Publications (8)41.27 Total impact
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Article: Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients.
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ABSTRACT: Estrogen receptor status in breast cancer is associated with response to hormonal therapy and clinical outcome. The additional value of progesterone receptor (PR) has remained controversial. We examine the value of PR for prognosis and response to tamoxifen on a population-based series of 4,046 invasive early stage breast cancer patients. Clinical information for age at diagnosis, stage, pathology, treatment and outcome was assembled for the study cohort; the median follow-up was 12.4 years. PR status was determined by immunohistochemistry using a rabbit monoclonal antibody on tissue microarrays built from breast tumor surgical excisions. Survival analyses, Kaplan-Meier functions and Cox proportional hazards regression models were applied to assess the associations between PR and breast cancer specific survival. Progesterone receptor was positive in 51% of all cases and 67% of estrogen receptor positive (ER+) cases. Survival analyses for both the whole cohort and ER+ cases given tamoxifen therapy showed that patients with PR+ tumors had 24% higher relative probability for breast cancer specific survival as compared to PR- patients, adjusted for ER, HER2, age at diagnosis, grade, tumor size, lymph node status and lymphovascular invasion covariates. Higher PR expression showed stronger association with patient survival. Log-likelihood ratio tests of multivariate Cox proportional hazards regression models demonstrated that PR was an independent statistically significant factor for breast cancer specific survival in both the whole cohort and among ER+ cases treated with tamoxifen. PR adds significant prognostic value in breast cancer beyond that obtained with estrogen receptor alone.Breast Cancer Research and Treatment 03/2009; 119(1):53-61. · 4.43 Impact Factor -
Article: Ovarian carcinoma subtypes are different diseases: implications for biomarker studies.
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ABSTRACT: Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous) are associated with different natural histories, most ovarian carcinoma biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis. In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1) in a population-based cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.2%-2.4%) but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1.2%-2.3%), but is a favourable prognostic marker within the high-grade serous subtype (RR 0.5, 95% CI 0.3%-0.8%). The association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. To avoid this effect, each subtype within a cohort should be analyzed discretely. Ovarian carcinoma subtypes are different diseases, and these differences should be reflected in clinical research study design and ultimately in the management of ovarian carcinoma.PLoS Medicine 01/2009; 5(12):e232. · 16.27 Impact Factor -
Article: Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of integrin-linked kinase (ILK).
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ABSTRACT: Integrin-linked kinase (ILK) was assesed as a therapeutic target in glioblastoma xenograft models through multiple endpoints including treatment related changes in the tumor microenvironment. Glioblastoma cell lines were tested in vitro for sensitivity toward the small-molecule inhibitors QLT0254 and QLT0267. Cell viability, cell cycle, and apoptosis were evaluated using MTT assay, flow cytometry, caspase activation, and DAPI staining. Western blotting and ELISA were used for protein analysis (ILK, PKB/Akt, VEGF, and HIF-1alpha). In vivo assessment of growth rate, cell proliferation, BrdUrd, blood vessel mass (CD31 labeling), vessel perfusion (Hoechst 33342), and hypoxia (EF-5) was done using U87MG glioblastoma xenografts in RAG2-M mice treated orally with QLT0267 (200 mg/kg q.d.). ILK inhibition in vitro with QLT0254 and QLT0267 resulted in decreased levels of phospho-PKB/Akt (Ser473), secreted VEGF, G2-M block, and apoptosis induction. Mice treated with QLT0267 exhibited significant delays in tumor growth (treated 213 mm3 versus control 549 mm3). In situ analysis of U87MG tumor cell proliferation from QLT0267-treated mice was significantly lower relative to untreated mice. Importantly, VEGF and HIF-1alpha expression decreased in QLT0267-treated tumors as did the percentage of blood vessel mass and numbers of Hoechst 33342 perfused tumor vessels compared with control tumors (35% versus 83%). ILK inhibition with novel small-molecule inhibitors leads to treatment-associated delays in tumor growth, decreased tumor angiogenesis, and functionality of tumor vasculature. The therapeutic effects of a selected ILK inhibitor (QLT0267) should be determined in the clinic in cancers that exhibit dysregulated ILK, such as PTEN-null glioblastomas.Molecular Cancer Therapeutics 02/2008; 7(1):59-70. · 5.23 Impact Factor -
Article: Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer
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ABSTRACT: Abstract Background The presence of the TMPRSS2-ERG fusion gene in prostate tumors has recently been associated with an aggressive phenotype, as well as recurrence and death from prostate cancer. These associations suggest the hypothesis that the gene fusion may be used as a prognostic indicator for prostate cancer. Methods In this study, fluorescent in situ hybridization (FISH) assays were used to assess TMPRSS2-ERG fusion status in a group of 214 prostate cancer cases from two population-based studies. The FISH assays were designed to detect both fusion type (deletion vs. translocation) and the number of fusion copies (single vs. multiple). Genotyping of four ERG and one TMPRSS2 SNPs using germline DNA was also performed in a sample of the cases (n = 127). Results Of the 214 tumors scored for the TMPRSS2-ERG fusion, 64.5% were negative and 35.5% were positive for the fusion. Cases with the TMPRSS2-ERG fusion did not exhibit reduced prostate cancer survival (HR = 0.92, 95% CI = 0.22–3.93), nor was there a significant difference in cause-specific survival when stratifying by translocation or deletion (HR = 0.84, 95% CI = 0.23–3.12) or by the number of retained fusion copies (HR = 1.22, 95% CI = 0.45–3.34). However, evidence for reduced prostate cancer-specific survival was apparent in those cases whose tumor had multiple copies of the fusion. The variant T allele of the TMPRSS2 SNP, rs12329760, was positively associated with TMPRSS2-ERG fusion by translocation (p = 0.05) and with multiple copies of the gene fusion (p = 0.03). Conclusion If replicated, the results presented here may provide insight into the mechanism by which the TMPRSS2-ERG gene fusion arises and also contribute to diagnostic evaluations for determining the subset of men who will go on to develop metastatic prostate cancer.BMC Cancer. 01/2008; -
Article: Cell cycle regulators show diagnostic and prognostic utility for differentiated thyroid cancer.
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ABSTRACT: Differentiated thyroid cancer (DTC) generally has a favorable outcome, but some patients develop local recurrence and/or distant metastases and ultimately die of their disease. Molecular markers that accurately predict tumor behavior are lacking. This study's aim was to ascertain the role of cell cycle regulators in predicting malignant histology and tumor behavior in DTC. Tissue microarrays consisting of 100 benign and 105 malignant thyroid lesions, plus 24 lymph node samples, were stained for p16, p21, p27, p53, p57, p63, cyclin D1, cyclin E, and mdm2. Statistical analysis was used to compare the expression of the markers in benign versus DTC lesions and correlate their expression with clinicopathologic characteristics. p16, p21, cyclin D1, and cyclin E showed significantly (P < .001) increased expression in DTCs compared with benign thyroid lesions (54.7% vs. 5%, 71.7% vs. 38%, 87.1% vs. 45.7%, and 72.3% vs. 37.4%, respectively). There was no significant difference in expression between benign lesions and DTC for the remaining markers. p16 expression correlated significantly with extrathyroidal tumor extension (P = .02) and the presence of cancer in lymph nodes (P = .03). A total of 73% vs. 45% of the cancers of patients with and without lymph node involvement, respectively, stained positive for p16 (P = .01). There is a statistically significant difference in the expression of p16, p21, cyclin D1, and cyclin E between DTCs and benign thyroid lesions, and p16 expression correlates with clinicopathologic variables predicting poor outcomes for DTC. These results suggest that evaluation of cell cycle derangement in thyroid tumors may serve as a useful tool for both DTC diagnosis and prognosis.Annals of Surgical Oncology 12/2007; 14(12):3403-11. · 4.17 Impact Factor -
Article: Identification of molecular markers altered during transformation of differentiated into anaplastic thyroid carcinoma.
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ABSTRACT: A change in tumor expression profile will be observed during the transformation of differentiated into anaplastic thyroid carcinoma. Cohort study. Population-based sample (British Columbia). Sequential archival cases of anaplastic thyroid cancer with an adjacent associated differentiated thyroid cancer focus, and with available paraffin blocks, that had been diagnosed and treated in British Columbia during a 20-year period (12 cases; January 1, 1984, through December 31, 2004) were identified through the provincial tumor registry for tissue microarray construction. Significant associations between marker staining and tumor pathologic diagnosis (differentiated vs anaplastic) were determined with contingency table and marginal homogeneity tests. A classifier algorithm was also used to identify useful and important molecular classifiers. Overall, there were 3 up-regulated and 5 down-regulated markers when comparing the anaplastic carcinoma with associated differentiated thyroid cancers. Contingency table statistics identified 5 markers (thyroglobulin, Bcl-2, MIB-1, E-cadherin, and p53) to be significantly differentially expressed by the anaplastic and differentiated tumor foci. These 5 markers and 3 others (beta-catenin, topoisomerase II-alpha, and vascular endothelial growth factor) were significant when evaluated using the marginal homogeneity test. Clustering and classification analysis based on these same 8 markers readily separated differentiated and anaplastic thyroid tumors with a high degree of accuracy. The markers we observed to change during thyroid tumor progression may not only show promise as molecular diagnostic or prognostic tools but also warrant further study as potential targets for treatment of disease.Archives of Surgery 09/2007; 142(8):717-27; discussion 727-9. · 4.24 Impact Factor -
Article: Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment.
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ABSTRACT: Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment. Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984-2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, beta-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin. A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0-100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: beta-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%). Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.Annals of Surgical Oncology 03/2007; 14(2):719-29. · 4.17 Impact Factor -
Article: Derangement of the E-cadherin/catenin complex is involved in transformation of differentiated to anaplastic thyroid carcinoma.
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ABSTRACT: Anaplastic thyroid cancer arises, or transforms, from pre-existing differentiated thyroid cancer. E-cadherin functions as a cell-cell adhesion molecule that complexes with catenin proteins for function. The objective of this study was to evaluate the change in E-cadherin/beta-catenin expression in the transformation of differentiated to anaplastic thyroid carcinoma. A tissue microarray was constructed from 12 anaplastic thyroid tumors and their adjacent associated differentiated foci. Immunohistochemistry was used to evaluate tumor expression of E-cadherin and beta-catenin. There was decreased expression of E-cadherin and beta-catenin by the anaplastic tumors when compared with the differentiated thyroid tumors from which they evolved. The expression of E-cadherin and beta-catenin was 92% and 67%, respectively, by the differentiated thyroid carcinoma, and 17% and 50%, respectively, by the anaplastic tumors. This report shows that derangement of the E-cadherin/catenin complex is associated with the transformation of differentiated into anaplastic thyroid carcinoma.The American Journal of Surgery 06/2006; 191(5):581-7. · 2.78 Impact Factor
