Jo Anne Zujewski, MDCancer Therapy Evaluation Program

Division of Cancer Diagnosis and TreatmentNational Cancer Institute

May, 2011

Targeted Therapy for Breast Cancer

No surgery

mastectomy

chemoTx + antiER

chemoTx + antiER + targeted

Incremental Benefit

No surgery

mastectomy

chemoTx + antiER

chemoTx + antiER + targeted

Incremental benefit

Each incremental step assumed that no pt is cured with the previous step

Each incremental step assumed that no pt is cured with the previous step

• Significant overtreatment• Necessity to conduct large trials to demonstrate small benefit

• Significant overtreatment• Necessity to conduct large trials to demonstrate small benefit

PNAS 2005

Molecular profiling

Subtypes and Prognosis

Sorlie T et al, PNAS 2001

RS = + 0.47 x HER2 Group Score

- 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1

Oncotype DX 21 Gene Recurrence Score (RS) Assay

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromolysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Category RS (0 – 100)Low risk RS < 18

Int risk RS ≥ 18 and < 31

High risk RS ≥ 31

B-20 Summary

• Patients with tumors that have high Recurrence Scores have a large absolute benefit of chemotherapy (similar results with CMF and MF)

• Patients with tumors that have low Recurrence Scores derive minimal, if any, benefit from chemotherapy

RS < 18 RS 18-30 RS ≥ 31

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

Low R isk Patients (R S < 18) T am + C hemo T am

0 2 4 6 8 10 12

Y ears

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

Int Risk (RS 18 - 30) Tam + C hemo Tam

0 2 4 6 8 10 12

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DR

FS

H igh R isk Patients (R S 31) T am + C hemo T am

Recurrence Score as a Continuous Predictor

0%

5%

10%

15%

20%

25%

30%

35%

40%

0 5 10 15 20 25 30 35 40 45 50

Recurrence Score

Dis

tant

Rec

urre

nce

at 1

0 Y

ears

Low Risk Group High Risk Group Intermediate Risk Group

My RS is 30, What is the chance of recurrence within 10 yrs?

My RS is 30, What is the chance of recurrence within 10 yrs?

95% CI

Schema: TAILORx

17

Node Neg, ER (+), Breast Cancer

Node Neg, ER (+), Breast Cancer

RS < 10HormoneTherapyRegistryN=1625

RS < 10HormoneTherapyRegistryN=1625

RS 11 – 25Randomize

Hormone Rxvs.

Chemotherapy + Hormone Rx

N=6908

RS 11 – 25Randomize

Hormone Rxvs.

Chemotherapy + Hormone Rx

N=6908

RS > 25Chemotherap

y+

Hormone RxN=1731

RS > 25Chemotherap

y+

Hormone RxN=1731

21-gene RSn=11,233

21-gene RSn=11,233

RegisterSpecimen banking

Accrual complete as of 10/06/2010

Breast Cancer: Stable from Preneoplasia to Metastasis

245 DCIS in population-based study:

Livasy, Human Pathol 2007

Subtype N (%)

Basal-like 19 (8%)

Luminal A 149 (61%)

Luminal B 23 (9%)

HER2+/ER- 38 (16%)

Unclass. 16 (6%)

Molecular subtype persists before and after therapy and in metastases:

**

*

Weigelt et al., Cancer Res, 2005

4 studies find basal-like present but uncommon in DCIS (5-10%)

HER2 cluster

Basal gene cluster

Luminal (hormone receptor-related) cluster

Proliferation cluster

Basal-like Breast Cancer• Comprise 15-20% of tumors

• Low ER (and related genes) expression

• Low HER2 cluster expression

usually “triple negative”

• High basal cluster – basal cytokeratins– EGFR– c-kit– others…

• Very proliferative

• Often p53 mutant

• Evidence of genomic instability

Surrogates: Clinical Phenotypes versus Molecular Subtypes

Triple negativeand

Basal-like

Basal but not triple negative

15-40% are ER+, PR+, or HER2+

Triple negativebut not basal10-30%Can also include “claudin-low”, a subtype notable for high expression of stem cell markers

“Triple negative” (ER negative, PR negative, and HER-2 negative) breast cancer is mostly the basal-like subtype

Defining the biology of ER- breast cancer

• Aberrant expression of transcription factors and growth factor receptors has been correlated with basal-like (triple negative) subtype of breast cancer

• Mechanisms of ER loss can vary:– ER promoter methylation in ER- breast cancer (25%)– Src activated ER degradation

• ER- tumors share similarities with BRCA-1 associated breast cancer– Clinical & pathological features – Gene profiling data

Hereditary Basal-like Sporadic Basal-like

BRCA1

Xiso XIST Loss

Triple Neg Cancer

GenomicInstability

??

??

BRCA1

Xiso XIST Loss

Triple Neg Cancer

GenomicInstability

Courtesy J. Garber

BRCA1-Associated and Sporadic Basal-like Breast Cancer

Characteristics Hereditary BRCA1 Triple Negative/Basal-Like1,2,3

ER/PR/HER2 status Negative Negative

TP53 status Mutant Mutant

BRCA1 status Mutational inactivation* Diminished expression*

Gene-expression pattern Basal-like Basal-like

Tumor histologyPoorly differentiated

(high grade)Poorly differentiated

(high grade)

Chemosensitivity to DNA-damaging agents

Highly sensitive Highly sensitive

TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast Cancers

3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-744 Miyoshi et al. Int J Clin Oncol 2008;13:395-400

*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44

1Perou et al. Nature. 2000; 406:747-7522Cleator et al.Lancet Oncol 2007;8:235-44 1

5

PARP Inhibitor Treatment Strategies

1. Sensitization to DNA damaging therapy

2. ‘Chemical synthetic lethality’ in genetically susceptible tumors

• BRCA1, BRCA2, others?

DNA Damage Repair Pathways

Double-Double-strandstrandbreaksbreaks(DSBs)(DSBs)

RecombinationRecombinationrepairrepair

ATMATMBRCABRCA DNA-PKDNA-PK

HRHR NHEJNHEJ

Type of damage:

Repairpathway:

Repairenzymes:

Bulky adducts

Insertions& deletions

O6-alkylguanine

Nucleotide-excision

repair

Mismatch repair

Directreversal

XP, polymerases

MSH2,MLH1

AGT

PARP-1 Inhibition Increases DNA DS Damage

PARP

Inhibition of PARP-1 prevents recruitment of repair factors to repair SSB

XRCC1

LigIII

PNK 1

pol β

Replication (S-phase)

DNA DSB

DNA SSB

Cellsurvival

Base Excision Repair

Synthetic Lethality:Selective effect of PARP-1 inhibition on cancer

cells with BRCA1 or BRCA2 mutation

Homologous Recombination

DNA Damage

PARP Inhibitor

BRCA Mutation

Cancer cell death

HER-2 as a Target for Therapy: NeoALTTO

HER-2

nucleus

cancer cell

cell division

Trastuzumab (Herceptin)Trastuzumab (Herceptin) Anti-HER-2 AntibodyAnti-HER-2 Antibody

Lapatinib (Tykerb)Lapatinib (Tykerb) Dual HER-1/HER-2 Dual HER-1/HER-2

Tyrosine Kinase InhibitorTyrosine Kinase Inhibitor

•Growth factor receptor: Overexpressed in 20-25% of breast Growth factor receptor: Overexpressed in 20-25% of breast cancerscancers•Neo-ALTTO: pre-operative study of trastuzumab; lapatinib; or the Neo-ALTTO: pre-operative study of trastuzumab; lapatinib; or the combinationcombination

pCR: COMBINATION 51.3%Trastuzumab 29.5%

Lapatinib 24.7%

Another HER-2 Targeted Therapy in DevelopmentTrastuzumab-DM1 (T-DM1)

Trastuzumab

Mertansine: anti-tubulinMertansine: anti-tubulin

The Truth About Targeted Therapy

• Cancers have redundant, modular pathways• Answers will not come from purely clinical trials in unselected

populations.• Real understanding of how to target will require more tissue-based

studies and global collaborations

Citri and Yarden, Nat Rev Mol Cell Biol 2006

EGFR

Clean preclinical model Messy clinical situation

Multiple ligandsHeterodimerizationMutated receptorsCleaved receptorsHorizontal activationKinase alterationsEpigenetic alterationsAlternate signaling pathways….

Courtesy of Lisa Carey

Copyright ©2008 American Association for Cancer Research

Tan, S.-H. et al. Clin Cancer Res 2008;14:8027-8041

Fig. 2Predicting response to Endocrine therapy

The Host: Metabolic factorsBody Size in Operable Breast Cancer

Obesity – Breast CancerObesity – Breast Cancer

Interaction of Estrogen and Insulin / IGF MechanismsInteraction of Estrogen and Insulin / IGF Mechanisms

AdiposeTissue

estrogens insulin IGFBP-1

IGF-IIGF-I SHBG

ER/PgR

ER/PgRIGF-IRIGF-IR

IR IR αα, , ββ

(free)++

++ ++

++

++

++

++++

++

*

*

ProliferationAnchorage Independent Growth

Reduced Apoptosis

* PI3K, ras-raf-MAP Kinase signalling pathways

++

inflammatory markers

adipocytokines(e.g. leptin, TNF)

++++

Molecular Action of Insulin

Adapted from Vigneri P et al., Endocr Relat Cancer 2009 Jul 20 (epub ahead of print)

Potential Treatment TargetsLifestyle • Weight Loss – LISA

• Physical Activity

• Diet – fat (WHI / WINS / WHEL)

– calories

PhysiologicMediators

• Insulin

• Glucose

• Adipocytokines (e.g. leptin)

Cellular Mediators

• AMPK

• PI3K / AKT/ mTOR pathway

• ras / raf / MEK pathway

• Insulin / IGF receptors

Copyright © American Society of Clinical Oncology

Goodwin P J et al. J Clin Oncol 2009; 27:3271-3273

Mechanism of Metformin Action

Pathologic Complete Response Between Study Groups(Metformin, No Metformin, Non-Diabetic)

Jiralersprong S et al. J Clin Oncol 2009; 20:3297-3302

NCIC CTG MA.32Multicentre Phase III Randomized Double-Blind Placebo

Controlled Trial in Early Stage Breast Cancer

Metformin850 mg po bid X 5 years

()

Identical PlaceboOne caplet po bid X 5 years

RANDOMIZE

FUNDED BY: NCI (US), CCS, BCRF, Apotex Canada

Biological Information Flow

Epigenetics

Gene Expression

Genetics

MICROENVIRONMENTMICROENVIRONMENT