Perfiles de expresión génica y nuevas dianas terapéuticas en cáncer de endometrio

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1 Perfiles de expresión génica y nuevas dianas terapéuticas en cáncer de endometrio Curso Corto Actualización en Patología Ginecológica David Hardisson Departamento de Anatomía Patológica

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3 CA. DE ENDOMETRIO TIPO 1 PERIMENOPAUSIA HIPERESTRONISMO ENDOMETRIOIDE BAJO GRADO Y ESTADIO HIPERPLASIA CA. DE ENDOMETRIO TIPO 2 POSTMENOPAUSIA SIN HIPERESTRONISMO SEROSO ALTO GRADO Y ESTADIO CA. INTRAEPITELIAL CARCINOMA ENDOMETRIOIDE CARCINOMA SEROSO

4 CARCINOMA ENDOMETRIOIDE ER p53 CARCINOMA NO ENDOMETRIOIDE ER p53

5 Patología molecular del carcinoma de endometrio Matias-Guiu X & Prat J. Histopathology 2013

6 INITIAL GENETIC CHANGES, INCLUDING PTEN INACTIVATION AND MICROSATELLITE INSTABILITY MAY OCCUR IN THE ABSENCE OF A CHANGE IN HISTOMORPHOLOGY. Hecht JL & Mutter GL. J Clin Oncol 2006

7 Patología molecular del carcinoma de endometrio Matias-Guiu X & Prat J. Histopathology 2013

8 Molecular bases of endometrial cancer: New roles for new actors in the diagnosis and the therapy of the disease Llauradó M et al. Mol Cell Endocrinol 2012

9 Guión de la presentación Fenotipo molecular (CEE vs CNEE). Dianas terapéuticas. Otros aspectos interesantes: mirna, CEE vs CEO.

10 36 carcinomas de endometrio: - 24 endometrioides - 11 no endometrioides Diferencias expresión en 66 genes genes sobrexpresados en CEE (regulados hormonalmente) genes sobreexpresados en CNEE ( 3 relacionados con mitosis). - STK15: aneuploidía y fenotipo agresivo. - Amplificado en >50% de CNEE y en ningún CEE (p<0.001).

11 cdna microarray analysis and immunohistochemistry reveal a distinct molecular phenotype in serous endometrial cancer compared to endometrioid endometrial cancer A low-density cdna microarray containing 492 genes was designed and constructed. The gene expression profiles of 32 endometrioid and 5 serous endometrial cancer tissue samples were compared. I, II, III: EA IV: SC Chen Y et al. Exp Mol Pathol 2011

12 SC EA Chen Y et al. Exp Mol Pathol 2011

13 Chen Y et al. Exp Mol Pathol 2011

14 cdna microarray analysis and immunohistochemistry reveal a distinct molecular phenotype in serous endometrial cancer compared to endometrioid endometrial cancer Serous adenocarcinoma exhibits distinct gene expression profiles, compared with those of endometrioid adenocarcinoma. These differences make it feasible to validate microarray data by immunohistochemistry, and they will ultimately allow us to identify tumors according to their immunohistochemical phenotype. The accuracy of classifying endometrial tumors using a system based on their gene expression patterns is much higher than the accuracy of the FIGO grading system. Thus, this gene expression pattern-based system may prove to be crucial in developing novel treatment strategies for endometrial cancers at the molecular level in future. Chen Y et al. Exp Mol Pathol 2011

15 USC EAC USC EAC 10 EAC 10 USC Good progn Poor progn Good progn Poor progn Early stage Late stage Early stage Late stage Early vs Late stage Good vs Poor prognosis

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17 The number of differentially expressed genes derived from USC vs. EAC-G3 comparison is consistently less than that derived from USC vs. EAC-G1 comparison USC versus EAC-G1 USC versus EAC-G3 USC EAC-G1 USC EAC-G3 USC versus EAC-G1 USC versus EAC-G3

18 High-grade EC exon 20 PIK3CA-AKT/p16+ TP53/p16+/exon 9 PIK3CA

19 Analysis of angiogenesis-related gene expression reveals a profile with prognostic implications in endometrioid endometrial carcinoma We generated a predictive model based on the expression of 5 angiogenesis-related genes (EGFR, FGFR2, GSK3B, PDK2, PIK3C3). According to the model, patients were divided into 2 risk groups, with 85% sensibility and 72% specificity. In a multivariate analysis including clinical variables the model was independently associated with overall survival. Hazard Ratio EGFR : FGFR : patients with EAC were included in this study. GSK3B : RNAs were collected from formalin-fixed paraffin-embedded samples. PDK : Specific TaqMan Gene Expression assays for 82 genes were selected and gene expression was determined by qrt-pcr with TaqMan Low Density Arrays (Applied Biosystems). PIK3C : Mendiola M et al. USCAP 2013

20 Personalized Health Care Fantasy or Reality? Here s my tumor s DNA sequence

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22 Drug-Dx Co-development Current regulatory paradigm requires early biomarker discovery Drug Dx Target Discovery Biomarker discovery Preclinical Dev t Biomarker Assay Dev t Phase 1 Phase 2 Phase 3 To maximize clinical benefit from our therapeutics: Informed decision making around indication choice Enable patient selection PMA filing, Clinical Validation approval, of biomarker hypothesis launch FDA draft white paper on Drug-Dx co-development Predictive biomarker: a test that can be done before treatment to predict whether a particular treatment is likely to be beneficial Pharmacodynamic biomarker: a test that can be done pre- and post-treatment to confirm target modulation FDA filing, approval, launch +

23 PI3K/PTEN Pathways: multiple nodes are candidates for molecules targeting core oncogenic pathways; potential for broad application, combinations, with strong biomarker hypotheses Bladder Gastric PTEN Breast Ovarian HNSCC HCC PI3K Prostate GBM NSCLC Endometrial CRC Melanoma Pancreatic Ras Matias-Guiu X & Prat J. Histopathology 2013 p110α oncogenic mutations in: 37% Endometrial 29% Breast 25% Colon 13% Bladder PIK3CA amplified in 30% ovarian, lung PTEN mutant/lost in: breast, prostate, glioblastoma, melanoma, pancreatic, endometrial, ovarian, lung, head and neck, hepatocellular, thyroid

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29 Ratner ES et al. Gynecol Oncol 2010

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31 2012 Pathwork Tissue of Origin Endometrial Test

32 Conclusiones Información masiva. Nuevos biomarcadores. Potenciales dianas terapéuticas. Nuevos procedimientos basados en técnicas moleculares: incorporación a los Servicios de Anatomía Patológica: integración morfología y patología molecular.

33 David Hardisson