Breast Cancer

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Breast Cancer

• Program Leaders
• Linda Malkas, PhD
• George W. Sledge, Jr, MD

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Program Overview

• 24 members and 12 Associate Members representing
  13 departments
• 5 basic science Biochemistry and Molecular
  Biology, Cellular and Integrative Physiology,
  Chemistry, Medical and Molecular Genetics,
  Microbiology and Immunology
• 10 clinical Clinical Pharmacology,
  Hematology/Oncology (Medicine), Gynecologic
  Oncology, Pathology and Laboratory Medicine,
  Pediatrics Hematology/Oncology Pharmacology and
  Toxicology, Radiology, Rheumatology, Surgery,
  Urology
• New members Abdel-Aziz, Fan ,Hocevar, Hoeltz,Jin
• Clinical research In CY 2005 there were 281
  newly registered patients with breast cancer.
  During the same time period 98 patients were
  enrolled on breast cancer therapeutic clinical
  trials, representing 35 of newly registered
  patients
• Breast Cancer publications since 2003 368
• 69 representing intra-programmatic collaboration
• 78 representing inter-programmatic collaboration

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Scientific Themes

• Genomic Damage Repair Mechanisms
• Angiogenesis and Therapeutic Anti-angiogenesis
• Therapeutic Response and Individualization
• Cell Signaling Pathway Alterations

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Scientific Accomplishments

• Successful development of anti-angiogenic therapy
  strategies for breast cancer
• Elucidation of clinically important mechanism of
  tamoxifen resistance via pharmacogenetics
• Development of novel biomarker of breast
  carcinogenesis

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Development of Anti-VEGF Therapy for Breast Cancer

• Clinical observation IU Phase II trial of
  bevacizumab demonstrates activity in heavily
  pretreated metastatic breast cancer.

• Laboratory observation Synergy of taxanes with
  bevacizumab

CI 0.3 0.27 0.16 0.24 plt.01
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E2100 Proof of Concept TrialStudy Chair Dr.
K. Miller
RANDOMI ZE
Eligibility - No prior Rx for mets - Adjuvant
taxane if gt12 mos. Exclusion -
Her-2 - CNS mets - Proteinuria - Uncontrolled
HTN
Arm A Paclitaxel (q wk) rhuMAb VEGF
Arm B Paclitaxel (q wk)
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E2100 Progression Free Survival
HR 0.51 (0.43-0.62) Log Rank Test plt0.0001
484 events reported
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E5103 Adjuvant Trial
Arm A AC gtT
AC q21d x 4
Paclitaxel 80 mg/m2/wk x 12
R ANDOMIZE
Arm B BAC gtBT
AC plus Bevacizumab 15 mg/kg q21d x 4
Paclitaxel 80 mg/m2/wk x 12 plus Bevacizumab 15
mg/kg q21d x 4
Arm C BAC gtBT gtB
Hormone therapy and radiation per standard care
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E2100 Follow-Up StudiesVEGF DNA
Polymorphisms(SNPs)
Chromatographs representative of genotypes
showing Single Nucleotide Polymorphisms
All polymorphisms (combined sites) --High
quality chromatographs in 145 of 159 (91) 83
primary tumor, 92 LN, 98 from LN- --100
concordance between samples that involved
malignancy (primary or LN) vs germline (95
CI, 0.88 to 1.00 )
E2100 blocks being analyzed!
Schneider, Breast Ca. Res. Treat. 2006
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Friends for Life Schema
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Association of genetic polymorphisms of
angiogenesis genes and breast cancer risk

• Prior studies
• conflicting results
• Very limited gene evaluation
• 1244 subjects 500 breast cancer
• Preliminary evaluation of first 600
• HIF1a, VEGF, VEGFR-2, eNOS, NRP-1, others
• VEGF 936C allele was marginally associated with
  breast cancer in the entire cohort (p0.0587).
• Conclusion- increased risk of breast cancer from
  polymorphic variability may be driven by VEGF

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Exploratory study evaluating the association of
polymorphisms of angiogenesis genes with hot
flashes

• Rationale- Hot flashes involve vasodilatation,
  however, complex etiology is not fully
  understood.
• Prior studies-none
• 1244 subjects 500 breast cancer
• Preliminary evaluation of first 600
• HIF1a, VEGF, VEGFR-2, eNOS, NRP-1
• HIF1 a 1744C allele frequency of 92.7 in those
  with symptoms versus 83.5 in controls (p0.0095).

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Tamoxifen is Metabolized by 2D6
CYP 2C9 CYP 2C19 CYP 2D6 CYP 3A4
Tamoxifen
4-OH-Tamoxifen
CYP 3A
Equipotent 10 fold higher conc.
N-Desmethyl- Tamoxifen
4-OH-N-Desmethyl- Tamoxifen (endoxifen)
CYP 2D6
Some SSRIs inhibit 2D6
Desta, et al. J Pharmacol Exp Ther. 2004
3101062-75
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CYP2D6 Genotype Predicts Endoxifen Concentration
Plt0.001, r20.24
Plasma Endoxifen (nM)
CYP2D64 (most common genetic variant associated
with the CYP2D6 poor metabolizer state)
Jin Y et al J Natl Cancer Inst 9730, 2005
CP1229323-4
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Inhibition of CYP2D6 Affects Endoxifen
Concentrations
Plasma Endoxifen (nM)
Wt/Wt, noinhibitor
Venlafaxine
Sertraline
Paroxetine
4/4, noinhibitor
Jin Y et al J Natl Cancer Inst 9730, 2005
CP1229323-8
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NCCTG 89-30-52
RANDOMIZATION
5 years of tamoxifen(n256)
Postmenopausal women Early ER breast cancer 541
women accrued
5 years tamoxifen 1 year fluoxymesterone(n285)
Ingle et al. Breast Cancer Res Treat. 2006 Mar 15

CP1229323-5
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Methods
Extensive metabolizers CYP2D6 Wt/Wt, no
inhibitor Intermediate metabolizers Wt/Wt on
moderate inhibitor Wt/4, no inhibitor Poor
metabolizers Wt/Wt on potent inhibitor Wt/4
on any inhibitor 4/4
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Relapse-Free Survival worse for PM
n115
EM
2-year RFS EM 98 IM 92 PM 68 Log Rank P0.009

n40
IM
PM
n16
Years after randomization
Breast cancer recurrence or death
CP1229323-16
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The Cancer Cells DNA Replication Apparatus Is
Altered in Function and Structure Leading to the
Discovery of a New Cancer Diagnostic
DNA Replication Fidelity
Human Cell DNA Synthesome
PCNA Profile in Human Breast Tumor
PCNA Profiles in Non-Malignant and Malignant
Breast Cells in Culture
csPCNAab Distinguishes Tumor from Normal Tissue
Extracts
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The Antibody in IHC Detects Cancer Cells
Specifically in Tissue
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The Cancer Specific Form of PCNA (csPCNA) is
Present in Patient Serum
csPCNA

• A Potential Serum Biomarker for Cancer?
• 2006 Friends For Life collected annotated serum
  from normal controls and BC patients

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Interactions with Other Programs

• Numerous inter-programmatic publications with
  Behavioral Oncology, EDT, and Hematopoiesis
  programs (78 since 2003)
• Inter-Programmatic Grants
• Champion/Sledge ACS Young Survivor Grant
• Flockhart/Carpenter PGRN grant (hot flash/AI)

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Responsibility of Program Leaders

• Foster research that is interdisciplinary and
  translational
• Coordinate Breast Cancer Program meetings
  (monthly and annual retreat)
• Coordinate Pilot Project RFAs
• Develop SPORE application
• Coordinate recruitment
• Mentor junior program members

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Program Activities

• Monthly program meeting
• Annual Amelia Project Research Conference
• IUCC Breast Cancer Program Retreat
• Annual Pilot Project Competition
• Infrastructure development
• Friends For Life/Mary Ellens Tissue Bank
• Tissue microarrays (TMA)
• Clinical Research Data Base

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Breast Cancer Future Plans

• Recruitment of new members
• Genomics
• Invasion Metastasis
• Molecular epidemiology
• Further infrastructure development
• Leveraging IUCC developmental funds through
  annual grant competition

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csPCNA in Human Breast Cancer
ELISA in development for csPCNA Friends For
Life 2006 collected annotated serum for
analysis (normals and breast cancer
patients)
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Interactions Between Themes

• Therapeutic individualization and Angiogenesis
  development of single nucleotide polymorphism
  (SNP) analysis of VEGF and VEGF-R
• Genomic damage Repair and Therapeutic
  individualization DOD COE

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Antibody Detects Cancer in Tissue