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Current status of biomarker research in NSCLC

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Current status of biomarker research in NSCLC

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    1. Current status of biomarker research in NSCLC Tony Mok The Chinese University of Hong Kong, Hong Kong

    4. EGR-1 and PTEN Early Growth Response gene 1 (EGR-1) is linked to tumour suppression via the PTEN pathway 125 cases of resected NSCLC RNA extraction and EGR-1 expression quantified by real-time PCR

    5. Low EGR-1 is a prognostic marker of poor survival outcome in resected NSCLC

    6. Metagene model in stage IA NSCLC Gene expression profile in 89 patients with early stage NSCLC Dukes’ Lung Metagene Model Microarray assays by Affymetrix GeneChips (U133Plus2) Validation in two cohorts of patients from two clinical trials Accuracy in prediction of recurrence: 72% and 79%

    7. Patient selection for adjuvant chemotherapy

    8. RRM1 and ERCC1 Ribonucleotide reductase M1 (RRM1) is a key enzyme in DNA synthesis low level expression of RRM1 is associated with poor survival Excision Repair Cross-Complementing Group 1 (ERCC1) plays a key role in the repair of damaged DNA high ERCC1 expression is associated with cisplatin resistance

    9. Automated quantitative assessment of RRM1 and ERCC1 Tissue microarray of 187 resected stage I NSCLC Immunofluorescence combined with automated quantitative analysis (AQUA) Also measure PTEN and cytokeratin

    10. RRM1 as a prognostic marker

    11. RRM1 and ERCC1 as prognostic markers

    13. ERCC1 as a predictor of response

    14. Response according to ERCC1 levels

    15. IALT study: adjuvant chemotherapy

    16. Test of interaction between ERCC1 and treatment: p<0.009 For ERCC1 –ve tumours 14-month benefit in overall survival for CT vs control 6-month benefit in overall survival for CT vs ERCC1 +ve tumours

    17. Prediction of survival by ERCC1, RRM1 or EGFR expression

    18. Biomarkers for chemotherapy: summary High RRM1 and ERCC1 expression is associated with longer survival after resection of early stage NSCLC (prognostic) High RRM1 and ERCC1 are predictors of lower tumour response rate and shorter survival for treatment with gemcitabine and cisplatin (predictive) Low ERCC1 expression is associated with survival benefit from adjuvant chemotherapy for NSCLC (predictive) These biomarkers have not been prospectively validated

    20. Potential biomarkers for EGFR TKIs

    21. EGFR TK mutations Three major types of mutation missense mutation in exons 18 and 21 G719A (4%) L858R (38%) deletions in exon 19 E746–A750 (45%)

    22. Refs. Zhang XT, et al. Ann Oncol 2005;16:1334-42 Shih JY, et al. Int J Cancer 2006;118:963-9 Mitsudomi T, et al. J Clin Oncol 2005;23:2513-20 Han SW, et al. J Clin Oncol 2005;23:2493-501 Takano T, et al. J Clin Oncol 2005;23:6829-37 Tokumo M, et al. Clin Cancer Res 2005;11:1167-73Refs. Zhang XT, et al. Ann Oncol 2005;16:1334-42 Shih JY, et al. Int J Cancer 2006;118:963-9 Mitsudomi T, et al. J Clin Oncol 2005;23:2513-20 Han SW, et al. J Clin Oncol 2005;23:2493-501 Takano T, et al. J Clin Oncol 2005;23:6829-37 Tokumo M, et al. Clin Cancer Res 2005;11:1167-73

    23. First-line EGFR TKIs in unselected Caucasian patients with advanced NSCLC

    24. First-line EGFR TKIs in selected Caucasian patients

    25. First-line gefitinib in selected Asian patients (EGFR TK mutations)

    26. Survival according to EGFR mutation status: BR.21

    27. Why? Lack of survival benefit in EGFR mutation-positive patients in BR.21 is probably due to the small sample size (10 vs 14 patients) Other hypothetical factors mutation type and presence of T790M mutation mutations in related genes ethnicity/polymorphisms gene expression levels

    28. EGFR gene copy number by FISH: BR.21

    29. Survival according to EGFR gene copy number: BR.21

    30. Survival according to EGFR protein expression (IHC): BR.21

    31. My simple view

    33. Selecting patients for adjuvant therapy by biomarker: RADIANT Primary endpoint = disease-free survival (all patients, EGFR IHC +ve and/or EGFR FISH +ve) Co-primary = disease-free survival in FISH +ve (USA); to be determined from the outcome of SATURN for Europe Planned n=945

    34. Marker identification trial (MERIT) Primary endpoint: differentially expressed genes (prediction of clinical benefit) Secondary endpoints: EGFR mutation analysis, molecular (explorative) assessment of putative alterations of downstream targets of EGFR

    35. SATURN: Sequential Tarceva in unresectable NSCLC Primary endpoint: PFS (25% increase in all and 30% increase in EGFR IHC +ve) Secondary endpoints: OS, PFS (EGFR –ve, TTP, safety)

    36. Biomarkers for EGFR TKIs: summary EGFR mutation seems to be a powerful predictor of tumour response to EGFR TKIs not established as a predictive marker (small sample size in BR.21) EGFR gene copy number (FISH) and EGFR protein expression (IHC) may be predictors of survival Prospective validation of these markers, as well as the assays, is required before they can be used in routine clinical practice this is being performed in the Roche-led SATURN and RADIANT studies of Tarceva

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