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Reginald V. N. Lord, Dennis Salonga,
Kathleen D. Danenberg,
Jeffrey H. Peters,
Tom R. DeMeester,
Ji Min Park,
Jan Johansson,
Kristin A. Skinner,
Para Chandrasoma,
Steven R. DeMeester,
Cedric G. Bremner,
Peter I. Tsai,
Peter V. Danenberg
[show abstract]
[hide abstract]
ABSTRACT: Barrett’s esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus
and csophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased
expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant
diseases. To identify’ biomarkers associated with each stage of the Barrett’s process, relative mRNA expression levels of
hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector
(TaqMan system) in Barrett’s intestinal metaplasia (n —14), Barrett’s dysplasia (n =10), Barrett’s adenocarcinoma (n = 14),
and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barren’s
esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal
metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Alann-Whitney U test). hTERT
expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and
were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher
in histologically normal squamous esophagus tissues from cancer panents than in normal esophagus tissues from patients vrith
no cancer (P = 0.013). Very high expression levels ([hTERT × 100: β-actin] >20) were found only in patients with cancer. These
findings suggest that telomerase activation is an important early event in the development of Barrett’s esophagus and esophageal
adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma,
and that a widespread cancer ‘field’ effect is present in the esophagus of patients with Barrett’s cancer.
Journal of Gastrointestinal Surgery 04/2012; 4(2):135-142. · 2.83 Impact Factor
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Jan Brabender,
Reginald V. Lord,
Kathleen D. Danenberg,
Ralf Metzger,
Paul M. Schneider,
Hiroyuki Uetake,
Kazuyuki Kawakami,
Ji Min Park, Dennis Salonga,
Jeffrey H. Peters,
Tom R. DeMeester,
Arnulf H. Hölscher,
Peter V. Danenberg
[show abstract]
[hide abstract]
ABSTRACT: The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia
to Barrett’s esophagus with dysplasia and ultimately adenocarcinoma. Understanding the cellular and molecular events in this
multistage process may contribute to improved diagnosis and treatment. Ornithine decarboxylase (ODC) is the first enzyme in
the biosynthesis of polyamines. Elevated ODC activity has been found to be associated with progression during Barrett’s esophagus,
but the regulation of ODC gene expression in the development of Barrett’s-associated adenocarcinoma has not been reported.
The aim of this study was to assess the prevalence and timing of ODC mRNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma
sequence. ODC mRNA expression levels, relative to the stably expressed internal reference gene β-actin, were measured using
a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method (ABI 7700 Sequence Detector System) in 104
specimens from 19 patients with Barrett’s esophagus without carcinoma and 22 patients with Barrett’s-associated adenocarcinoma.
The median ODC mRNA expression levels were significantly increased in Barrett’s esophagus tissues compared to matched normal
tissues in patients without adenocarcinoma of the esophagus (P = 0.002; Wilcoxon test). A significant progressive increase
in ODC mRNA expression was detectable through the stages of the metaplasia-dysplasia-carcinoma sequence in patients with Barrett’s-associated
adenocarcinoma (r = 0.719;P ≤0.001; Spearman’s rho test). These findings show that upregulation of ODC mRNA expression is an early event in the
development and progression of Barrett’s-associated adenocarcinoma of the esophagus, and they suggest that high ODC mRNA expression
levels may be a clinically useful biomarker for the detection of occult adenocarcinoma.
Journal of Gastrointestinal Surgery 04/2012; 5(2):174-182. · 2.83 Impact Factor
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Jan Brabender,
Paul Marjoram,
Reginald V N Lord,
Ralf Metzger, Dennis Salonga,
Daniel Vallböhmer,
Hartmut Schäfer,
Kathleen D Danenberg,
Peter V Danenberg,
Florin M Selaru,
Stefan E Baldus,
Arnulf H Hölscher,
Stephen J Meltzer,
Paul M Schneider
[show abstract]
[hide abstract]
ABSTRACT: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the esophagus disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous esophagus epihelium of patients with Barrett's esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's disease.
Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis.
A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARalpha, RARgamma, RXRalpha, RXRbeta, SPARC, TSPAN, and VEGF. Based on the expression signature of the normal appearing squamous esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%.
This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's esophagus disease. Based on the gene expression signature of the normal esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's esophagus disease.
Cancer Epidemiology Biomarkers & Prevention 10/2005; 14(9):2113-7. · 4.12 Impact Factor
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Sylke Schneider,
Kazumi Uchida,
Jan Brabender,
Stephan E Baldus,
JiMin Yochim,
Kathleen D Danenberg, Dennis Salonga,
Pei Chen,
Denice Tsao-Wei,
Susan Groshen,
Arnulf H Hoelscher,
Paul M Schneider,
Peter V Danenberg
[show abstract]
[hide abstract]
ABSTRACT: To find out if neoadjuvant therapy could alter tumor response determinants that might affect tumor sensitivity to the treatment, we investigated intratumoral expressions of genes associated with chemosensitivity, radiosensitivity, or both before and after radiochemotherapy.
Twenty-four patients with locally advanced, resectable esophageal cancer (cT2-4,Nx,M0) received neoadjuvant 5-FU/cisplatin/36 Gy treatment followed by transthoracic en bloc esophagectomy. Expression levels of thymidylate synthase, dihydropyrimidine dehydrogenase, excision repair cross-complementing gene 1 , glutathione S-transferase Pi, epidermal growth factor receptor, and HER2 were measured in matched preradiochemotherapy endoscopic tumor biopsies and in postradiochemotherapy resection specimens. mRNA was isolated from formalin-fixed, paraffin-embedded, laser microdissected tumor tissues, and a quantitative fluorescent dye real-time reverse transcription polymerase chain reaction system was used for gene expression measurement.
There was a significant reduction in the expression levels of thymidylate synthase (p < 0.01), dihydropyrimidine dehydrogenase (p = 0.03), excision repair cross-complementing gene 1 (p < 0.01), glutathione S-transferase Pi (p = 0.03), HER2 (p < 0.01), and epidermal growth factor receptor (p = 0.04). The change in the levels of epidermal growth factor receptor mRNA in post- compared with pretreatment specimens was significantly associated with the histopathologic grade of regression (p = 0.01).
The expression levels of a set of genes that are possible determinants of 5-FU/cisplatin/radiation therapy antitumor activity are significantly downregulated by neoadjuvant radiochemotherapy in esophageal cancer.
Journal of the American College of Surgeons 04/2005; 200(3):336-44. · 4.55 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are important in regulating the development, growth and differentiation of cells and have inhibitory effects on non-small cell lung cancer (NSCLC) cell growth. A comprehensive analysis of all RAR and RXR subtypes mRNA expression in a large series of patients with NSCLC and their role in the development and progression of this disease is lacking. Using a quantitative real-time RT-PCR method, we analyzed the mRNA expression of all retinoid receptor subtypes in tumor and matching normal-appearing tissues of 88 patients with NSCLC. Gene expression in tumor tissues was detected with the following frequencies: RARalpha 100%, RARbeta 94%, RARgamma 94%, RXRalpha 100%, RXRbeta 100% and RXRgamma 92%. Levels of mRNA expression in tumor tissues compared with matching normal-appearing tissue were equal or reduced with the following frequencies: RARalpha 76.1%, RARbeta 59.1%, RARgamma 39.8%, RXRalpha 67.1%, RXRbeta 54.5% and RXRgamma 88.6%, and were significantly associated with any one other subtype. The probability of survival was significantly different among patients with low gene expression in no or any two subtypes, any three or four subtypes or any five or six subtypes (P = 0.004, log rank test). Multivariate analysis confirmed low gene expression status as a significant independent unfavorable prognostic factor (P = 0.015). Our results show that decreased expression of all RAR and RXR receptor subtypes is a frequent event in NSCLC. Widely co-regulated down-regulation of expression of all retinoid subclasses suggests a fundamental dysregulation of the retinoid pathway in this cancer. Quantitation of RAR and RXR mRNA expression levels in tumor tissue is a candidate prognostic marker and surrogate biomarker for chemopreventive trials in NSCLC.
Carcinogenesis 04/2005; 26(3):525-30. · 5.70 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The Barrett's multistage process is characterized histopathologically by progression from Barrett's intestinal metaplasia to Barrett's esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett's esophagus disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett's esophagus without carcinoma (BE group), 20 patients with Barrett's-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux disease (CG). RXR-alpha mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-gamma was significantly increased (P < 0.001) at higher stages in Barrett's esophagus. RXR-beta expression was highest in Barrett's tissues and was significantly increased compared to normal squamous tissues (P=0.01; Wilcoxon test) and adenocarcinoma tissues (P=0.018, Mann-Whitney test). RXR-alpha and RXR-beta mRNA expression was significantly associated in normal squamous esophagus tissues (r(2)=0.49; P < 0.001; Spearman test), Barrett's tissues (r(2)=0.63; P < 0.001), and adenocarcinoma tissues (r(2)=0.68; P=0.001). There were significant differences in RXR-alpha (P=0.011) and RXR-beta (P=0.005) mRNA expression in histopathologically normal squamous esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett's esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this disease, and that a widespread "field-effect" is present in the normal esophagus of patients with esophageal adenocarcinoma.
Journal of Gastrointestinal Surgery 07/2004; 8(4):413-22. · 2.83 Impact Factor
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Jan Brabender,
Paul Marjoram, Dennis Salonga,
Ralf Metzger,
Paul M Schneider,
Ji Min Park,
Sylke Schneider,
Arnulf H Hölscher,
Jing Yin,
Stephen J Meltzer,
Kathleen D Danenberg,
Peter V Danenberg,
Reginald V Lord
[show abstract]
[hide abstract]
ABSTRACT: In order to identify genes or combination of genes that have the power to discriminate between premalignant Barrett's esophagus and Barrett's associated adenocarcinoma, we analysed a panel of 23 genes using quantitative real-time RT-PCR (qRT-PCR, Taqman and bioinformatic tools. The genes chosen were either known to be associated with Barrett's carcinogenesis or were filtered from a previous cDNA microarray study on Barrett's adenocarcinoma. A total of 98 tissues, obtained from 19 patients with Barrett's esophagus (BE group) and 20 patients with Barrett's associated esophageal adenocarcinoma (EA group), were studied. Triplicate analysis for the full 23 gene of interest panel, and analysis of an internal control gene, was performed for all samples, for a total of more than 9016 single PCR reactions. We found distinct classes of gene expression patterns in the different types of tissues. The most informative genes clustered in six different classes and had significantly different expression levels in Barrett's esophagus tissues compared to adenocarcinoma tissues. Linear discriminant analysis (LDA) distinguished four genetically different groups. The normal squamous esophagus tissues from patients with BE or EA were not distinguishable from one another, but Barrett's esophagus tissues could be distinguished from adenocarcinoma tissues. Using the most informative genes, obtained from a logistic regression analysis, we were able to completely distinguish between benign Barrett's and Barrett's adenocarcinomas. This study provides the first non-array parallel mRNA quantitation analysis of a panel of genes in the Barrett's esophagus model of multistage carcinogenesis. Our results suggest that mRNA expression quantitation of a panel of genes can discriminate between premalignant and malignant Barrett's disease. Logistic regression and LDAs can be used to further identify, from the complete panel, gene subsets with the power to make these diagnostic distinctions. Expression analysis of a limited number of highly selected genes may have clinical usefulness for the treatment of patients with this disease.
Oncogene 07/2004; 23(27):4780-8. · 6.37 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to better define the role of osteopontin (OPN) and osteonectin [also known as secreted protein acidic and rich in cysteine (SPARC)] in lung tumorigenesis by comparing the expressions of these genes in lung tumor tissue and matched normal tissue and by determining the prognostic significance of the gene expressions.
Quantitative real-time reverse transcription-PCR was used to analyze OPN and SPARC mRNA expression in normal lung tissue and matching tumor samples from 82 patients with non-small cell lung cancer. Gene expression data for each patient were matched to survival data.
The overall median mRNA expression level of OPN was about 20-fold higher in tumor tissues than in matching normal lung tissues (P < 0.001), whereas SPARC gene expression was not significantly different in both tissue types. Forty of 82 patients had high (>or=4.1) intratumoral OPN expression, and 15 of 82 patients had high (>or15.5) SPARC expression. High OPN expression in the tumor tissue was associated with inferior survival (P = 0.014), whereas high SPARC expression showed a trend toward longer survival (P = 0.095). The impact of high OPN and low SPARC expression on patient survival was additive (P = 0.001).
The large increase in OPN expression in tumors compared with normal tissue and its association with survival suggest a role for OPN in lung tumorigenesis.
Clinical Cancer Research 03/2004; 10(5):1588-96. · 7.74 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: In recent years, gene expression quantitation of tumor cells has become of principal importance to analyze gene patterns responsible for cancer development, progression, and resistance to treatment. Whereas semi-quantitative methods, such as Northern blotting analysis, allow only a dichotomous differentiation between positive and negative gene expressions, the real-time quantitative polymerase chain reaction (qRT-PCR) combines a large range of results with an accurate and highly reproducible quantitation of genes. In addition to forward and reverse primers, as used in a conventional PCR, the qRT-PCR system utilizes a probe that is labeled with a fluorescent dye. The probe is an oligonucleotide, homologous to a DNA sequence between the two flanking PCR primers. Degradation of the probe by the activity of the Taq DNA polymerase generates a fluorescent signal that will be detected by means of a laser integrated in the sequence detector. This chapter will cover the isolation of total RNA from frozen tissue, the transcription of RNA to cDNA, and the analysis of the relative gene expression by qRT-PCR. Although in principle applicable to any gene of interest, we will use as an example the qRT-PCR analysis of p16INK4a, whose gene product is involved in cell cycle and senescence checkpoint control.
Methods in molecular biology (Clifton, N.J.) 02/2004; 281:91-103.
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Rafael Rosell,
Giorgio Scagliotti,
Kathleen D Danenberg,
Reginald V N Lord,
Gerold Bepler,
Silvia Novello,
Janine Cooc,
Lucio Crinò,
José Javier Sánchez,
Miquel Taron,
Corrado Boni,
Filippo De Marinis,
Maurizio Tonato,
Maurizio Marangolo,
Felice Gozzelino,
Franceso Di Costanzo,
Massimo Rinaldi, Dennis Salonga,
Craig Stephens
[show abstract]
[hide abstract]
ABSTRACT: Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.
Oncogene 07/2003; 22(23):3548-53. · 6.37 Impact Factor
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Reginald V N Lord,
Ji Min Park,
Kumari Wickramasinghe,
Steven R DeMeester,
Stefan Oberg, Dennis Salonga,
Jon Singer,
Jeffrey H Peters,
Kathleen D Danenberg,
Tom R Demeester,
Peter V Danenberg
[show abstract]
[hide abstract]
ABSTRACT: This study was undertaken to investigate the role of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor in the development and progression of Barrett esophagus and adenocarcinomas of the esophagus and gastroesophageal junction.
Vascular endothelial growth factor and basic fibroblast growth factor messenger RNA expression levels, relative to the control gene encoding beta-actin, were measured by using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector system) in specimens of Barrett intestinal metaplasia (n = 16), dysplasia (n = 11), adenocarcinoma (n = l 5), and matching normal squamous esophageal tissues (n = 35). Vascular endothelial growth factor and basic fibroblast growth factor protein expression and CD31(+) microvessel density were assessed by means of immunohistochemistry in 25 tissue sections that included representative areas for each of these Barrett stages.
Expression levels were significantly increased in adenocarcinoma compared with in either normal squamous mucosa (P <.0001 for both genes) or intestinal metaplasia (vascular endothelial growth factor, P =.002; basic fibroblast growth factor, P <.0001). Vascular endothelial growth factor levels were also significantly higher in cancer tissues compared with dysplasia tissues (P =.024, Mann-Whitney U test). Basic fibroblast growth factor expression was also significantly increased in Barrett dysplastic mucosa compared with in intestinal metaplasia or normal esophageal mucosa. Microvessel density was generally higher in adenocarcinoma compared with in preneoplastic Barrett tissues. The pattern of vascular endothelial growth factor and basic fibroblast growth factor protein expression was similar to the messenger RNA expression pattern, with the exception that mucin-containing goblet cells stained intensely for vascular endothelial growth factor and only weak vascular endothelial growth factor staining was present in some adenocarcinomas.
Vascular endothelial growth factor and basic fibroblast growth factor messenger RNA expression levels are significantly upregulated in esophageal and gastroesophageal junction adenocarcinomas, suggesting a role for these angiogenic factors in the development of these cancers. Vascular endothelial growth factor and basic fibroblast growth factor messenger RNA expression levels are also increased in some Barrett esophagus tissues, with this increase occurring at an earlier stage for basic fibroblast growth factor than for vascular endothelial growth factor. Basic fibroblast growth factor protein expression pattern is similar to the messenger RNA expression pattern, but unlike the messenger RNA findings, vascular endothelial growth factor protein expression is strongest in goblet cells.
Journal of Thoracic and Cardiovascular Surgery 02/2003; 125(2):246-53. · 3.41 Impact Factor
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Jan Brabender,
Henning Usadel,
Ralf Metzger,
Paul M Schneider,
JiMin Park, Dennis Salonga,
Denise D Tsao-Wei,
Susan Groshen,
Reginald V Lord,
Naoko Takebe,
Sylke Schneider,
Arnulf H Hölscher,
Kathleen D Danenberg,
Peter V Danenberg
[show abstract]
[hide abstract]
ABSTRACT: Hypermethylation of the O(6)-methylguanine DNA methyltransferase (MGMT) promoter region leads to transcriptional repression of the MGMT gene and is a common event in primary human neoplasia. The purpose of this study was to determine the frequency and clinical relevance of MGMT gene promoter hypermethylation in curatively resected non-small cell lung cancer (NSCLC).
MGMT hypermethylation, expressed as the ratio between methylated MGMT to unmethylated MYOD1 in genomic DNA, was analyzed in normal and matching tumor tissue from 90 patients with NSCLC, and a control group of 10 patients without cancer using a methylation-specific fluorogenic Real-Time PCR (Taqman) system.
Hypermethylation of the MGMT promoter was detected in 34 of 90 (38%) tumor specimens and 16 of 90 (18%) matching normal lung tissues of patients with NSCLC, and in 0 (0%) cases of the control group without lung cancer. The mean MGMT methylation level was significantly higher in tumor than in matching normal tissue (P < 0.001). MGMT methylation in normal tissue was always accompanied with MGMT methylation in matching tumor tissue. Patients without MGMT promoter hypermethylation showed a significantly better survival than patients with MGMT promoter hypermethylation (P = 0.017). Multivariate analysis revealed MGMT promoter methylation as an independent unfavorable prognostic factor (P = 0.030).
MGMT promoter hypermethylation is a common event in patients with primary NSCLC. This epigenetic alteration is associated with inferior survival, suggesting that MGMT promoter hypermethylation might be an important biomarker for a biological aggressive disease in NSCLC.
Clinical Cancer Research 01/2003; 9(1):223-7. · 7.74 Impact Factor
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Silvia C Formenti,
Darcy Spicer,
Kristin Skinner,
Deidre Cohen,
Susan Groshen,
Anna Bettini,
Wesley Naritoku,
Michael Press, Dennis Salonga,
Denice Tsao-Wei,
Kathy Danenberg,
Peter Danenberg
[show abstract]
[hide abstract]
ABSTRACT: The objective of this study was twofold: first, to identify patients with locally advanced breast cancer (LABC) who will achieve a pathological response to a preoperative regimen of concurrent paclitaxel and radiation; and second, to explore associations between molecular markers from the original tumors and pathological response.
Patients with previously untreated LABC were eligible to receive a regimen of preoperative concurrent paclitaxel, 30 mg/m(2) twice a week for a total of 8 weeks, and radiation delivered Weeks 2--6, 45 Gy at 1.8 Gy per fraction to the breast, ipsilateral axilla, and supraclavicular nodes. At mastectomy, pathologic findings were classified as pathological complete response (pCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of < or = 10 microscopic foci of invasive cells; no pathological response (pNR) = pathological persistence of tumor. For each patient, pretreatment breast cancer biopsies were prospectively analyzed by immunohistochemistry (IHC) for estrogen and progesterone (ER/PR) hormonal receptors, HER2/neu and p53 overexpression. Estrogen receptor (ER), HER2/neu, metablastin, beta-tubulin III and IV, microtubule-associated protein-4 (MAP-4), bcl-2, bax, and cyclooxygenase-2 (COX-2) gene expression were measured using real-time quantitative polymerase chain reaction (PCR).
A total of 36 patients had pretreatment biopsies and were evaluable for the analysis of the association of molecular markers with pathological response. Pathological response in the mastectomy specimen was achieved in 12 of these 36 patients (33%). Only HER2/neu and ER gene expression were found to be significantly associated with the extent of pathological response to the regimen, i.e., tumors with low HER2/neu gene expression and negative estrogen receptors were more likely to respond to the tested regimen (p = 0.009 and p = 0.006, respectively). Conversely, p53 protein expression measured by IHC did not appear to be associated with pathological response (p = 0.67).
Further studies in LABC should assess whether patient selection for treatment based on the original tumor molecular characteristics could affect their chance to achieve a pathological response.
International Journal of Radiation OncologyBiologyPhysics 03/2002; 52(2):397-405. · 4.11 Impact Factor
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Jan Brabender,
Kathleen D Danenberg,
Ralf Metzger,
Paul M Schneider,
Reginald V Lord,
Susan Groshen,
Denice D Tsao-Wei,
JiMin Park, Dennis Salonga,
Arnulf H Hölscher,
Peter V Danenberg
[show abstract]
[hide abstract]
ABSTRACT: Retinoid X receptors (RXRs) have inhibitory effects on non-small cell lung cancer (NSCLC) cell growth, and RXRbeta expression is reduced in NSCLC specimens compared with normal lung tissue. We hypothesized that suppressed RXR expression might be a prognostic factor of worse clinical outcome in patients with NSCLC.
Using a quantitative real-time reverse transcription-PCR (TaqMan) method, we analyzed RXRalpha, RXRbeta, and RXRgamma mRNA expression in normal lung tissue and matching tumor samples from 88 patients with NSCLC.
The median mRNA expression levels of all three RXR subtypes were frequently decreased in tumor tissues compared with matching normal lung tissue (RXRalpha, 67%; RXRbeta, 55%; RXRgamma, 89%). The RXRalpha(P = 0.001) and RXRgamma(P < 0.001) median expression levels were significantly lower in the tumors. Patients whose tumors exhibited low RXRbeta expression levels had a statistically significant worse overall survival (P = 0.0005), whereas a trend toward worse survival was observed for patients with low RXRalpha expression. Multivariate analysis indicated that low RXRbeta expression is an independent predictor of worse survival in patients with NSCLC (P = 0.017).
Suppressed mRNA expression of all three RXR subtypes is a frequent event in NSCLC. Reduced RXRbeta expression might be an important biomarker for more aggressive disease in patients with NSCLC.
Clinical Cancer Research 03/2002; 8(2):438-43. · 7.74 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The prognostic role of epidermal growth factor recep-tor (EGFR) and HER2-neu remains controversial in pa-tients with non-small cell lung cancer (NSCLC). We studied the association between the mRNA expression of EGFR, HER2-neu, and survival in primary tumor and matching nonmalignant tissues from 83 patients with NSCLC. Anal-ysis was performed using a quantitative real-time PCR sys-tem (Taqman). EGFR and HER2-neu mRNA expression was detectable in all (100%) specimens analyzed. Twenty-nine (34.9%) patients had high HER2-neu expression, and 28 (33.7%) patients had high EGFR expression. A high HER2-neu and EGFR coexpression was detectable in 14 (16.9%) patients. High HER2-neu expression was associated with inferior survival (P 0.004), whereas high EGFR expression showed a trend toward inferior survival (P 0.176). The impact of HER2-neu and EGFR coexpression on patients' survival was additive (P 0.003). Multivariate analysis determined high HER2-neu expression (P 0.041), and high EGFR/HER2-neu coexpression (P 0.030) as significant and independent unfavorable prognostic factors. These findings indicate that HER2-neu and EGFR play a crucial role in the biological behavior of NSCLCs. Testing of molecular marker coexpression (EGFR and HER2-neu) im-proves the estimation of prognosis and appears to define low-and high-risk groups for treatment failure in curatively resected NSCLC.
