Improvement of the clinical applicability of the Genomic Grade Index through a qRT-PCR test performed on frozen and formalin-fixed paraffin-embedded tissues

BACKGROUND: Proliferation and tumor differentiation captured by the genomic grade index (GGI) are important prognostic indicators in breast cancer (BC) especially for the estrogen receptor positive (ER+) disease. The aims of this study were to convert this microarray index to a qRT-PCR assay (PCR-GGI), which could be realized on formalin fixed paraffin embedded samples (FFPE), and to assess its prognostic performance and predictive value of clinical benefit in early and advanced ER+ BC patients treated with tamoxifen. METHODS: The accuracy and concordance of the PCR-GGI with the GGI was assessed using BC patients for which frozen and FFPE tissues as well as microarray data were available (n = 19). The evaluation of the prognostic value of the PCR-GGI was assessed on FFPE material using a consecutive series of 212 systemically treated early BC patients. The predictive performance for tamoxifen benefit was assessed using two ER+ BC populations treated either with adjuvant tamoxifen only (n = 77+139) or first-line tamoxifen for advanced disease (n = 270). RESULTS: The PCR-GGI is based on the expression of 8 genes (4 representative of the GGI and 4 reference genes). A significant correlation was observed between the microarray-derived GGI and the qRT-PCR assay using frozen (rho = 0.95, p < 10E-06) and FFPE material (rho = 0.89, p < 10E-06). The prognostic performance of the PCR-GGI was confirmed on FFPE samples (HRunivar. = 1.89; [95CI:1.01-3.54], p = 0.05). The PCR-GGI further identified two subgroups of patients with statistically different time to distant metastasis free survival (DMFS) across the two cohorts of ER+ BC patients treated with adjuvant tamoxifen. Additionally, the PCR-GGI was associated with response to tamoxifen in the advanced setting (HRunivar. = 1.98; [95CI:1.51-2.59], p = 6.9E-07). CONCLUSION: PCR-GGI recapitulates in an accurate and reproducible manner the performances of the GGI using frozen and FFPE samples

Low CD10 mRNA Expression Identifies High-Risk Ductal Carcinoma In Situ (DCIS)

PURPOSE: Optimal management of breast ductal carcinoma in situ (DCIS) is controversial, and many patients are still overtreated. The local death of myoepithelial cells (MECs) is believed to be a pre-requisite to tumor invasion. We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS. The aim of our study was to retrospectively evaluate the prognostic value of CD10 in DCIS. EXPERIMENTAL DESIGN: CD10 expression was evaluated by quantitative RT-PCR and immunohistochemistry using paraffin-embedded samples of normal breast tissue (n = 11); of morphologically normal ducts associated with DCIS (n = 10); and of DCIS without an invasive component (n = 154). RESULTS: CD10 immunostaining was only observed in MECs in normal tissue and in DCIS. Normal tissue showed high mRNA expression levels of CD10, whereas DCIS showed a variable range. After a median follow-up of 6 years, DCIS with CD10 expression below the levels observed in normal tissue (71%) demonstrated a higher risk of local relapse (HR = 1.88; [95CI:1.30-2.70], p = 0.001) in univariate analysis. No relapse was observed in patients expressing high CD10 mRNA levels (29%) similar to the ones observed in normal tissue. In multivariate analysis including known prognostic factors, low CD10 mRNA expression remained significant (HR = 2.25; [95%CI:1.24-4.09], p = 0.008), as did the recently revised Van Nuys Prognostic Index (VNPI) score (HR = 2.03; [95%CI:1.23-3.35], p = 0.006). CONCLUSION: The decrease of CD10 expression in MECs is associated with a higher risk of relapse in DCIS; this knowledge has the potential to improve DCIS management

Etude du métabolisme du carbamoylphosphate, intermédiaire thermolabile des voies de biosynthèse de l'arginine et des pyrimidines, chez des archaea hyperthermophiles

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Etude du métabolisme du carbamoylphosphate, intermédiaire thermolabile des voies de biosynthèse de l'arginine et des pyrimidines, chez des archaea hyperthermophiles

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Topoisomerase-II as a predictive marker for response to anthracyclines

info:eu-repo/semantics/publishe

The RT-PCR Genomic Grade Index

Application Number: PCT/EP2008/054620Publication number: WO2009/056366info:eu-repo/semantics/publishe

HER2 et topo-isomérase II alpha: deux marqueurs d'intérêt clinique dans le cancer du sein.

HER-2 and potentially topoisomerase II alpha are clinically useful parameters in breast cancer. The gene status and protein expression are, for both markers, used as predictive markers in research or clinical practice. New guidelines for HER-2 testing from ASCO and CAP have been recently published and new definition for HER-2 gene amplification will probably decrease the impact of polysomy 17 on HER-2 FISH status evaluation. Different forms of HER-2 receptor (p95HER-2, p185HER-2) could be considered as prognostic or predictive markers in the future if preliminary results are confirmed. The topoisomerase II alpha case is more complex as the results of preclinical and clinical studies seem to be contradictory. The results of the clinical studies are so far, encouraging but need to be confirmed. Moreover studies should be designed to define which one of the protein or the gene or both should be evaluate as predictive markers of response to anthracyclines chemotherapy. More studies are needed today to consider this marker for daily practice.English AbstractJournal ArticleReviewinfo:eu-repo/semantics/publishe

HER-2/neu Gene and protein in breast cancer

info:eu-repo/semantics/publishe

HER2 and topoisomerase IIa: Useful clinical markers in breast cancer

info:eu-repo/semantics/publishe

Resistance to trastuzumab: a necessary evil or a temporary challenge?

The aim of this review article is to examine the potential mechanisms of resistance to trastuzumab. In the clinical setting, when trastuzumab is given as a single agent for first-line treatment of HER2-overexpressing metastatic breast cancer, it is associated with a 40% objective response rate. In the remaining cases, no tumor regression is observed, although HER2 protein is overexpressed and/or the corresponding gene is amplified. Hence, some other factors besides HER2 must play a role in determining the level of sensitivity to trastuzumab. The identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Moreover, thorough understanding of the HER2 pathway is essential to the identification of new predictive markers of response to trastuzumab that will help to better define the patients who are most likely to benefit from this drug.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe