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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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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


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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


Trastuzumab her2 monoclonal igg1 antibody postulated mechanisms of action l.jpg
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


Human fc riiia cd16 polymorphisms l.jpg
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.


Human fc riia cd32 polymorphisms l.jpg
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.


Fc r genotype outcome with monoclonal ab therapy l.jpg
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


Previous studies of fc r genotypes in trastuzumab treated breast cancer discordant results l.jpg
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


Purpose l.jpg
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).


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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


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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


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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)


Bcirg 006 disease free survival 3 rd planned analysis overall population n 3222 l.jpg
BCIRG 006 Disease Free Survival3rd Planned Analysis – Overall Population (N=3222)


Disease free survival subset of patients who were genotyped l.jpg
Disease free survival:Subset of patients who were genotyped


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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


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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


Dfs trastuzumab arms fc riiia genotype no statistically significant difference by genotype l.jpg
DFS Trastuzumab Arms FcRIIIa genotypeNo statistically significant difference by genotype

Log Rank p=0.98 (VV vs. VF vs. FF)

(14%)

(40%)

(46%)


Dfs trastuzumab arms by fc riia genotype no statistically significant difference by genotype l.jpg
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%)


Dfs trastuzumab arms fc riiia 158v v and or fc riia 131 hh vs others l.jpg
DFS: Trastuzumab Arms FcRIIIa-158V/V and/or FcRIIa-131/HH vs Others

Log Rank p=0.67


Metastatic breast cancer cohort retrospective analysis l.jpg
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


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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


Summary l.jpg
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


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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


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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