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Dr. Hurvitz received research/grant support from Genentech/Roche

Analysis of Fc  Receptor 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

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Dr. Hurvitz received research/grant support from Genentech/Roche

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  1. Analysis of FcReceptor IIA and IIIA Polymorphisms: Correlation with Outcome in Trastuzumab-Treated Her2/neu Amplified Early and Metastatic Breast Cancer PatientsPOSITIVE DISCLOSURES • Dr. Hurvitz received research/grant support from Genentech/Roche • Dr. Stern is an employee of Genentech and stockholder 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/Roche 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

  2. Analysis of Fc Receptor IIa and IIIa Polymorphisms: Correlation with Outcome in Trastuzumab-Treated Her2/neu Amplified Early 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 Abstract 64

  3. Trastuzumab: αHer2-Monoclonal IgG1 Antibody Postulated Mechanisms of Action FcR NK Cell 2. FcR engagement (e.g. Antibody-Dependent Cellular Cytotoxicity, ADCC) 1. Growth Factor Receptor Blockade Inactivation of AKT signaling Decreased Cell Proliferation Induction of Apoptosis Tumor Cell Preclinical evidence for role of ADCC: Efficacy of trastuzumab against breast cancer xenografts was largely dependent on FcR binding Clynes et al. Nature Med. 2000;6:443-446

  4. Human FcRIIIa (CD16) polymorphisms • FcRIIIa is expressed on both NK cells and macrophages; ADCC effectors in vivo • Gene dimorphism encoding FcRIIIa: phenylalanine (F) or a valine (V) at position 158 • This residue interacts with IgG1 Fc • Human IgG1 binds more strongly to homozygous V/V NK cells than to others • Frequency of genotype in population: • 158 V/V 13%, V/F 47%, F/F 40% Wu et al, J. Clin. Invest.100:1059, 1997. Lehrnbecher, Blood, 1999;94;4220-4232.

  5. Human FcRIIa (CD32) polymorphisms • Gene dimorphism encoding FcRIIa: • histidine (H) or arginine (R) at position 131 • Human IgG1 binds more strongly to homozygous FcRIIa-131 H/H immune cells than to H/R or R/R • Frequency in general population: • 131 H/H 21%, H/R 58%, R/R 21% Wu et al, J. Clin. Invest.100:1059, 1997. Lehrnbecher, Blood, 1999;94;4220-4232.

  6. FcR Genotype: Outcome with Monoclonal Ab Therapy • Rituximab anti-CD20-antibody for non-Hodgkin’s lymphoma: • FcRIIIa-158V/V and FcRIIa-131H/H genotypes associated with improved response rates and PFS. Question: Does FcR genotype play a role in the response to trastuzumab? • Such an association would: • provide evidence that the immune system plays a role in the anti-tumor activity of trastuzumab • support the development of engineered monoclonal antibodies with an increased affinity for FcR to improve drug efficacy Cartron, Blood 2002;99:754-758. Weng, W-Ki, et al. JCO 2003

  7. Previous studies of FcR genotypes in trastuzumab-treated breast cancer: Discordant Results FcRIIa FcRIIIa • Foster, et al1: No association between FcRIIIa genotype and response in retrospective analysis of trial evaluating trastuzumab monotherapy in relapsed MBC (N=63) • Musolino et al, 20082:Assessed role of FcR genotypes in predicting efficacy of trastuzumab in 54 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

  8. Purpose • Determine whether FcRIIIa 158 V/F and/or FcRIIa 131 H/R genotypes are associated with disease free survival (DFS) in large cohort 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 FcRIIIa158 V/F and/or FcRIIa131 H/R genotypes are associated with time to progression (TTP).

  9. Methods • Serum & whole blood samples from breast cancer patients treated in the BCIRG-006 study who signed optional consent to have samples taken • Genotype (FcRIIIA 158V/F and FcRIIA 131 H/R) was determined by Sanger sequencing and Sequenom mass spectrometry • DFS was calculated by Kaplan-Meier and compared using log-rank test using data from third planned analysis

  10. BCIRG 006 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACT Her 2+ (Central FISH) N+ or high riskN- 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACTH 1 Year Trastuzumab 6 xDocetaxel and Carboplatin 75 mg/m2 AUC 6 N=3,222 TCH Stratified by Nodes and Hormonal Receptor Status 1 Year Trastuzumab Slamon et al. SABCS 2006

  11. BCIRG 006 Subpopulation Enrolled in BCIRG 006 (N=3,222) Did not consent or provide sample (N=1,936) Patients signed optional consent and samples sent in (N=1,286) FcRIIA FcR IIIA Genotyping failed (N=97) Genotyping failed (N=68) FcR IIIA (N=1,189) FcR IIA (N=1,218)

  12. BCIRG 006 Disease Free Survival3rd Planned Analysis – Overall Population (N=3222)

  13. Disease free survival:Subset of patients who were genotyped

  14. Disease free survival (DFS):Genotyped patients with stratification Stratified for major prognostic factors: age, LN, hormone receptor status, size, surgery type: HR 0.74 [0.56, 0.98] p=0.036

  15. Patient Characteristics • Prognostic factors among the 3 FcRIIIA and 3 FcRIIA genotypes were well balanced for: • Lymph node status • ER/PR status • Menopausal status • Tumor size • Age • Her2/neu FISH ratio

  16. DFS Trastuzumab Arms FcRIIIa genotypeNo statistically significant difference by genotype Log Rank p=0.98 (VV vs. VF vs. FF) (14%) (40%) (46%)

  17. DFS: Trastuzumab arms by FcRIIa genotypeNo statistically significant difference by genotype Log Rank p=0.76 (H/H vs. H/R vs. R/R) (26%) (50%) (24%)

  18. DFS: Trastuzumab Arms FcRIIIa-158V/V and/or FcRIIa-131/HH vs Others Log Rank p=0.67

  19. 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 regimen • FcRIIIA 158V/F and FcRIIA 131H/R genotypes determined • Time to progression calculated from start of first exposure to trastuzumab to time of disease progression or death • Compared genotypes survival curves using log ranktest • Cox proportional hazards regression model used for HRs • Prior therapies in metastatic setting before receiving trastuzumab • 43 patients had no prior chemo • 10 pts had 1-4 prior chemo regimens

  20. Time to Progression by FcR GenotypeNo significant differences in TTP according to FcR genotypes among 53 MBC patients treated with trastuzumab FcRIIIa FcRIIa N=15 N=26 N=12 N=6 N=25 N=21

  21. Summary • BCIRG 006 Early Breast Cancer Cohort • Largest FcR genotyping analysis of trastuzumab-treated breast cancer patients to date, • We found no statistically significant correlation between FcRIIIa and FcRIIa genotypes and DFS. • Limitations of study • Incomplete genotyping of entire study population • Trastuzumab benefit less robust in cohort of patients with serum/whole 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 FcR genotypes and TTP

  22. Conclusions • In contrast to the Musolino study, but similar to the Foster study, we saw no difference in clinical outcome based on FcR genotypes in both early and metastatic breast cancer cohorts. • These data do not support the hypothesis that polymorphism-related differences in FcR affinity cause differential outcome to trastuzumab therapy

  23. Dennis Slamon, MD, PhD John Timmerman, MD Jan Tillisch, MD Mark Pegram, MD Yiou Tseng Mark Sliwkowski, PhD Anne Blackwood-Chirchir. MD Mona Shing, MD Fan Zhang, PhD Deepali Bhatt ASCO Foundation, Young Investigator Award 2007 NIH Loan Repayment Program Genentech Research Grant Patients Acknowledgements

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