Biology of Cancer. Pharmakogenetics.. Expression Signatures.. Mutated Genes.. Micro-RNAs Epigenetics..Methylation.. Technology

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3 Biology of Cancer Pharmacology Histology Grade Technology Molecular Biology Pharmakogenetics.. Expression Signatures.. Mutated Genes.. Micro-RNAs Epigenetics..Methylation.. Technology

4 Erlotinib Gefitinib Cetuximab EGFR, HER2 Cell membrane EGFR-TK pathways Proliferation Akt PI3K Invasion ATP EGFR-TK P STAT Gene transcription cell-cycle progression Nucleus Angiogenesis GeneKor SA ATP SOS GRB2 MAPK RAS MEK RAF Metastasis Resistance to apoptosis

5 Prognostic Provides information on outcome, regardless of which treatment is used Predictive Provides information on outcome with regards to a specific therapy Many biomarkers have both predictive and prognostic value Controlled studies or meta-analyses are required to determine the prognostic and predictive contributions made by a particular marker GeneKor SA

6 We#are#con)nually#discovering#more#driver# muta)ons# #more#poten)al#targets Lung Adenocarcinoma Pao#and#Hutchinson,#Nature#Medicine#2012.#18:349D351# 6

7 NSCLC και EGFR IPASS TRIAL Σωµατικές µεταλλάξεις στην περιοχή κινάσης τυροσίνης του υποδοχέα του επιδερµικού αυξητικού παράγοντα (EGFR) βελτιωµένη ανταπόκριση σε θεραπεία µε Iressa (Gefitinib) και επιβίωση Έλεγχος EGFR µεταλλαγών στην κλινική πράξη Συχνότητα µεταλλαγών εθνο-εξαρτώµενη: ~30% σε Ασιάτες και ~15% στους Καυκάσιους PFS HR 2.85 HR 0.48 Gefitinib EGFR M+ (n=132) Gefitinib EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) EGFR M+ HR=0.48, 95% CI 0.36, 0.64 p< EGFR M- HR=2.85, 95% CI 2.05, 3.98 p< Time from randomisation (months) Mok et al., Gefitinib or Carboplatin Paclitaxel in Pulmonary Adenocarcinoma, The New England Journal of Medicine 2009; 361

8 ASCO 2010

9 k-ras constitutively activating somatic mutations of the RAS-RAF-MAPK pathway mediate resistance to upstream targeting Update: N o =1414, 213 (15.06%) KRAS RR = 6/213 (2.81%) WT RR = 323/1201 (26.09%) Linardou H, et al. Lancet Oncology 2008; 9:962-72

10 Notable(advances:(Study#uncovers#the#first#promising# targeted#therapy#for#a#common#subtype#of#nsclc## altera)ons#in#the#kras%gene(are#the#most#common# molecular#markers#in#nsclc#(20d30%#of#pa)ents)# no#effec)ve#targeted#therapies#for#this#subset#of# pa)ents#with#nsclc# phase#ii#trial#:#selume3nib,(which(blocks(mek,#a#key# protein#in#the#kras#signaling#pathway,#is#being# explored#in#clinical#trials#for#the#treatment#of#various# types#of#cancer#harboring#kras%muta)ons## Janne%PA,%et%al.%J%Clin%Oncol%30:480s,%2012%(suppl;%abstr%7503)%

11 Results( selume3nib#plus#standard#docetaxel#chemotherapy# (44#pa)ents)#vs#placebo#plus#docetaxel#(43#pa)ents)# as#2 nd #Dline#treatment#for#advanced#NSCLC# Overall#survival#was#substan)ally#longer#in#the# selume)nib#arm#compared#with#the#placebo#arm#(9.4# v%5.2#months),#as#was#the#)me#to#disease# progression#(5.3#v%2.1#months).# This%is%the%first%prospecIve%study%showing%a%clinical% benefit%from%targeted%therapy%for%paients%with%any% type%of%kraspmutated%cancer.%the#findings#of#this# study#may#influence#standard#treatment#of#not#only# NSCLC#but#also#all#other#cancers#with#KRAS%

12 NSCLC Stage IIIb or IV and PS 0-2 EML4-ALK positive EFGR mutation positive EML4-ALK and EFGR mutation negative and nonsquamous histology EML4-ALK and EFGR mutation negative and squamous cell histology Bevacizumab eligible Bevacizumab ineligible Consider crizotinib Consider erlotinib or gefitinib Consider carboplatin/ paclitaxel + bevacizumab or cisplatin or carboplatin combined with pemetrexed or docetaxel or gemcitabine or paclitaxel Consider cisplatin/vinorelbine ± cetuximab or cisplatin or carboplatin combined with pemetrexed, docetaxel, or gemcitabine or paclitaxel Consider cisplatin/vinorelbine ± cetuximab or cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:

13 BATTLE: Phase II NSCLC Biomarker Study Umbrella protocol Core biopsy EGFR KRAS/BRAF VEGF RXR/CyclinD1 Biomarker profile Randomization: Equal Adaptive Erlotinib Equal (n = 25) Adaptive (n = 33) Vandetanib Equal (n = 23) Adaptive (n = 29) Erlotinib + Bexarotene Equal (n = 21) Adaptive (n = 15) Primary endpoint: 8-wk disease control rate; 30% assumed Kim ES, et al. AACR Abstract LBA1. Reprinted with permission. Sorafenib Equal (n = 26) Adaptive (n = 72)

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15 NGS data indicates that ~70% NSCLC have driver mutations

16 Analysis IHC Typically 18 druggable or resistant protein targets Total of 28 IHCs use depends on tumor type and progression Microarray Looking at the over or under expression of the full genome of 24K gene targets, but summarizing 80 druggable or resistant targets FISH Identifying gene copy number alterations in tumor tissue (HER2, EGFR, c-myc, TOP2A, EML4-ALK in validation) Mutational Analysis Identifying gene mutations in tumor tissue (KRAS, BRAF, EGFR, c-kit, PIK3CA) Evidence Engine 16 Output Unique molecular blueprint of patient tumor Genes Over / Underexpression Quantitative protein expression Mutations Gene copy number aberrations Literature-based prioritized ranking of druggable targets in tumor and their associated therapies Information on therapies that might not otherwise have been considered based on the lineage of the tumor 2010 Caris Life Sciences, Inc. All rights reserved.

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18 Gene Kor S.A. comm itted to biotec hnolo gical innov ation

19 Subtype(1( harbors#aberra)ons#in#the#egfr#gene/pathway# #a#set#of# targetable#muta)ons#with#commercially#available#inhibitors#as# well#as#newer#agents#on#the#horizon.# West L, Vidwans SJ, Campbell NP, Shrager J, et al. (2012) A Novel Classification of Lung Cancer into Molecular Subtypes. PLoS ONE 7(2): e doi: /journal.pone

20 Target therapy EGFR EML4-ALK translocation ROS1 Translocation K-ras Chemotherapy??? ERCC1 RRM1 BRCA1 TS??

21 GeneKor SA

22 Bepler G., ASCO 2008 GeneKor SA

23 ERCC1 Χαµηλά επίπεδα έκφρασης Υψηλά επίπεδα έκφρασης RRM1 Χαµηλά επίπεδα έκφρασης RRM1 Υψηλά επίπεδα έκφρασης RRM1 Χαµηλά επίπεδα έκφρασης RRM1 Υψηλά επίπεδα έκφρασης Gemcitabine / Cisplatin BRCA1 Υψηλά επίπεδα έκφρασης BRCA1 Χαµηλά επίπεδα έκφρασης BRCA1 Υψηλά επίπεδα έκφρασης BRCA1 Χαµηλά επίπεδα έκφρασης BRCA1 Υψηλά επίπεδα έκφρασης BRCA1 Χαµηλά επίπεδα έκφρασης Taxanes / Pemetrexed Pemetrexed / Cisplatin Taxanes / Gemcitabine Pemetrexed / Gemcitabine Docetaxel Docetaxel / Pemetrexed GeneKor SA

24 RRM1(expression( High# CT#without#Gemcitabine# Low# Ct#with#Gemcitabine# ERCC1(expression( ERCC1(expression(( High# Low# High# Low# Docetaxel( Docetaxel( Gemcitabine( Gemcitabine( &( &(( &( &( Navelbine( Carbopal3n( Docetaxel( Carbopla3n( ( Bepler%et%al,%JCO:%2741P46,%2007%

25 Retrospective data and preliminary prospective trials suggest that the administration of chemotherapy based on molecular analysis of the primary tumor is a reasonable approach and must be tested further. Treatment decisions should, most likely, be based on multimarkers analysis, rather than in one single gene expression Prospective randomized trials are urgently required to test the value of pharmacogenomic approaches in the daily clinical practice.

26 Pathologist: Selects appropriate tissue block Representative block containing a high number of tumour cells Selects and marks tumour cells Area should contain >30% tumour cells DNA extracted from tumour cells only.

27 Material: Fixed Paraffin Embedded Tissue Back-To-The-Future! GeneKor SA

28 Quality Assurance GeneKor SA

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30 To Conclude.. GeneKor SA

31 Επιστηµονικός Διευθυντής: Γεώργιος Νασιούλας Επιστηµονική οµάδα Άντζελα Απέσσου Ειρήνη Παπαδοπούλου Μάχη Σαρηγιάννη Samuel Murray Μπέσυ Μαριάτου-Μετξά Τµήµα επιστηµονικής ενηµέρωσης Νικόλαος Τσούλος Βασιλική Φλώρου Δηµήτρης Λαχανάς Χρυσάνθη Βιολάκη Εξυπηρέτηση πελατών Άννα Κοκοτάκη Κων/να Τσιοδούλου Θανάσης Υφαντής