Pharmacogenomic Approaches. Luis Paz-Ares Hospital Universitario Virgen del Rocio Seville, Spain

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1 Pharmacogenomic Approaches Luis Paz-Ares Hospital Universitario Virgen del Rocio Seville, Spain

2 Pharmacogenetics & Pharmacogenomics Medicine tailored to the individual Genetic information, including the sequence of the human genome, is allowing for a more systematic understanding of the relationship of genetic variations to drug efficacy. The Study of how genetic differences influence variability in patients responses to drugs. Personalized drugs.

3 Pharmacogenetics & Pharmacogenomics Medicine tailored to the individual So, we need to know target PK determinants Where to look tumor individual (blood!) What to analyze DNA, RNA, Proteins, biochemical activity Single or complex biomarkers Biomarkers of Genetic variability

4 Predictive Tumor Markers for NSCLC Treatment Gene Abnormality Drug Response p53 Mutation Multiple K-ras Mutation Platinum β tubulin Increased Isotype 3 Taxanes RRM1 Increased Expression Gemcitabine ERCC 1 Increased Expression Platinum BRCA1 Increased Expression Platinum TS Increased Expression Antifolates ALK fusion genes Present ALK inh EGFR mutation Present EGFR TKIs

5 Some Examples Chemotherapy DNA repair genes (ERCC1, RRM1, BRCA1) Folate Path (TS, MTAP, ) Targeted therapy EGFR ALK

6 Some Examples Chemotherapy DNA repair genes (ERCC1, RRM1, BRCA1) Folate Path (TS, MTAP, ) Targeted therapy EGFR ALK

7 ERCC1 in Platinum-based Treatments ERCC1 is part of the DNA repair system NER Increased ERCC1 levels: better DNA repair (better prognosis!!) Low EECR1 levels: Poor DNA repair eficiency (platinum treatments more efficcacious)

8 ERCC1 in NSCLC Resected NSCLC Stage IV gem/cis P=0.01 P=0.03 Bepler et al. Chest 2005 Lord et al. CCR 2002 Prognosis and predicting survival according to ERCC1 levels (terciles) Low levels gem/cis Etoposide a better partner than gemcitabine

9 GILT Trial: ERCC1-customized chemotherapy in advanced NSCLC R A N D O M I Z E 1:2 Control arm docetaxel / cisplatin Experimental arm ERCC1 levels GENOTYPE B1 docetaxel / cisplatin (low ERCC1 mrna) GENOTYPE B2 docetaxel / gemcitabine (high ERCC1 mrna) Cobo et al. J Clin Oncol, 2007

10 GILT Trial: ERCC1-customized chemotherapy in advanced NSCLC Cobo et al. J Clin Oncol, 2007

11 BRCA1: a determinant of cisplatin response Increased BRCA1 in MCF-7 & SKOV-3 cisplatin-resistant cell lines (Husain et al. Cancer Res 1998) Predictive power of ERCC1 ~ XPD < RRM1 < BRCA1 in gem/cis (Rosell et al. Oncogene 2003, CCR 2004, CCR 2004; Taron et al. Hum Molec Gen 2004) Beljanski, Marzilli, Doetsch. Mol Pharmacol 2004

12 Restoring BRCA1 confers paclitaxel & vinorelbine sensitivity in BRCA1 mutant HCC1937 cell line paclitaxel vinorelbine % Control H C C B R H C C E V % Control H C C B R H C C E V M o l a r i t y o f T a x o l M o la r it y o f V in o r e lb i n e HCCBR116: IC 50 = 7.73 x 10 9 M HCCEV1: IC 50 = 6.21 x 10 6 M HCCBR116: IC 70 = 1.9 x 10 9 M HCCEV1: IC 70 = 1.7 x 10 5 M Kennedy et al, ASCO 2003 Quinn et al. Cancer Res 2003

13 Spanish Customized Adjuvant Therapy (SCAT( SCAT) ) and BRCA1 Expression Customization (BREC( BREC) CONTROL Docetaxel/Cis SCAT: Resected II-IIIA BREC: IV EXPERIMENTAL Q 1 BRCA1 Q 2 & 3 BRCA1 Gem/Cis Docetaxel/Cis Q 4 BRCA1 Docetaxel

14 Customized Treatment in NSCLC Based on EGFR Mutation and BRCA1 mrna Expression All Patients (n=123) EGFR Group (n=12) Low BRCA1 Group (n=38) Intermediat e BRCA1 Group (n=40) High BRCA1 Group (n=33) Outcome % % % % % Complete response Partial response Stable disease Progressive disease Not be determined Overall response rate Intent to treat Survival Median, mo 12 mo NR (>28 11 mo 9 mo 11 mo mo) 1-year year months Rosell R. et al. PLOS One 2009

15 Cis/Pem vs Cis/Gem in First-line NSCLC Scagliotti GV et al, J Clin Oncol 2008

16 Thymidilate Synthase Expression in Normal Lung Tissue & Lung Cancer (N=56) Snap Frozen Tissues FFPE Tissues TS mrna levels Significantly Higher in Lung Cancer than in normal lung tissue Significantly Higher in Squamous Cell Carcinoma of the Lung Ceppi P et al., Cancer 2006

17 ITACA Adjuvant Trial Taxanes ERCC1 High TS High Low High Profile 4 Profile 3 Profile 2 Control Pem Control Cis/Gem Low TS Control Cis/Pem Low Profile 1 Control Control = Investigators choice; Primary end-point =overall survival; Sample size =700 patients

18 Prognostic and predictive value confirmed in IPASS 1.0 Probability of PFS Gefitinib EGFR M+ (n=132) Gefitinib EGFR M (n=91) CP EGFR M+ (n=129) CP EGFR M (n=85) Time from randomisation (months) Mok, et al. ESMO 2008

19 SLCG Phase III Trial in EGFR-mutated NSCLC EURTAC/GECP 06/01 Eligibility: No prior Rx Stage IIIB or IV Mutated EGFR ECOG PS 0-20 R A N D O M I Z E Erlotinib 150 mg/day PO Platinum-based Chemo Cross- over at PD PIs: L Paz-Ares & R Rosell