San Filippo Neri Hospital- Rome

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1 Pharmacogenetics in Breast Cancer Giampietro Gasparini, MD San Filippo Neri Hospital- Rome

2 TUMOR PATIENT Few histotypes but more molecular diseases Pharmacogenomics DRUG Age and PS Comorbidities Compliance Ethnics Genetics Pharmacokinetics Pharmacodynamics Pharmacogenetics

3 MOLECULAR PORTRAIT OF BREAST CANCER Basal like HER2 Normal Luminal B Luminal A Above average 476 cdna clones Average Below average Not determined 85 arrays

4 .. Results Identification of 5 breast cancer subgroups with different prognosis Identification of nonresponder patients.but No predictive activity of absolute value (different outcome in selected responsive patients) No predictive determinants of toxicity?

5 Drugs Work Better for Some People Than for Others Factors influencing different response: Pharmacokinetics Environmental Genetics

6 Toward Personalized Therapy Tumor genetic profiling Pharmacogenetics Therapeutic drug monitoring Pharmacokinetics Predictive indicators Drug-to-drug interactions

7 Pharmacogenetics Pharmacogenetics may help in understanding some of the differences in therapeutic activity and toxicity of anticancer drugs Pharmacology Drugs Genome Genome

8 Interethnic Genetic Differences in Activity and Toxicity to Anticancer Drugs Polymorphisms : Structural modifications of DNA with a frequency 1%

repeats/microsatellites short (2bp) long (20-30 30opù) più) Genetic

9 90% SNPs Pharmacogenetics Study of Patient s Genetic Polymorphisms (Single nucleotide polymorphisms) 10% Insertions and deletions Tandem repeats/microsatellites short (2bp) long ( opù) più) Genetic duplications Pseudogenes Untrascripted esonic sequences with high homology with expressed genes

10 Are the Results of Clinical Trials Really Valid Worldwide? Ethnic-related incidence of tumors or toxicity Gastric cancer: Japanise vs Caucasian Gefinitib pulmonary toxicity: Japanise vs Caucasian Ethnic-related frequency of SNPs Tamoxifen Taxanes Careful interpretation of clinical results in a single ethnic population Can we change the paradigm of clinical trials by using pharmacogenetics?

11 The New Proposed Paradigm for Clinical Trials Perform the trial in different ethnic populations Make the optimal biological characterization of each single tumor + Pharmacogenetics Variability to drug activity/toxicity Tailored therapy

12 Pharmacogenetics (Haplotype and Genotype) Transport (MDR1, MRP2, RFC, ) Metabolism phase I (CYP) phase II (UGT, GST, ) Target (EGFR, VEGFR, TS,) Metabolite Drug Metabolite Drug Target

Pharmacogenetic and Pharmacogenomic Diagnostic Biomarkers (approved by FDA) TOXICITY UGT1A1*28 (irinotecan) [Invader Assay] TPMT (6-MP, azatioprine) [pro-predict Py] CYP2C9 (warfarin) [Amplichip]

13 Pharmacogenetic and Pharmacogenomic Diagnostic Biomarkers (approved by FDA) TOXICITY UGT1A1*28 (irinotecan) [Invader Assay] TPMT (6-MP, azatioprine) [pro-predict Py] CYP2C9 (warfarin) [Amplichip] CYP2D6 (atomoxetina) [Amplichip] EFFICACY/RESISTANCE CYP2D6 (tamoxifen) [ AmpliChipCYP450Test ] Expression levels of Her2/neu (trastuzumab) Mutations of K-RAS (cetuximab, panitumumab ) Chromosome Philadelphia/ Bcr-abl (imatinib) C-kit (imatinib) Not approved EGFR mutations (gefitinib, erlotinib)

14 Tamoxifen: The Key-Pharmacogenetic Step CYPs-cytochrome P450 metabolism

15 CH3 Tamoxifen Biotransformation CH3 CH2 c c OCH2CH2N CYP3A4 CYP3A4 CYP2B6 CYP3A5 Tamoxifen CYP2C9 OCH2CH2N CYP2D6 CYP2C9 CYP2C19 CYP1A2 CH3 H CYP2D6 CH3 CH3 CYP2C19 c c CH3 CH2 CH2 N-desmethyltamoxifen CYP2B6 CYP2C9 CYP2C19 c c OCH2CH2N OH 4-hydroxytamoxifen CYP3A4 CH3 OCH2CH2N CYP2D6 H 5-10 nm (average ~7 nm) CH3 CH3 CH3 CH2 c c 4-hydroxy-N-desmethyltamoxifen y des e y o e (Endoxifen) nm (average ~ 90 nm) Borges S, et al. Clin Pharmacol Ther. 2006;80: OH

16 Tamoxifen and Polymorphisms Polymorphic genetic variations of tamoxifen-metabolizing t i enzymes ( Concomitant administration of CYP2D6 inhibitors may affect tamoxifen-related clinical outcomes CYP3A4 promoter variant also involved in tamoxifen metabolism Polymorphism of the SULT1A1 gene (SULT1A*2 variant) ER genotypes (ESR-XbaI I and ESR2-02) may be associated with tam-associated lipid changes and may contribute to interindividual variability to tamoxifen benefits

17 Tamoxifen Polymorphisms POLYMORPHISM Ethnical Clinical CLASSES CYPs Frequency Implication Poor CYP2D6: metabolizer *3, * 4, * 5, * 6 CAUCASIANS (RARE IN ASIANS AND BLACK AFRICANS) Nonfunctional variants worse DFS (Goetz MP, Schroth W) Worse PFS (Schroth W) Intermediate metabolizer CYP2D6 * 10, *17, * 41 ASIANS (RARE IN EUROPEAN CAUCASIANS) Worse recurrence, decreased RFS, worse PFS (in adyuvant setting) (Schroth W) Extensive metabolizer CYP2D6 * 2xn CAUCASIANS Favorable RFS, to be confirmed

18 Endoxifen, But Not 4-hydroxytamoxifen, y Degrades The Estrogen Receptor In Breast Cancer Cells: A Differential Mechanism Of Action Potentially Explaining CYP2D6 SABCS 2008 John R. Hawse, Xianglin Wu, Malayannan Subramaniam, Matthew P. Goetz, Thomas C. Spelsberg, James N. Ingle Hawse JR, et al. Cancer Res. 2009;69(Suppl 2): Abstract 19. Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 57.

19 Relapse-Free Time According to CYP2D6 Metabolizer Status (n=108) (n=65) (n=16) HR 4.0 PM relative to EM Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 6037.

20 Pharmacogenetic (CYP2D6) And Gene Expression Profiles (HOXB13/IL17BR And Molecular Grade Index) For Prediction Of Adjuvant Endocrine Therapy Benefit In The ABCSG 8 Trial SABCS 2008 MP Goetz, M Ames, M Gnant, M Filipits, H Heinzl, R Jakesz, RG Greil, CMarth, HSamonigg, VS Suman, SS Safgren, M Kuffel, R Weinshilboum, M Erlander, X Ma, J Ingle

21 ABCSG Trial 8 Structure Switch point R an Tamoxifen Tamoxifen (2 years) (3 years) Primary surgery d o m i z Tamoxifen Anastrozole e (2 years) (3 years) Primary endpoint: event-free survival Switching period Sequencing period Jakesz R, et al. Lancet. 2005;366(9484):

22 Relapse-Free Time According to CYP2D6 in Women Receiving Adjuvant Tamoxifen Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 6037.

23 CYP2D6 and Risk of Breast Events ARM A: TAM for 5 Years (n = 67) Relative Risk to EM P Value CYP2D6 PM 383( ( ) CYP2D6 IM 0.87 ( ).689 ARM B: TAM to Anastrozole (n = 55) CYP2D6 PM 1.02 ( ).985 CYP2D6 IM 0.81 ( ).538

24 Adjuvant Tamoxifen and CYP2D6 CYP2D6 associated with recurrence Goetz et al. 2005, (USA) Hawse et al (AUSTRIA) Schroth et al (Germany) Kiyotani et al (Japan) Newman et al (UK) Xu et al (China) CYP2D6 not associated with recurrence Wegman et al. 2005, (Sweden) 1 Goetz MP et al J Clin Oncol 2005;23(36): Goetz MP et al Cancer Res 2009;69(Suppl 2): Abstract 1. Goetz MP, et al. J Clin Oncol 2005;23(36): Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract Hawse JR, et al. Cancer Res. 2009;69(Suppl 2): Abstract Schroth W, et al. J Clin Oncol. 2007;25(33): Kiyotani K, et al. Cancer Sci. 2008;99(5): Newman WG, et al. Clin Cancer Res. 2008;14(18): Xu Y, et al. Ann Oncol. 2008;19(8): Wegman P, et al. Breast Cancer Res. 2005;7(3):R284-R Wegman P, et al. Breast Cancer Res. 2007;9(1):R7.

25 Aromatase Inhibitors: The Key- Pharmacogenetic acoge et c Step CYPs-cytochrome P450 enzyme aromatase by CYP 19A1 or aromatase atase geneses

26 POLYMORPHISMS ENVOLVED IN EXEMESTANE ACTIVITY CYP3A4*1B CYP3A5*3 3 exemestane CYP19A1gene exemestane CYP19 Ex G>T (TTTA)n repeats Ex C>T Ex7+47C>T RIZ1 Delezione Pro704 ER1 497 C>T 256 A>G (TA)n repeats ER G>A 1730A>G (CA)n repeats CYP17 Ex1+27T>C (5 UTR) CYP1B1*3 COMT Ex4-12G>A UGT1A1*28

27 AIs Polymorphysms > 80 CYP 19 polymorphysms o p ys s resulting in 44 haplotypes from each of the 4 ethnic groups have been identified. Arg 39 variant OF CYP19A1: Present in 6.7% Han Chinese American (rare in other ethnic groups); Cys 264 variant OF CYP19A1: Higher frequencies in Han Chinese Americans and African Americans (11.7%- 22.5%) than Caucasian or Mexican Americans (2.5%- 5%) CYP19A1 3 -untranslated region variant: Associated to higher RR and TTP in postmenopausal ER+ metastatic disease treated with letrozole

28 ROLE OF THE CYP19 Ex11+410G>T AND OTHER GENETIC POLYMORPHISMS ON RESPONSE TO EXEMESTANE AS FIRST LINE TREATMENT IN PATIENTS WITH METASTATIC BREAST CARCINOMA Giuseppe Toffoli, MD, Director Pharmacology CRO Aviano Giampietro Gasparini, Study Coordinator CIPOMO

29 STUDY DESIGN Patients enrollment and treatment 394 patients will be enrolled for pharmacogenetic analysis. In 100 patients will be done also PK analysis Th t 25 / /d At l t 8 Therapy: exemestane 25 mg/po/day. At least 8 weeks on therapy are required for evaluation.

30 Taxanes: The Key-Pharmacogenetic Step Metabolism (CYP3A4, CYP3A5) Transport-efflux (ABCB1) gene polymorphisms

31 Taxanes Docetaxel is metabolized by CYP3A4/5,while paclitaxel by CYP2C8/CYP3A4 There is controversy whether polymorphisms in the ABCB1 gene, encoding P-glycoprotein, correlate to efficacy of taxanes In a prospective study with paclitaxel in metastatic breast cancer the genotype ABCB GG showed a significant correlation with resistance 1 In a retrospective analysis of the CALCB 9871 study (109 patients) no difference was found between Caucasian and African-American patients in terms of docetaxel toxicity regarding polymorphisms CYP3A4, CYP3A5, and ABCB Chang H, et al. Ann Oncol. 2008;20(2): Lewis LD, et al. Clin Cancer Res. 2007;13(11):

32 Taxanes Interethnic differences in docetaxel PK and toxicities exist between south-east populations (Chinese vs Indian vs Malays) 1 CYP3A4*1B is a promoter polymorphism with different ethnic incidences: 45% in African-American, 2-9% in Caucasian; rare in Asian 2 Caucasian patients harboring both CYP3A4*1B +/- CYP3A5*1 alleles have higher docetaxel clearance 3,4 ( In Caucasian patients treated with docetaxel, the polymorphism C1236T in the ABCB1 gene was significantly related to decreased clearance (-25%) 5 Docetaxel-induced d neuropathy, hematological l toxicities, iti and OS are linked to ABCB1 allelic variants 6 1 H SY t l Ph i J (2) St d H t l Ph i (7) Hor SY, et al. Pharmacogenomics J. 2008;8(2): Steed H, et al. Pharmacogenomics. 2008;8(7): Baker SD, et al. Clin Pharmacol Ther. 2009;85(2): Tran A, et al. Clin Pharmacol Ther. 2006;79(6): Bosch TM, et al. Clin Cancer Res. 2006;12(19): Sissung TM, et al. Clin Cancer Res. 2008;14(14):

33 Bevacizumab: The Key- Pharmacogenetic Step VEGF as the Therapeutic Target

34 Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100 Bryan P. Schneider, Molin Wang, Milan Radovich, George W. Sledge, Sunil Badve, Ann Thor, David A. Flockhart, Bradley Hancock, Nancy Davidson, Julie Gralow, Maura Dickler, Edith A. Perez, Melody Cobleigh, Tamara Shenkier, Susan Edgerton, Kathy D. Miller Schneider BP, et al. J Clin Oncol. 2008;26(28):

35 Kaplan-Meier Curve for Overall Survival (OS) in Experimental Arm by Genotype; (A) Vascular Endothelial Growth Factor (VEGF)-2578 C/A; (B) VEGF-1154 G/A The VEGF-2578 AA genotype and the VEGF-1154 AA genotype predicted a favorable median OS for patients in the combination arm but did not predict an improved median OS for patients in the control arm and did not predict a superior PFS or RR for either arm. There was a significant incremental benefit from each addition of the VEGF-1154 A allele. Schneider BP, et al. J Clin Oncol. 2008;26(28):

36 RESULTS Patients with VEGF-2578 AA and VEGF-1154 AA genotype have a superior OS compared with patients with alternative genotypes The allele frequency of VEGF-2578 AA and VEGF-1154 AA in white population is frequent and ranges from 33% to 49% The VEGF-634 CC and VEGF-1498 TT genotypes correlated with less grade 3 or 4 hypertension (0% and 8%, respectively) as compared to the combined alternate genotypes (P =.005 and P =.022, respectively) Patients with grade 3 or 4 hypertension have a superior OS as compared to pts with no hypertension (38.7 months vs 25.3 months, respectively; P =.002) Schneider BP, et al. J Clin Oncol. 2008;26(28):

37 CRITICISMS The combination of paclitaxel/bevacizumab showed prolonged PFS (11.8 months vs 5.9 months) and RR (36.9% vs 21.2%) 2%) as compared to paclitaxel alone (E2100 Study), but. No significant difference was observed on OS (26.7 months vs 25.2 months; P=.16) The grade 3/4 toxicity was higher in the experimental arm (hypertension: 14.8% vs 0%; proteinuria: 3.6% vs 0%; cerebrovascular ischemia. 1.9% vs 0%) The RR and PFS observed in the control arm are worse than that usually observed in first-line therapy: Why? Retrospective analysis of pharmacogenetics on tumor specimens and not as usually performed on blood samples Schneider BP, et al. J Clin Oncol. 2008;26(28):

38 TAKE HOME MESSAGE The results on pharmacogenetic studies are promising but mainly obtained in retrospective analysis Pharmacogenetic studies emphasize the relevance of ethnical diversities It is reasonable to hypothesize that pharmacogenetic analysis coupled with molecular characterization of each single tumor may lead to improved personalized therapy Data need to be validated d in prospective clinical i l ti trials

PHARMACOGENETICS OF BREAST CANCER

PHARMACOGENETICS OF BREAST CANCER MALGORZATA JAREMKO, PhD Mount Sinai School of Medicine, Department of Genetics and Genomic Sciences Outlines Breast cancer therapeutic situation Pharmacogenetics of antiestrogen