Analysis of Fc-Receptor IIA and IIIA Polymorphisms- .ppt

1、Analysis of FcReceptor IIA and IIIA Polymorphisms: Correlation with Outcome in Trastuzumab-Treated Her2/neu Amplified Early and Metastatic Breast Cancer Patients POSITIVE DISCLOSURES,Dr. Hurvitz received research/grant support from Genentech/Roche Dr. Stern is an employee of Genentech and stockholde

2、r in Roche Jeremy Stinson is an employee of Genentech and stockholder in Roche Dr. Seshagiri is an employee of Genentech and stockholder in Roche Dr. Robert receives research/grant support from Genentech and is on the Roche Speakers Bureau Dr. Valero receives research/grant support from Genentech/Ro

3、che and is on the Roche Speakers Bureau Dr. Crown receives research/grant support from Roche and is on the Roche Speakers Bureau Dr. Slamon is on the speakers bureau for Genentech,Analysis of Fc Receptor IIa and IIIa Polymorphisms: Correlation with Outcome in Trastuzumab-Treated Her2/neu Amplified E

4、arly and Metastatic Breast Cancer Patients,Sara A. Hurvitz, David Betting, Howard M. Stern, Emmanuel Quinaux, Jeremy Stinson, Somasekar Seshagiri, Ying Zhao, Marc Buyse, John Mackey, Nicholas J. Robert, Vicente Valero, John Crown, Adrian Driga, Valerie Bee, Dennis J. Slamon, John M. Timmerman,Abstra

5、ct 64,1. Growth Factor Receptor Blockade Inactivation of AKT signaling Decreased Cell Proliferation Induction of Apoptosis,Tumor Cell,Trastuzumab: Her2-Monoclonal IgG1 Antibody Postulated Mechanisms of Action,Preclinical evidence for role of ADCC: Efficacy of trastuzumab against breast cancer xenogr

6、afts was largely dependent on FcR binding Clynes et al. Nature Med. 2000;6:443-446,Human FcRIIIa (CD16) polymorphisms,Wu et al, J. Clin. Invest.100:1059, 1997. Lehrnbecher, Blood, 1999;94;4220-4232.,FcRIIIa is expressed on both NK cells and macrophages; ADCC effectors in vivoGene dimorphism encoding

7、 FcRIIIa: phenylalanine (F) or a valine (V) at position 158This residue interacts with IgG1 FcHuman IgG1 binds more strongly to homozygous V/V NK cells than to othersFrequency of genotype in population: 158 V/V 13%, V/F 47%, F/F 40%,Human FcRIIa (CD32) polymorphisms,Wu et al, J. Clin. Invest.100:105

8、9, 1997. Lehrnbecher, Blood, 1999;94;4220-4232.,Gene dimorphism encoding FcRIIa: histidine (H) or arginine (R) at position 131Human IgG1 binds more strongly to homozygous FcRIIa-131 H/H immune cells than to H/R or R/RFrequency in general population: 131 H/H 21%, H/R 58%, R/R 21%,FcR Genotype: Outcom

9、e with Monoclonal Ab Therapy,Rituximab anti-CD20-antibody for non-Hodgkins lymphoma: FcRIIIa-158V/V and FcRIIa-131H/H genotypes associated with improved response rates and PFS. Question: Does FcR genotype play a role in the response to trastuzumab?Such an association would: provide evidence that the

10、 immune system plays a role in the anti-tumor activity of trastuzumab support the development of engineered monoclonal antibodies with an increased affinity for FcR to improve drug efficacy,Cartron, Blood 2002;99:754-758. Weng, W-Ki, et al. JCO 2003,Previous studies of FcR genotypes in trastuzumab-t

11、reated breast cancer: Discordant Results,Foster, et al1: No association between FcRIIIa genotype and response in retrospective analysis of trial evaluating trastuzumab monotherapy in relapsed MBC (N=63) Musolino et al, 20082: Assessed role of FcR genotypes in predicting efficacy of trastuzumab in 54

12、 Her2+ MBC receiving trastuzumab + taxane.,1. Foster, Ostland, Mass, et al. Proceedings ASCO, 2002. 21(Abstract No: 227) 2. Musolino et al. J Clin. Oncol. 2008: 26,Purpose,Determine whether FcRIIIa 158 V/F and/or FcRIIa 131 H/R genotypes are associated with disease free survival (DFS) in large cohor

13、t of patients with Her2/neu-amplified early stage breast cancer treated with trastuzumab.In a separate cohort of Her2+ metastatic breast cancer patients treated with trastuzumab, determine whether FcRIIIa158 V/F and/or FcRIIa131 H/R genotypes are associated with time to progression (TTP).,Methods,Se

14、rum & whole blood samples from breast cancer patients treated in the BCIRG-006 study who signed optional consent to have samples taken Genotype (FcRIIIA 158V/F and FcRIIA 131 H/R) was determined by Sanger sequencing and Sequenom mass spectrometry DFS was calculated by Kaplan-Meier and compared using

15、 log-rank test using data from third planned analysis,4 x AC 60/600 mg/m2,4 x Docetaxel 100 mg/m2,6 x Docetaxel and Carboplatin75 mg/m2 AUC 6,1 Year Trastuzumab,N=3,222,1 Year Trastuzumab,ACT,ACTH,TCH,Her 2+ (Central FISH)N+ or highrisk N-,4 x AC 60/600 mg/m2,4 x Docetaxel 100 mg/m2,BCIRG 006,Strati

16、fied by Nodes and Hormonal Receptor Status,Slamon et al. SABCS 2006,Enrolled in BCIRG 006 (N=3,222),FcR IIIA,Patients signed optional consent and samples sent in (N=1,286),Genotyping failed (N=68),FcRIIA,FcR IIIA (N=1,189),FcR IIA (N=1,218),Genotyping failed (N=97),Did not consent or provide sample

17、(N=1,936),BCIRG 006 Subpopulation,BCIRG 006 Disease Free Survival 3rd Planned Analysis Overall Population (N=3222),Disease free survival: Subset of patients who were genotyped,Disease free survival (DFS): Genotyped patients with stratification,Stratified for major prognostic factors: age, LN, hormon

18、e receptor status, size, surgery type:HR 0.74 0.56, 0.98 p=0.036,Patient Characteristics,Prognostic factors among the 3 FcRIIIA and 3 FcRIIA genotypes were well balanced for:Lymph node statusER/PR statusMenopausal status Tumor sizeAgeHer2/neu FISH ratio,DFS Trastuzumab Arms FcRIIIa genotype No stati

19、stically significant difference by genotype,(14%),Log Rank p=0.98 (VV vs. VF vs. FF),(40%),(46%),DFS: Trastuzumab arms by FcRIIa genotype No statistically significant difference by genotype,Log Rank p=0.76 (H/H vs. H/R vs. R/R),(26%),(50%),(24%),DFS: Trastuzumab Arms FcRIIIa-158V/V and/or FcRIIa-131

20、/HH vs Others,Log Rank p=0.67,Metastatic breast cancer cohort: Retrospective analysis,Prospectively collected DNA from 53 women with Her2/neu amplified and/or overexpressed metastatic breast cancer treated with trastuzumab-based regimenFcRIIIA 158V/F and FcRIIA 131H/R genotypes determinedTime to pro

21、gression calculated from start of first exposure to trastuzumab to time of disease progression or death Compared genotypes survival curves using log rank test Cox proportional hazards regression model used for HRsPrior therapies in metastatic setting before receiving trastuzumab 43 patients had no p

22、rior chemo 10 pts had 1-4 prior chemo regimens,Time to Progression by FcR Genotype No significant differences in TTP according to FcR genotypes among 53 MBC patients treated with trastuzumab,N=6 N=25 N=21,N=15 N=26 N=12,FcRIIIa,FcRIIa,Summary,BCIRG 006 Early Breast Cancer Cohort Largest FcR genotypi

23、ng analysis of trastuzumab-treated breast cancer patients to date, We found no statistically significant correlation between FcRIIIa and FcRIIa genotypes and DFS.Limitations of study Incomplete genotyping of entire study population Trastuzumab benefit less robust in cohort of patients with serum/who

24、le blood available for genotyping Despite this limitation, there appears to be no statistically significant difference in outcome among genotypes Metastatic cohort In 53 women with Her2/neu positive metastatic breast cancer, we found no significant correlation between FcR genotypes and TTP,Conclusio

25、ns,In contrast to the Musolino study, but similar to the Foster study, we saw no difference in clinical outcome based on FcR genotypes in both early and metastatic breast cancer cohorts.These data do not support the hypothesis that polymorphism-related differences in FcR affinity cause differential

26、outcome to trastuzumab therapy,Acknowledgements,Dennis Slamon, MD, PhD John Timmerman, MD Jan Tillisch, MD Mark Pegram, MD Yiou TsengMark Sliwkowski, PhD Anne Blackwood-Chirchir. MD Mona Shing, MD Fan Zhang, PhD Deepali BhattASCO Foundation, Young Investigator Award 2007 NIH Loan Repayment Program Genentech Research GrantPatients,