40%, respectively (p=10-12, Fisher exact test). Then, we compared tumor tissue and CTCs for CNAs. As time from diagnosis of metastatic disease to samples collection increased, we observed significantly higher heterogeneity within CTCs from the same patient (median ρ between CTCs was 86% for pt1, 84% for pt2 and 28% for pt3, p & lt;0.01) and between CTCs and tumor tissue from the same patient (median ρ was 78% for pt1, 67% for pt2 and 21% for pt3, p & lt;10-4). Interestingly, in pt3 one CTC was more similar to the metastasis than the other 2 (ρ of 53%, 21% and 21%). When a phylogenetic tree was constructed for pt3 by combining SNVs and CNAs data, three clones were identified: one clone with an AKT1 (E17K) and a TP53 (R248W) mutation and a 8p deletion, a second clone with the above profile plus an 8q amplification and a third clone with an AKT1 and an ESR1 (Y537N) mutation and 1p deletion. The metastasis was similar with the first clone. Conclusions: These data suggest that tumor tissue and single CTC exome sequencing analyses provide complementary information to map tumor heterogeneity. Further validation for potential clinical applications is needed. Citation Format: Ignatiadis M, Rothé F, Peeters D, Rouas G, Smeets D, Haan J, Lambrechts D, Campbell P, Piccart M, Voet T, Dirix L, Venet D, Sotiriou C. Exome sequencing of circulating tumor cells in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P1-01-10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
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    Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 17 ( 2016-09-01), p. 5103-5114
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 17 ( 2016-09-01), p. 5103-5114
    Abstract: Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-2980
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
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    Abstract PD6-5: Pooled analysis of circulating tumor cells in metastatic breast cancer: Findings from 1944 individual patients data
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 24_Supplement ( 2013-12-15), p. PD6-5-PD6-5
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. PD6-5-PD6-5
    Abstract: Background: Clinical validity of CTCs (CellSearch®) in metastatic breast cancer (MBC) patients has previously been assessed in studies with limited statistical power. We aimed to pool all European studies to obtain high-level evidence on the prognostic value of CTCs, to investigate their effects across different clinico-pathological characteristics and therapies and to further validate the MD Anderson/Institut Curie/Fox Chase CTC-based prognostic nomogram established in first-line treated MBC patients (Giordano et al, Clin Cancer Res 2013). Material and methods: Methods were predefined in a written protocol. In December 2012, we searched for eligible studies that accrued patients in 2003-2012. We contacted all European laboratories using CellSearch®. We used likelihood ratio tests (LR) in Cox regression models stratified by study to assess the independent prognostic value of CTC when added to a clinicopathological (CP) model for progression-free (PFS) and overall survival (OS). Landmark analyses were used to assess the prognostic effect of early changes in CTC. The CTC-based nomogram (http://cancernomograms.com/CTCOnline.html) score was retrieved for every patient; we calculated C-indices, drew calibration plots and Kaplan-Meier curves according to quintiles of the nomogram score. Results: We collected individual data of 1944 MBC patients, from 20 different studies (some unpublished), from 17 centers in 7 European countries. We observed 1507 PFS events and 929 deaths. Baseline CTC count was significantly associated with several patient characteristics, such as performance status (PS, p & lt;10-4), synchronous metastasis (p & lt;10- 2) tumor subtype (p & lt;10-4), liver & bone metastases (p & lt;10-4), CEA & CA15-3 levels (p & lt;10-4). The CP model for OS included PS, MBC subtypes, number of previous lines of treatment, patient's age, metastasis-free interval, metastatic sites (p & lt;0.01 for all). In a multivariate analysis containing the CP model parameters and CTC count at baseline, elevated CTC count (≥5) was a significant independent predictor of OS (n = 1444, HR = 2.7, 95%CI [2.2-3.2], LR p & lt;10-4). Baseline serum markers added either no or marginal effect to the CP plus baseline CTC model for OS. In contrast, early changes in CTC status at week 3-5 significantly added prognostic information for OS to the model with CP factors and baseline CTC+ (n = 569, HR = 1.8 [2.2-3.2], LR p & lt;0.001). In the population of interest (MBC treated by first line chemotherapy, n = 402 patients, 176 deaths), the CTC-based nomogram exhibited a good C-index for OS (0.69), was well calibrated and showed clear separation of the survival curves. Additional results, including subgroup analyses by tumor subtype and treatments will be presented at the meeting. Conclusions: This pooled analysis is the largest study ever reported on CTC in MBC, with a previously unreached statistical power. It provides a clear level-of-evidence 1 on the independent prognostic value of CTCs before and during treatment in MBC. Also, the CTC-based prognostic nomogram is independently validated. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-5.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS13-PD6-5
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    Abstract P2-08-08: Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P2-08-08-P2-08-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P2-08-08-P2-08-08
    Abstract: Background: The European Pooled Analysis of CTC (EPAC) in metastatic breast cancer, based on 1,944 individual data from patients with various tumor types and clinical settings (Bidard et al, Lancet Oncol 2014), has established CTC count (CellSearch) at baseline and during therapy as a level of evidence 1 independent prognostic biomarker and demonstrated its superiority over serum blood markers. As part of the study pre-planned objectives, we sought to establish nomograms allowing accurate individual survival predictions. Methods: Using individual data from 17 centers, we built simplified multivariate prognostic models taking into account the independent prognostic clinico-pathological (CP) characteristics including CTC count, dichotomized using the 5CTC/7.5ml threshold, at baseline and at 3-5 weeks after the start of a new treatment regimen, and derived nomograms for progression-free survival (PFS) and overall survival (OS) prediction at baseline and after 3-5 weeks of treatment. We report here the internal validation of these nomograms. Discrimination of the models was assessed using the c-index estimated by a jackknife procedure and the calibration was visually assessed through 10-fold crossvalidated calibration plots at 1,2,3 years for OS and 1,2 years for PFS. Results: Multivariate models at baseline for PFS and OS were fitted on 1501 and 568 individual patient data with CTC count at baseline and CTC count at baseline and after 3-5 weeks, respectively. Models include tumor subtype, the number of previous chemotherapy lines (0/1/≥2), PS, age ( & lt;=50/ & gt;50-65/ & gt;65 years), metastasis-free intervals (0/ & gt;0-3/ & gt;3 years), metastatic sites (liver and CNS) and CTC count at baseline and eventually at 3-5 weeks of treatment. The C-index increased from 0.722 to 0.755 (increase in C-index:0.033, 95% CI [0.019;0.045]) when adding baseline CTC to the CP only model for OS (n=1501). For those patients with CTC values at 3-5 weeks (n=568), there was an additional increase in the C-index when adding CTC at 3-5 weeks to a model with already CP and baseline CTC from 0.731 to 0.743 (increase in C-index 0.013, 95% CI [-0.004;0.025] ). The model with CP and baseline CTC counts showed a good calibration for OS at 1,2,3 years and the model with CP, baseline CTC and CTC count at 3-5 weeks a moderately good calibration. Similar results were obtained for PFS. Conclusion: From the largest database with individual CTC data, we were able to build PFS and OS survival nomograms, with satisfactory discrimination and calibration. Our planned next step is to validate the nomogram in an additional cohort. Citation Format: Bidard F-C, Peeters D, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, Fernandez de Lascoiti A, de Mattos-Arruda L, Ignatiadis M, van Laere SJ, Meier-Stiegen F, Sandri M-T, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson S-J, Raimondi C, Rutten A, Janni W, Munzone E, Carañana V, Agelaki S, Almici C, Dirix L, Solomayer E, Zorzino L, Reis-Filho JS, Squifflet P, Pantel K, Beije N, Sleijfers S, Pierga J-Y, Michiels S. Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P2-08-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Abstract 448: Molecular analysis of BRAF gene and PTEN gene expression in metastatic colorectal cancer patients: Feasibility study
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 448-448
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 448-448
    Abstract: Introduction There are numerous causes triggering CRC. 25-80% of CRC shown a deregulation in Epidermal Growth Factor Receptor (EGFR) pathway. Two signaling pathways downstream of the EGFR are dysregulated in CRC the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K) pathway. Activating mutations in KRAS and BRAF (MAPK pathway) and PIK3CA affect prognosis and/or response to anti-EGFR MoAb. PTEN is a downstream effector of EGFR pathway and is involved in PI3K pathway. Loss of PTEN protein expression can occur through epigenetic silencing and mutation or allelic loss. Immunohistochemistry (IHC) is the most effective way to assay for loss of PTEN expression. IHC lack of reproducibility and this has lead to discordant results regarding the concordant in paired CRC metastases and primary tumors.The aim of the work was to asses the feasibility of PTEN gene expression analysis from FFPE tissue in CRC samples. Materials and methods We selected a series of 33 patients, already tested for KRAS mutational status and resulted wild-type. At the time of the study mutational status of NRAS gene has not a role as predictive marker, so was not performed. A retrospective analysis on CRC FFPE tissue was performed. As control samples we have selected specimen of colorectal surgery not tumor-associated (diverticulitis). On these samples BRAF mutational analysis and PTEN gene expression was performed. For BRAF analysis, DNA was extracted by means of QIAamp DNA FFPE tissue kit (Qiagen, USA). BRAF mutational status was assed through direct automated sequencing (3100 Genetic Analyzer, Applied Biosystems) and TaqMan mutation detection assay (ABI PRIM 7900HT, Applied Biosystems). For PTEN gene expression, total RNA was obtained through the miRNeasy FFPE tissue kit (Qiagen, USA), according to manufacturer instructions, and reverse transcribed. PTEN expression was assessed by means of TaqMan probes. Results According to BRAF mutational status we have found 10/33 (30%) mutated samples. PTEN expression levels were evaluated by the comparison of tumor samples vs diverticula samples, the data obtained were then integrated with those from BRAF mutational analysis. Interestingly we found that all the BRAF mutated samples present also a down-regulation of PTEN. Statistical analyses were conducted through the X2 test with the Yatesha correction (p=0.00023). The p-value was also calculated Exact Fisher Test (p= 0.00021) to confirm the results. Conclusion The determination of PTEN gene expression level is feasible with real-time PCR using TaqMan probe technology. BRAF analysis might be used as prognostic and/or predictive marker in CRC patients’ treatment. The identification of a validated method for PTEN analysis would establish it as a molecular marker meriting further investigation in large numbers of available primary tumors from patients with CRC. Further analyses are requested to confirm these data. Citation Format: Christian D. Rolfo, Marta Castiglia, Daniela Cabibi, Valentina Calo', Florinda Di Piazza, Viviana Bazan, Fabio Brocco, Stefano Caruso, Loredana Bruno, Konstantinos Papadimitriou, Francesco Passiglia, Marc Peeters, Patrick Pauwels, Antonio Russo. Molecular analysis of BRAF gene and PTEN gene expression in metastatic colorectal cancer patients: Feasibility study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2014-448
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-448
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
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    TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 13 ( 2015-07-01), p. 2984-2992
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 13 ( 2015-07-01), p. 2984-2992
    Abstract: Purpose: Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models. The effect of oxygen modification on the combination treatment was evaluated and the effect of TH-302 on the hypoxic fraction (HF) was monitored using [18F]HX4-PET imaging and pimonidazole IHC stainings. Experimental Design: Rhabdomyosarcoma R1 and H460 NSCLC tumor-bearing animals were treated with TH-302 and radiotherapy (8 Gy, single dose). The tumor oxygenation status was altered by exposing animals to carbogen (95% oxygen) and nicotinamide, 21% or 7% oxygen breathing during the course of the treatment. Tumor growth and treatment toxicity were monitored until the tumor reached four times its start volume (T4×SV). Results: Both tumor models showed a growth delay after TH-302 treatment, which further increased when combined with radiotherapy (enhancement ratio rhabdomyosarcoma 1.23; H460 1.49). TH-302 decreases the HF in both models, consistent with its hypoxia-targeting mechanism of action. Treatment efficacy was dependent on tumor oxygenation; increasing the tumor oxygen status abolished the effect of TH-302, whereas enhancing the HF enlarged TH-302′s therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by [18F]HX4-PET imaging and the T4×SV. Conclusions: The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [18F]HX4 hypoxia PET imaging for patient selection. Clin Cancer Res; 21(13); 2984–92. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-0018
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 9
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    Vitamin D–Associated Genetic Variation and Risk of Breast Cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 24, No. 3 ( 2015-03-01), p. 627-630
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 24, No. 3 ( 2015-03-01), p. 627-630
    Abstract: Background: Two recent genome-wide association studies (GWAS) identified SNPs in or near four genes related to circulating 25-hydroxyvitamin D [25(OH)D] concentration. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. Results: We found no association between any of the four SNPs or their polygenic score and breast cancer risk. Conclusions: Our findings do not support an association between vitamin D status, as reflected by 25(OH)D–related genotypes, and breast cancer risk. Impact: These findings may contribute to future meta-analyses and scientific review articles, and provide new data about the association between vitamin D–related genes and breast cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 627–30. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-14-1127
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 10
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    First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 15 ( 2020-08-01), p. 3990-3998
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 15 ( 2020-08-01), p. 3990-3998
    Abstract: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery. Experimental Design: We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer. Results: cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio. Conclusions: cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-4156
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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