Situación actual y futuro de la determinación de biomarcadores en
Anuncio
Situación actual y futuro de la determinación de biomarcadores en el SNS Emilio Alba Servicio de Oncología Médica H. Univ V. de la Victoria. Málaga Departamento de Medicina. Universidad de Málaga. IBIMA ÍNDICE • La situación actual • Expectativas • Conceptos generales • Conclusiones ”TRADITIONAL” ANTITUMORAL THERAPY DRON PREDATOR Key cancer biomarkers in patient care Clinical biomarker use Clinical objective Screening Detect and treat early stage cancers in the asymptomatic population1 Definitively establish the presence of cancer1 Diagnostic Prognostic Predictive Predict the probable outcome of cancer regardless of therapy1 Predict treatment safety and/or efficacy outcome2 1. Committee on Developing Biomarker‐Based Tools for Cancer Screening Diagnosis and Treatment. Washington, D.C. The National Academic Press 2007; 2. Heinemann V, et al. Cancer Treat Rev 2013; 39:592‐601. DIANAS ¨DRUGGABLES¨ • Proteínas • Función enzimática conocida • La actividad enzimática se vehicula a través de su ¨catalytic cleft¨ • Esto solo se cumple en el 20% de las proteínas conocidas Biomarker‐guided treatment has the potential to improve clinical outcomes Predictive biomarkers Efficacy Concentrate therapeutic interventions on patients likely to benefit Safety Spare potential side effects in patients not likely to benefit Efficiency Spare expense in patients not likely to benefit Conley BA, Taube SE. Prognostic and predictive markers in cancer. Dis Markers 2004;20:35‐43. Kelloff GJ, Sigman CC. New science‐based endpoints to accelerate oncology drug development. Eur J Cancer 2005;41:491‐501. President's Council of Advisors on Science and Technology. Priorities for Personalized Medicine. 2008. Heinemann V, et al. Cancer Treat Rev 2013;39(6):592‐601. Examples of predictive biomarkers in oncology Tumour type Biomarker Breast cancer Hormone receptors HER‐2 overexpression Gastric cancer HER‐2 overexpression Drug SERMs, AI, Fulvestrant Trastuzumab, Pertuzumab, TDM1 Lapatinib Trastuzumab CML BCR/ABL fusion gene Imatinib GIST c‐KIT mutation Imatinib NSCLC EGFR mutation Gefitinib, erlotinib mCRC RAS mutation status Panitumumab, cetuximab Melanoma BRAF V600 Vemurafenib, Dabrafenib NSCLC ALK positive Crizotinib Endocrine Therapy of Breast Cancer 5FU was synthesized in 1957 Plataformas genómicas Oncotype Mammaprint PAM50 Oncotype DX® 21‐Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki‐67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 CD68 REFERENCE Beta‐actin GAPDH RPLPO GUS TFRC RS = + 0.47 x HER2 Group Score ‐ 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 ‐ 0.08 x GSTM1 ‐ 0.07 x BAG1 Category RS (0 ‐100) Low risk RS <18 Int risk RS 18 ‐ 30 High risk RS ≥ 31 Paik et al. N Engl J Med. 2004;351:2817‐2826. A signature consisting of 70 significant prognosis genes was identified Supervised classification prognosis Leave‐one‐out cross‐validation 78 tumours Good signature Threshold Poor signature Threshold set with 10% false negatives 91% sensitivity, 73% specificity van’t Veer LJ, et al. Nature 2002;415:530–6 Intrinsic Subtype Clinical Assay Development • The final classifier consists of 50 genes and 5 centroids (provided at https://genome.unc.edu/). • The CV classification accuracy of the 50 genes versus the 2000 genes was 93%. • The assay is called the “PAM50” Parker et al., JCO, February 9, 2009 Most published signatures are not significant better predictors than random signatures of identical size Venet D. BMC Bioinformatics 2011 TOTAL n= 946 ER-/HER2n= 189 HER2+ n= 129 ER+/HER2n= 628 A Model for Breast Cancer Development over Molecular Time International Cancer Genome Consortium. Cell 2012; 149: 994 Intratumoral Mutational Heterogeneity Gerlinger et al. NEJM 2012; 363:883 Conclusiones • La biología molecular ha identificado biomarcadores de enorme utilidad en la clínica. • El bloqueo de una diana no suele ser suficiente (la evolución es una ley de la naturaleza). • Una aproximación mas empírica (plataformas genéticas) también funciona. • Biológicamente las plataformas genéticas sugieren mas asociación que causación. • Para mejorar los resultados son necesarias estrategias alternativas: Identificar y bloquear la ¨driver mutation¨ (prevención?) Tratamientos multidiana Tratamientos intermitentes Estrategias no erradicativas
