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Pharmacogenetics in Breast Cancer...RG il CM th HS i VS SS fR Greil, C Marth, H Samonigg, V Suman, S...
Transcript of Pharmacogenetics in Breast Cancer...RG il CM th HS i VS SS fR Greil, C Marth, H Samonigg, V Suman, S...
PharmacogeneticsPharmacogenetics in Breast in Breast PharmacogeneticsPharmacogenetics in Breast in Breast CancerCancer
Giampietro Gasparini, MDGiampietro Gasparini, MDSan Filippo Neri Hospital- Rome
TUMOR PATIENT
Few histotypes • Age and PSFew histotypesbut
more molecular
• Age and PS
• Comorbidities
• Compliancediseases
Pharmacogenomics
• Ethnics
• GeneticsDRUG
gPharmacokinetics Pharmacodynamics
Pharmacogeneticsg
MOLECULAR PORTRAIT OF BREAST CANCERHER2HER2 NormalNormal Luminal BLuminal B
Basal likeBasal likeHER2HER2 NormalNormal Luminal BLuminal B
Luminal ALuminal A
Above average
Average
Below average
Not determined
476 cDNA clones
85 arrays
R lt….. ResultsIdentification of 5 breast cancer subgroups with different prognosisIdentification of nonresponder patientsIdentification of nonresponder patients
….but
No predictive activity of absolute value (different outcome in selected “responsive” patients)
No predictive determinants of toxicity
??
Drugs Work Better for Some People Drugs Work Better for Some People Than for OthersThan for Others
Factors influencingdifferent response:different response:
Pharmacokinetics
Environmental
Genetics
Toward Personalized Therapy
• Tumor genetic profiling
• Pharmacogenetics
• Therapeutic drug monitoring• Therapeutic drug monitoring
PharmacokineticsPredictive indicatorsDrug-to-drug interactions
Pharmacogenetics
Pharmacogenetics may help in understanding some of the differences in therapeutic activity and
toxicity of anticancer drugs
Pharmacology GenomeDrugsDrugs
GenomeGenome
Interethnic Genetic Differences in Activity and Toxicity to Anticancer Drugs
Polymorphisms : Structural modifications of DNA with a frequency ≥ 1%DNA with a frequency ≥ 1%
Pharmacogenetics Study of Patient’s Genetic Polymorphisms
90% SNPs (Single nucleotide polymorphisms)
10%Insertions and deletionsTandem repeats/microsatellites
short (2bp)long (20-30 o più)o g ( 0 30 o p ù)
Genetic duplicationsPseudogenes
Untrascripted esonic sequences with high homology withUntrascripted esonic sequences with high homology with expressed genes
Are the Results of Clinical Trials Really Valid Worldwide?
• Ethnic-related incidence of tumors or toxicityGastric cancer: Japanise vs CaucasianGefinitib pulmonary toxicity: Japanise vsGefinitib pulmonary toxicity: Japanise vs Caucasian
• Ethnic-related frequency of SNPsq yTamoxifenTaxanes
Careful interpretation of Can we change the clinical results in a single
ethnic populationparadigm of clinical trials by
using pharmacogenetics?
The New Proposed Paradigm for Clinical TrialsThe New Proposed Paradigm for Clinical Trials
Perform the trial in different ethnic populations
Make the optimal biological characterization of eachMake the optimal biological characterization of each single tumor
++Pharmacogenetics
Variability to drug activity/toxicity
Tailored therapy
PharmacogeneticsPharmacogenetics(Haplotype and Genotype)
Transport (MDR1, MRP2, RFC,…)Metabolism → phase I (CYP)
→ phase II (UGT, GST,…)Target (EGFR, VEGFR, TS,) DrugDrug
Metabolite
Metabolite Drug
Target
TOXICITY
Pharmacogenetic and Pharmacogenomic Diagnostic Biomarkers (approved by FDA)
TOXICITYUGT1A1*28 (irinotecan) [Invader Assay]
TPMT (6-MP, azatioprine) [pro-Predict Py]
CYP2C9 ( f i ) [A li hi ]CYP2C9 (warfarin) [Amplichip]
CYP2D6 (atomoxetina) [Amplichip]
EFFICACY/RESISTANCEEFFICACY/RESISTANCE
CYP2D6 (tamoxifen) [ [ AmpliChipCYP450Test ] ]
Expression levels of Her2/neu (trastuzumab)
Mutations of K-RAS (cetuximab, panitumumab )
Chromosome Philadelphia/ Bcr-abl (imatinib)
C-kit (imatinib)C kit (imatinib)
Not approvedEGFR mutations (gefitinib, erlotinib)
Tamoxifen: The Key-Pharmacogenetic Step
CYPs cytochrome P450CYPs-cytochrome P450 metabolism
Tamoxifen Biotransformation CH3
OCH2CH2NCH3
c cCH3 CH2
CYP3A4CYP3A4 CYP2B6CYP3A5 Tamoxifen CYP2C9CYP2C19CYP2D6 CYP2D6CYP2C9
CYP2C19CYP1A2 CH3
CH3 OCH2CH2NOCH2CH2N CH3
Hc c
c c CH3 CH2CH3 CH2
OHOH
4-hydroxytamoxifenN-desmethyltamoxifen CYP2B6CYP2C9CYP2C19 CYP3A4
CH3
OCH2CH2NCYP2D6 5 10 nM (a erage 7 nM)CYP2D6 H 5-10 nM (average ~7 nM)c c
CH3 CH2
OH
4-hydroxy-N-desmethyltamoxifenyd o y des e y a o e(Endoxifen)
10-200 nM (average ~ 90 nM)Borges S, et al. Clin Pharmacol Ther. 2006;80:61-74.
Tamoxifen and PolymorphismsP l hi ti i ti f t if t b li iPolymorphic genetic variations of tamoxifen-metabolizingenzymes ( http://www.imm.ki.se./cyp)Concomitant administration of CYP2D6 inhibitors mayConcomitant administration of CYP2D6 inhibitors mayaffect tamoxifen-related clinical outcomesCYP3A4 promoter variant also involved in tamoxifenmetabolismPolymorphism of the SULT1A1 gene (SULT1A*2 variant)ER t (ESR Xb I d ESR2 02) bER genotypes (ESR-XbaI and ESR2-02) may beassociated with tam-associated lipid changes and maycontribute to interindividual variability to tamoxifenb fitbenefits
Tamoxifen PolymorphismsPOLYMORPHISM Ethnical Clinical POLYMORPHISM
CLASSES CYPs Frequency Implication
Poor CYP2D6: CAUCASIANSNonfunctional variants•worse DFS (Goetz MPPoor
metabolizer *3, * 4, * 5, * 6(RARE IN ASIANS AND
BLACK AFRICANS)
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 adyuvantsetting) (Schroth W)g) ( )
ExtensiveCYP2D6 * 2xn CAUCASIANS Favorable RFS, to be
metabolizerCYP2D6 2xn confirmed
Endoxifen, But Not 4-hydroxytamoxifen, , y y ,Degrades The Estrogen Receptor In BreastCancer 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. IngleIngle
Hawse JR, et al. Cancer Res. 2009;69(Suppl 2): Abstract 19.Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 57.
Relapse-Free Time According to CYP2D6Relapse-Free Time According to CYP2D6 Metabolizer Status
(n=108)
(n=65)(n=65)
(n=16)
HR 4.0PM relative to EM
Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 6037.
Pharmacogenetic (CYP2D6) And GenePharmacogenetic (CYP2D6) And Gene Expression Profiles (HOXB13/IL17BR AndMolecular Grade Index) For Prediction OfMolecular Grade Index) For Prediction Of Adjuvant Endocrine Therapy Benefit In
The ABCSG 8 TrialThe ABCSG 8 Trial
SABCS 2008 MP Goetz, M Ames, M Gnant, M Filipits, H Heinzl,
R Jakesz,R G il C M th H S i V S S S fR Greil, C Marth, H Samonigg, V Suman, S Safgren,
M Kuffel,R Weinshilboum M Erlander X Ma J IngleR Weinshilboum, M Erlander, X Ma, J Ingle
ABCSG Trial 8 Structure Switch point
Tamoxifen Tamoxifen(2 years) (3 years)R
an
Primary dsurgery o
miz Tamoxifen Anastrozolee (2 years) (3 years)( y ) ( y )
Primary endpoint: Switching periodevent-free survivalSequencing period
Jakesz R, et al. Lancet. 2005;366(9484):455-462.
Relapse-Free Time According to CYP2D6 inRelapse Free Time According to CYP2D6 in Women Receiving Adjuvant Tamoxifen
Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 6037.
CYP2D6 and Risk of Breast Events
ARM A: TAM for 5 Years(n = 67) Relative Risk to EM P Value
CYP2D6 PM 3 83 (1 27 11 55) 017CYP2D6 PM 3.83 (1.27-11.55) .017
CYP2D6 IM 0.87 (0.44-1.71) .689
ARM B: TAM to Anastrozole (n = 55)
CYP2D6 PM 1.02 (0.21-4.83) .985
CYP2D6 IM 0.81 (0.40-1.61) .538
Adjuvant Tamoxifen and CYP2D6• CYP2D6 associated with recurrenceGoetz et al. 2005,1 20082 (USA)Hawse et al. 20083 (AUSTRIA)Schroth et al. 20074 (Germany)Kiyotani et al. 20085 (Japan)Newman et al. 20086 (UK)Xu et al. 20087 (China)• CYP2D6 not associated with recurrenceWegman et al. 2005,8 20079 (Sweden)
1 Goetz MP et al J Clin Oncol 2005;23(36):9312 9318 2 Goetz MP et al Cancer Res 2009;69(Suppl 2): Abstract1. Goetz MP, et al. J Clin Oncol 2005;23(36):9312-9318. 2. Goetz MP, et al. Cancer Res. 2009;69(Suppl 2): Abstract 57 3. Hawse JR, et al. Cancer Res. 2009;69(Suppl 2): Abstract 19. 4. Schroth W, et al. J Clin Oncol. 2007;25(33):5187-5193. 5. Kiyotani K, et al. Cancer Sci. 2008;99(5):995-999. 6. Newman WG, et al. Clin Cancer Res. 2008;14(18):5913-5918. 7. Xu Y, et al. Ann Oncol. 2008;19(8):1423-1429. 8. Wegman P, et al. Breast Cancer Res. 2005;7(3):R284-R290. 9. Wegman P, et al. Breast Cancer Res. 2007;9(1):R7.
Aromatase Inhibitors: The Key-Pharmacogenetic Stepa acoge et c Step
CYPs-cytochrome P450 enzyme Caromatase by CYP 19A1 or
aromatase genesa o atase ge es
POLYMORPHISMS ENVOLVED IN EXEMESTANE ACTIVITY
CYP19A1gene
CYP19CYP19Ex11+410 G>T(TTTA) t
CYP3A4*1BCYP3A4*1BCYP3A5*3CYP3A5*3 CYP19A1gene
exemestane exemestane
(TTTA)n repeatsEx10+1558 C>TEx7+47C>T
CYP3A5 3CYP3A5 3
RIZ1RIZ1Delezione Pro704
ER1ER1497 C>T
Delezione Pro704
CYP17CYP17Ex1+27T>C (5’UTR)
CYP1B1*3CYP1B1*3OO497 C>T
256 A>G(TA)n repeats
ER2ER21082 G>A
COMT COMT Ex4-12G>A
UGT1A1*28UGT1A1*28
1730A>G(CA)n repeats
AI P l hAIs Polymorphysms> 80 CYP 19 polymorphysms resulting in 44 haplotypes 80 C 9 po y o p ys s esu t g ap otypesfrom each of the 4 ethnic groups have been identified.Arg39 variant OF CYP19A1: Present in 6.7% Han Chinese American (rare in other ethnic groups);Cys264 variant OF CYP19A1: Higher frequencies in Han Chinese Americans and African Americans (11 7%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 letrozoledisease treated with letrozole
ROLE OF THE CYP19 Ex11+410G>T ANDROLE OF THE CYP19 Ex11+410G>T AND OTHER GENETIC POLYMORPHISMS ON
RESPONSE TO EXEMESTANE AS FIRST LINERESPONSE TO EXEMESTANE AS FIRST LINE TREATMENT IN PATIENTS WITH METASTATIC
BREAST CARCINOMABREAST CARCINOMA
Giuseppe Toffoli, MD, Director Pharmacology CRO Aviano
Giampietro Gasparini, Study Coordinator CIPOMO
STUDY DESIGNPatients enrollment and treatmentPatients enrollment and treatment
394 patients will be enrolled forpharmacogenetic analysis.
In 100 patients will be done also PK analysis
Th t 25 / /d At l t 8Therapy: exemestane 25 mg/po/day. At least 8weeks on therapy are required for evaluation.
Taxanes: The Key-Pharmacogenetic StepStep
Metabolism (CYP3A4, CYP3A5)
Transport-efflux (ABCB1) gene polymorphisms
Taxanes Docetaxel is metabolized by CYP3A4/5 ,while paclitaxel by y , p yCYP2C8/CYP3A4
There is controversy whether polymorphisms in the ABCB1 di P l t i l t t ffi f tgene, encoding P-glycoprotein, correlate to efficacy of taxanes
In a prospective study with paclitaxel in metastatic breast cancer the genotype ABCB1 2677 GG showed a significantcancer the genotype ABCB1 2677 GG showed a significant correlation with resistance1
In a retrospective analysis of the CALCB 9871 study (109 p y y (patients) no difference was found between Caucasian and African-American patients in terms of docetaxel toxicity regarding polymorphisms CYP3A4, CYP3A5, and ABCB12
1. Chang H, et al. Ann Oncol. 2008;20(2):272-277. 2. Lewis LD, et al. Clin Cancer Res. 2007;13(11):3302-3311..
TaxanesInterethnic differences in docetaxel PK and toxicities exist between south east populations (Chinese vs Indian vs Malays)1south-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 Asian2AsianCaucasian patients harboring both CYP3A4*1B +/- CYP3A5*1°alleles have higher docetaxel clearance3,4 (I C i ti t t t d ith d t l th l hiIn Caucasian patients treated with docetaxel, the polymorphism C1236T in the ABCB1 gene was significantly related to decreased clearance (-25%)5
D t l i d d th h t l i l t i iti d OSDocetaxel-induced neuropathy, hematological toxicities, and OS are linked to ABCB1 allelic variants6
1 H SY t l Ph i J 2008 8(2) 139 146 2 St d H t l Ph i 2008 8(7) 8031. Hor SY, et al. Pharmacogenomics J. 2008;8(2):139-146. 2. Steed H, et al. Pharmacogenomics. 2008;8(7):803-815. 3. Baker SD, et al. Clin Pharmacol Ther. 2009;85(2):155-163. 4. Tran A, et al. Clin Pharmacol Ther. 2006;79(6):570-580. 5. Bosch TM, et al. Clin Cancer Res. 2006;12(19):5786-5793. 6. Sissung TM, et al. Clin Cancer Res. 2008;14(14):4543-4549.
Bevacizumab: The Key-Bevacizumab: The Key-Pharmacogenetic Step
VEGF as the Therapeutic Target
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 BreastPaclitaxel 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):4672-4678.
Kaplan Meier Curve for Overall Survival (OS) in Experimental Arm by Genotype;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 andthe VEGF-1154 AA genotypepredicted a favorable median OS forpredicted a favorable median OS forpatients in the combination arm butdid not predict an improved medianOS for patients in the control arm andOS for patients in the control arm anddid not predict a superior PFS or RRfor either arm. There was a significantincremental benefit from eachincremental benefit from eachaddition of the VEGF-1154 A allele.
Schneider BP, et al. J Clin Oncol. 2008;26(28):4672-4678.
RESULTS• Patients with VEGF-2578 AA and VEGF-1154 AA genotype have asuperior OS compared with patients with alternative genotypes
• The allele frequency of VEGF-2578 AA and VEGF-1154 AA in whiteq ypopulation is frequent and ranges from 33% to 49%
• The VEGF-634 CC and VEGF-1498 TT genotypes correlated with lessThe VEGF 634 CC and VEGF 1498 TT genotypes correlated with lessgrade 3 or 4 hypertension (0% and 8%, respectively) as compared to thecombined alternate genotypes (P = .005 and P = .022, respectively)
• Patients with grade 3 or 4 hypertension have a superior OS as comparedto pts with no hypertension (38.7 months vs 25.3 months, respectively;P = .002))
Schneider BP, et al. J Clin Oncol. 2008;26(28):4672-4678.
CRITICISMS• The combination of paclitaxel/bevacizumab showed prolonged PFS (11.8 monthsvs 5 9 months) and RR (36 9% vs 21 2%) as compared to paclitaxel alone (E2100vs 5.9 months) and RR (36.9% vs 21.2%) as compared to paclitaxel alone (E2100Study), but….
• No significant difference was observed on OS (26.7 months vs 25.2g (months; P = .16)
• The grade 3/4 toxicity was higher in the experimental arm (hypertension:g y g p ( yp14.8% 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 usuallyobserved in first-line therapy: Why?
• Retrospective analysis of pharmacogenetics on tumor specimens andnot as usually performed on blood samples
Schneider BP, et al. J Clin Oncol. 2008;26(28):4672-4678.
TAKE HOME MESSAGE• The results on pharmacogenetic studies are promising butThe results on pharmacogenetic studies are promising butmainly obtained in retrospective analysis
• Pharmacogenetic studies emphasize the relevance ofethnical diversities
• It is reasonable to hypothesize that pharmacogeneticanalysis coupled with molecular characterization of eachy psingle tumor may lead to improved personalized therapy
D t d t b lid t d i ti li i l t i l• Data need to be validated in prospective clinical trials