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

0.0016-8%94%Vimentin<0.00117%80%Cyclin E<0.00622%51%P53 protein<0.00113%82%P53 mutation<0.0018%57%EGFR<0.00111%29%C-KIT--14%62%CK 5/6--26%0%ErbB2--78%14%ERP valueNon-Basal-likeBasal-like

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)

Luminal A/B Luminal A/B 2/30 2/30 ( 7%)( 7%) 4/62 4/62 ( 7%)( 7%)

Normal breastNormal breast--like like 0/10 ( 0%) N/A0/10 ( 0%) N/AerbB2+erbB2+ 9/20 9/20 (45%) (45%) 4/114/11 (36%)(36%)

BasalBasal--likelike 10/22 10/22 (45%)(45%) 9/34 9/34 (26%)(26%)

p<0.001p<0.001 p=0.003p=0.003

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)

5%18%24%24%Path CR

51%65%76%Clinical Response (CR+PR)

Luminal(n=36)

HER2+/ER-(n=55)

Basal-like(n=33)

Response to Neoadjuvant Anthracycline and Taxane

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36

p=0.008

months

BasalERH2Distant Disease

or Death

BasalLuminal

HER2+

0.00.10.20.30.40.50.60.70.80.91.0

Sur

vivi

ng

10 20 30 40 50 60 70ddfstime (distant disease or death)

otherpCR p=0.02

C9344 DiseaseC9344 Disease--free Survival by ER and HER2free Survival by ER and HER2

Years

Pro

porti

on

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 < 50% / ER negative

No TaxolTaxol

Years

Pro

porti

on

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 < 50% / ER positive

No TaxolTaxol

Years

Pro

porti

on

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 >= 50% / ER negative

No TaxolTaxol

Years

Pro

porti

on

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 >= 50% / ER positive

No TaxolTaxol

ER Neg ER Pos

HER

2 N

EGH

ER2

POS

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

Hayes, ASCO 2006

Triple-negative carcinoma: potential therapeutic targets

Cell Cell CycleCycle

Transcriptional ControlTranscriptional Control

MAP MAP KinaseKinase PathwayPathway AktAkt PathwayPathway

EGFR EGFR Tyrosine Tyrosine

KinaseKinase

CC--KIT KIT tyrosine tyrosine kinasekinase

Cell DeathCell DeathAfter After CleatorCleator S et al. Lancet S et al. Lancet

OncolOncol. 2006:8:235. 2006:8:235--244244

EGFREGFR--Targeting Trials in Stg4 Triple NegativesTargeting Trials in Stg4 Triple Negatives

Weekly Weekly IrinotecanIrinotecanCarboplatinCarboplatinUS US

OncologyOncology

CetuximabCetuximab

Weekly Weekly IrinotecanIrinotecanCarboplatinCarboplatin ++

CetuximabCetuximab

CetuximabCetuximabInterInter--

SPORE*SPORE*

CarboplatinCarboplatin + + CetuximabPD Cetuximab

CarboplatinCarboplatin ++CetuximabCetuximab

*UNC, UCSF, DFCI, UAB, IU, Mayo, JHU, GT, Baylor, Duke, MDACC, Wash U

Proposed CALGB Triple Negative Proposed CALGB Triple Negative NeoadjuvantNeoadjuvant Trial SchemaTrial Schema

W W SikovSikov, PI, PI

CarboplatinPaclitaxelPaclitaxel

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

ClassClass N (%)N (%) ER+%ER+% ppaa

BRCA1BRCA1Age <45Age <45 59 (24.7)59 (24.7) 19.019.0Age 45Age 45--5555 72 (30.1)72 (30.1) 31.131.1Age 55Age 55--6565 108 (45.2)108 (45.2) 38.038.0 p=0.020p=0.020

BRCA2BRCA2Age <45Age <45 43 (48.8)43 (48.8) 83.783.7Age 45Age 45--5555 35 (39.8)35 (39.8) 71.471.4Age 55Age 55--6565 10 (11.4)10 (11.4) 80.080.0 p=0.418p=0.418

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

Core BiopsyCore Biopsy

CisCis Platinum Platinum 75mg/m2 q3wks 75mg/m2 q3wks x 12x 12 weeksweeks**

Standard Standard Adjuvant Adjuvant Therapy Therapy per MDper MD

Tissue:Tissue: Blood:Blood: ImagingImaging

5q, 8q LOH5q, 8q LOH BRCA1BRCA1 MammoMammo

IHC: BRCA1, CK5/6IHC: BRCA1, CK5/6 USUS

MicroarraysMicroarrays: : cDNAcDNA, SNP, SNP MRIMRI

FANCF FANCF methylationmethylation

Radiation damage assayRadiation damage assay

* * Additional MRI and Core Additional MRI and Core bxbx after 1 dose of CDDP: radiation damage assayafter 1 dose of CDDP: radiation damage assay

Responses to NeoResponses to Neo--Adjuvant CDDP Adjuvant CDDP (n=28)(n=28)

Response Clinical PathologicComplete 4 (14%) 6 (21%)Partial 10 (35%) 4 (14%)Stable 6 (21%) 9 (33%)No Response 4 (14%) 5 (18%)Progression 4 (14%) 4 (14%)Grade 3 toxicity 1

2 BRCA1 carriers have had path CR: Age at Dx also significantly associated with response

Bevacizumab in Clinical SubsetsGroup Ratio 95% Conf IntER+, PR+ER+, PR-ER-, PR-No adj chemoNon-taxane Taxane Age 27 - 49Age 50 - 64Age 65 - 85DFI 0 - 24 mos.DFI > 24 mos.< 3 sites3 or more sitesOverall

0.390.860.470.600.510.380.450.440.790.570.470.480.540.51

(0.29, 0.53)(0.52, 1.43)(0.35, 0.63)(0.44, 0.82)(0.39, 0.67)(0.25, 0.59)(0.32, 0.63)(0.33, 0.58)(0.53, 1.17)(0.43, 0.75)(0.37, 0.60)(0.37, 0.61)(0.41, 0.71)(0.43, 0.62)

0.0 0.5 1.0 1.5

N20080

184

680

17823486

155232111

204294252245

Miller K, SABCS 05

CCisplatinisplatin plus plus BBevacizumabevacizumab in in Triple Negative Breast CancerTriple Negative Breast Cancer

PI: P Ryan, MD PhD MGH, DF/HCCPI: P Ryan, MD PhD MGH, DF/HCC

Women with Women with newly newly

diagnosed 2cm diagnosed 2cm ER/PR/HER2ER/PR/HER2--breast cancerbreast cancer

SSUURRGGEERRYY

Standard Standard AC or ACTAC or ACT

Research Research Biopsy, BloodBiopsy, Blood

q3 weeksq3 weeks

Tissue for Tissue for ResearchResearch

Poly (ADPPoly (ADP--ribose) polymerase (PARP)ribose) polymerase (PARP)

Involved in DNA base-excision repair

Binds directly to DNA damage

Produces large branched chains of poly(ADP-ribose)

Lig3XRCC1

PolßPNK

A A TuttTutt and A Ashworthand A Ashworth

CCDDP DDP -- Kudos Kudos PPARPARP--Inhibitor trial Inhibitor trial in Triple Negative Breast Cancerin Triple Negative Breast Cancer

PI: J Garber, MD MPH, DFCI: DF/HCC, Val PI: J Garber, MD MPH, DFCI: DF/HCC, Val D’HebronD’Hebron

Women with Women with newly newly

diagnosed diagnosed >>2cm 2cm

ER/PR/HER2ER/PR/HER2--breast cancerbreast cancer

Oral Oral PARP PARP INHIBITORINHIBITOR

BID x 72 daysBID x 72 daysSSUURRGGEERRYY

Standard Standard TreatmentTreatment

Research Research Biopsy, Blood

Tissue for Tissue for ResearchBiopsy, Blood Research