Preoperative Treatment of the Preoperative Treatment of the Triple Triple - - Negative (Basal Phenotype) Negative (Basal Phenotype) Breast Cancer Breast Cancer Judy E. Garber, MD MPH Judy E. Garber, MD MPH Dana Farber Cancer Institute Dana Farber Cancer Institute Boston, MA 26 March 2007 Boston, MA 26 March 2007
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Preoperative Treatment of the Triple Negative …Preoperative Treatment of the Triple-Negative (Basal Phenotype) Breast Cancer Judy E. Garber, MD MPH Dana Farber Cancer Institute Boston,
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Preoperative Treatment of the Preoperative Treatment of the TripleTriple--Negative (Basal Phenotype) Negative (Basal Phenotype)
Breast CancerBreast Cancer
Judy E. Garber, MD MPHJudy E. Garber, MD MPHDana Farber Cancer InstituteDana Farber Cancer Institute
Boston, MA 26 March 2007 Boston, MA 26 March 2007
ER neg ER pos
SorlieSorlie, et al. PNAS 2001, et al. PNAS 2001
Gene Expression Profiles and IHC of BasalGene Expression Profiles and IHC of Basal--like like Breast CancersBreast Cancers
Nielsen, T. O. et al. Nielsen, T. O. et al. ClinClin Cancer Res 2004;10:5367Cancer Res 2004;10:5367--53745374
IHC Features of Basal-like v. Non-Basal-like Breast Cancers
CleatorCleator S et al. Lancet Oncology 2007;8:235S et al. Lancet Oncology 2007;8:235--244244
Risk Factors By Subtype
2.31 (0.88-6.88)
1.72 (1.21-2.45)
2.35 (1.03-5.38)
3.17 (1.69-5.92)
FHx
1.02 (0.74-1.42)
1.00 (0.90-1.12)
0.97 (0.73-1.28)
0.87 (0.66-1.14)
BMI postmen
0.88 (0.48-1.60)
0.71 (0.57-0.88)
0.53 (0.25-1.12)
1.18 (0.86-1.64)
BMI premen*(per 5kg↑)
1.10 (0.78-1.57)
1.13 (1.01-1.28)
1.09 (0.81-1.46)
1.02 (0.82-1.28)
Menopause
1.04 (0.70-1.55)
1.08 (0.95-1.23)
0.87 (0.60-1.05)
0.95 (0.71-1.27)
Age FTB
0.91(0.09-8.83)
0.56 (0.07-4.56)
0.50 (0.24-1.06)
0.42 (0.21-0.84)
1.50 (0.19-11.77)
1.15 (0.17-7.63)
2.36 (0.43-13.01)
1.80 (0.37-8.85)
No births 1
>2
0.98 (0.75-1.28)
0.90 (0.95-1.08)
1.14 (0.86-1.50)
0.78 (0.68-0.89)
Menarche*(per 2y↑)
Luminal B(n=48)
Luminal A(n=552)
HER2+/ER-(n=61)
Basal-like (n=95)
Yang XR et al, CEBP 2007Yang XR et al, CEBP 2007
Overall and Relapse Free Survival Based on Tumor Overall and Relapse Free Survival Based on Tumor Subclasses Defined with Gene Expression PatternsSubclasses Defined with Gene Expression Patterns
SorlieSorlie, et al. PNAS 2001, et al. PNAS 2001
Correlation and Molecular Classification and Pathologic CR
SubtypeSubtype TT--FAC FAC (n=82)(n=82) ACAC--TT22 (n=108)(n=108)
Rosier R et al. Rosier R et al. ClinClin Cancer Res 2005;11:5678Cancer Res 2005;11:5678--5685 5685 Carey L et al. Carey L et al. ClinClin Cancer Res, in pressCancer Res, in press
Intrinsic Subtypes and AC-T Sensitivity (Lisa Carey – UNC)
No No CarboplatinCarboplatinN=600ER/PR/HER2-Stage II-IIIB Carboplatin
PaclitaxelPaclitaxelNo No CarboplatinCarboplatin
SURGERY
Dose-denseAC
RT prn
Bevacizumab
Breast imaging Blood MUGA Tumor Biopsy*
Breast imaging Blood
Breast imagingBlood MUGA
Phase I Trial of UCN01 and Irinotecan in Resistant Solid Tumors
2 Partial Responses in ER/PR/HER2 Negative Breast Cancer Pts
PrePre--study Photograph of Local Diseasestudy Photograph of Local Disease After 2 Cycles of TherapyAfter 2 Cycles of Therapy
PM PM FracassoFracasso et al., et al., SitemanSiteman Cancer Center, Cancer Center, Washington University, St. Louis MOWashington University, St. Louis MO
2 Partial Responses in ER/PR/HER2 Negative Breast Cancer Pts
CTEP Extension for TNBC TrialCTEP Extension for TNBC Trial
Proposed Trial: Proposed Trial: UCN01 and Irinotecan in Triple Negative Breast Cancers
P P FracassoFracasso, H , H PwinicaPwinica--WormsWorms
SURGERY
IrinotecanIrinotecan q week/ q week/ UCNUCN--01 day 1 of 21: 01 day 1 of 21: cycle is 42dayscycle is 42days
ER/PR/HER2ER/PR/HER2--Stage Stage IIII--IIIB
UnspecifiedUnspecified RT RT prnprnIIIB
A Classic Hereditary Breast/Ovarian A Classic Hereditary Breast/Ovarian Cancer KindredCancer Kindred
Breast, 49Breast, 497373
Breast, 38Breast, 385555
Breast, 29Breast, 29Ovary, 42Ovary, 42
d 45d 45
6262
2929
Breast, 49Breast, 495757
8080
Breast, 32Breast, 32
BRCA1 and BRCA2: Caretaker Genes
Maintenance of genomic integrity through: • DNA damage recognition and repair• Transcriptional regulation of gene
expression• Chromatin remodeling• Cell cycle checkpoint control
Venkitaraman AR. Cell. 2002;108:171-182.
% ER+ Breast Cancers in BRCA1/2Carriers by Age at Diagnosis
FoulkesFoulkes WD WD ClinClin Cancer ResCancer Res 2004:10;20292004:10;2029--3434
BASALBASAL--LIKE BREAST CANCERSLIKE BREAST CANCERS80% of BRCA1 mutation-associated cancers sort with the “basal-like” group of ER(-) breast cancers
••10% of breast cancers 10% of breast cancers •• ER(ER(--) PR() PR(--) HER2() HER2(--))•• Poorly differentiatedPoorly differentiated•• High grade, High grade, AneuploidAneuploid•• EGFR+, EGFR+, cyclincyclin E+E+•• Express basal keratinsExpress basal keratins
CK5/6; CK5/6; VimentinVimentin•• Little DCISLittle DCIS•• Poor prognosisPoor prognosis•• Different stem cell?Different stem cell?
BRCA1BRCA1--deficient cells develop gross deficient cells develop gross chromosomal abnormalities with DNA damagechromosomal abnormalities with DNA damage
ShenShen et al, 1998et al, 1998
BasalBasal--like Tumors Show DNA like Tumors Show DNA Damage SensitivityDamage Sensitivity
Permission of D Silver, MD PhDPermission of D Silver, MD PhD
Working Model for BRCA1- and Sporadic Breast Cancer Pathogenesis
YehielyYehiely F et F et al.Trendsal.Trends in in MolecMolec Med 2007;12:537Med 2007;12:537--544.544.
BRCA1BRCA1--Deficient Cancer Cells Have a Deficient Cancer Cells Have a Defect in DNA Double Strand Break RepairDefect in DNA Double Strand Break Repair
γγ--Radiation MitomycinMitomycin CCRadiation
BRCA1 -/-
+BRCA1
Scully, Ganesan et al, Mol. Cell 1999Scully, Ganesan et al, Mol. Cell 1999 MoynahanMoynahan et al, Cancer Res 2001et al, Cancer Res 2001
BRCA1BRCA1--Deficient Cells Are Deficient Cells Are Hypersensitive to Hypersensitive to CisplatinCisplatin
CISPLATIN DOXORUBICIN PACLITAXEL
TassoneTassone et al, 2003 BJCet al, 2003 BJC
RecurrenceRecurrence--Free Interval Probabilities in Free Interval Probabilities in Patients with Advanced Ovarian CancersPatients with Advanced Ovarian Cancers
Boyd J et al. JAMA 283:2260, 2000
DF/HCC DF/HCC NeoAdjuvantNeoAdjuvant Platinum Platinum in Triple Negative Breast Cancerin Triple Negative Breast Cancer
> 2cm, Stage II/ III> 2cm, Stage II/ IIIER/PR/Her ER/PR/Her NegNegBreast Cancer on Breast Cancer on