recent advances in breast cancer therapy...cleopatra placebo trastuzumab 6mg/kg qtrastuzumab 6mg/kg...

RECENT ADVANCES IN BREAST CANCER THERAPY

Dr. Bhuvaneswari Ramaswamy MD MRCPyOhio State University

Breast Cancer – IntroductionIncidence of Invasive Breast cancer in the US

230, 480 (~124.3 per 100,000)

Life time Risk 1 in 8 women

Prevalence 2,747,459

Median Age of Diagnosis 61

Mortality 39,270y ,

Race IncidenceAll Races 124.3/100,000

White 127.3 per 100,000 women

Black 121.2 per 100,000 women

Asian/Pacific Islander 94.5 per 100,000 women

American Indian/Alaska Native 80.6 per 100,000 women

Hispanic b 92.7 per 100,000 women

Based on Survaillance Epidemiology and End Result DatabaseAmerican Cancer Society, Cancer Facts & Figures. 2006

Breast Cancer: Then and NowBreast Cancer: Then and NowThen Now

• ~75% of women survived ≥5 years

• Mastectomy was the only

• ~95% of women survive ≥5 years

• Lumpectomy is availabley ysurgical option

• Single-agent chemotherapy was standard of care

p y• Combination chemotherapy

is the standard of care• Hormonal therapy is widely

• Hormonal therapy with tamoxifen was under investigation only

py yused

• Receptor-based therapy is widely used

• Genes involved in breast cancer development have not yet been identified

• Understanding of genetic components have expanded

National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/cancer-advances-in-focus/breast.

Age-adjusted Cancer Death Rates for F l b Sit US 1930 2005Females by Site, US, 1930-2005

Adapted from American Cancer Society. Cancer Facts and Figures 2009.

BREAST CANCER MORTALITY BY STAGEMORTALITY BY STAGE

Stages of Breast CancergLocalized Disease:

Distribution 60%Metastatic Disease

Distribution 5 7%– Distribution - 60%– 5-Year Survival – 98%

– Distribution 5-7%– 5-year survival 23%

Locally Advanced– Distribution 33%– Distribution 33%– 5-year Survival 84%

Based on Survaillance Epidemiology and End Result Database

Biology of Breast Cancergy

HormoneReceptor (+)

65-75%

Breast Cancer

65 75%

HER2+15 20%15-20%

TN*TN15% *Triple Negative

HER-2Basal-like L i l ALuminal B“Normal”HER-2Basal-like Luminal A

Sorlie T et al, PNAS 2001

Outcomes Based on Molecular Subtype

9Sorlie T et al, PNAS 2001

Molecular-Genetic ProfilingMolecular Genetic ProfilingTissue Patients FDA Validation?

MammoPrint fresh Node neg ER+, ER -

yes MindAct

W d H li f h ERWound Healing fresh ER+ no no

Oncotype DX paraffin Node neg yes TAILORxyp p gER+

y

HOXB 13/ IL 17b Ratio

paraffin ER+ no noIL-17b Ratio

CYP 2D6 blood all yes no

ONCOTYPE DX ASSAYONCOTYPE DX ASSAY

Paik S et al. NEJM 2004

FATHER OF TARGETED THERAPYTHERAPY

Dr. Elwood JensenESTROGEN RECEPTORESTROGEN RECEPTOR

• “A lady with growth neoplastic• A lady with growth neoplasticThought surgical ablation too drastic.She preferred that her illShe preferred that her illCould be cured with a pill,Which today is no longer fantastic ”Which today is no longer fantastic.

ATLAS STUDYATLAS STUDY

6846 women with ER+ Observation

operable breast cancer who had had 5 years of adjuvant (N=6846*) R

Tamoxifen x 5 yrs

Objectives:• Recurrence Rate*Numbers of Patients for the Analysis:

(1) P ti t ith ER ti d ER k • Breast Cancer Mortality(1) Patients with ER negative and ER unknown breast cancer (N=6048) were excluded from the analysis of the study’s primary objectives.(2) All 12,894 patients were included in safety

l ianalysis.

SABC 2012, Abstract S1-2; Lancet. 2012 Dec 4 [ahead of print]

ATLAS StudyATLAS Study

• After mean of 7 4 woman years of followAfter mean of 7.4 woman years of follow up (30,000 w-y in years 5-9, 16,000 in years 10-14 2000 later)years 10 14, 2000 later)

• Compliance was 80%

SABC 2012, Abstract S1-2; Lancet. 2012 Dec 4 [ahead of print]

BREAST CANCER MORTALITY BY STAGEMORTALITY BY STAGE

Survival Improvement in Metastatic Breast Cancer Patients

100

Cancer Patients

75

al, %

Censored events

P<0.001

Period 1994-2000Period 1987-1993

25

50

Surv

iva

00 12 24 36 48 60

MonthsMonths

• Survival of breast cancer patients presenting with metastases at diagnosis has improved over time, strongly suggesting that improvement is related to treatment

Andre F, et al. J Clin Oncol. 2004; 22(16):3302-3308.

Survival Improvement in Metastatic B t C P ti tBreast Cancer Patients

• A recent study from M.D. Anderson Cancer Center that compared length of survival of metastatic breast cancer patients treated at their institution in five-year incrementsincrements

• Median survival had doubled to 51 months (range 33-69 months) in 1995-2000 from a median survival of 27

h ( 21 33 h ) l fi limonths (range 21-33 months) only five years earlier, 1990-1994.

• Five years after their diagnosis with metastatic diseaseFive years after their diagnosis with metastatic disease, 40 percent of these patients were still alive, as compared with 29 percent during 1990-1994.

Metastatic Breast Cancer – Systemic Therapy Options Depend on Tumor BiologyTherapy Options Depend on Tumor Biology

Metastatic Breast CancerCancer

Hormone Receptor Positive

HER-2/neuPositive Triple Negative

Endocrine Therapy Chemotherapy

Anti-HER-2/neuAgents with

chemotherapy or ChemotherapyTherapy py chemotherapy or endocrine therapy

py

20

Bone Modifying Therapy (Patients with Skeletal Metastases)

Denosumab (RANKL Inhibitor)Denosumab (RANKL Inhibitor)

21

Taken from Robert G. Josse,MD 2009 CGS Annual Scientific Meeting

Denosumab 322 centers:E

Stage IV

•Europe•North & South America,•Japan•Australia•India

Zoledronic Acid 4 mg IV Q28D

+gBreast CancerSkeletal

•South Africa

RPlacebo SQ Q28D

The primary end point:•Time to 1st on-study SRE (non-i f i it t t)Metastases

N=2046

RDenosumab 120

mg SQ Q28D

inferiority test).

Secondary end points:•Time to 1st on study SRE (superioritymg SQ Q28D

+Placebo IV Q28D

•Daily supplementation with calcium (>500 mg) and

•Time to 1st on-study SRE (superiority•test)•Time to 1st and subsequent SREs.•Safety

•Daily supplementation with calcium (>500 mg) and vitaminD (>400U) was strongly recommended. •Chemotherapy and hormonal therapy were allowed (except for oral or intravenous bisphosphonates or unapproved investigational agents).

Exploratory end points:•Overall Survival•Disease ProgressionS

22

•Skeletal Morbidity Rate•Chage from baseline to week 13 in uNTx and BSAP

Stopeck et al. J Clin Oncol 2010; 28:5132-9

Time to First Skeletal Related Event

23

Stopeck et al. J Clin Oncol 2010; 28:5132-9

Time to First and Subsequent Sk l t l E tSkeletal Event

24

Stopeck et al. J Clin Oncol 2010; 28:5132-9

HER Family: Receptors and Ligands

HR

G(N

RG

1)

Ligandbindingdomaindomain

Transmembrane

Tyrosinekinase

HER1 HER2 HER3 HER4domain

H b t I t J R di t O l Bi l Ph 2004 59( l) 21 R k ki Bi h Bi h R C 2004 319 1Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21; Roskoski. Biochem Biophys Res Commun. 2004;319:1;Rowinsky. Annu Rev Med. 2004;55:433.

HER2 Overexpression in Breast CancerHER2 is overexpressed in ~ 18-25% of breast cancers

N l (1 )Normal (1x)~ 25,000-50,000 HER2 receptors

Overexpressed HER2 (10-100x)Up to ~ 2,000,000 HER2 receptors

1. Excessive cellular division2. Increased ability to form

tumors in experimental mice3. Increased ability to form

metastasesPegram MD et al Cancer Treat Res 2000;103:57-754. Secretion of vascular

endothelial growth factors

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182.

0.8

1.0

Disease F0 4

0.6

0.8

Free Survival

0.4

0.2

0.8

1.0

Overall Survival

0.6

0.4 Survival0.2

Slamon DJ et al. Science 1987;239: 177-235

Months

Efficacy in Early Breast Cancer: SummaryTrial/ Trial/ NN Med Med HR HR HR HR Absol. % Absol. % Absol %Absol %a /a /

Experimental Experimental RegimenRegimen

ededf/uf/u DFSDFS

pp--valuevalueOSOS

pp--valuevalue

bso %bso %diff DFSdiff DFS

bso %bso %diff OSdiff OS

NSABP/N9831NSABP/N9831 396396 2 92 9 0 480 48 0 650 65 12 8 @ 412 8 @ 4 3 2 @ 4 y3 2 @ 4 yNSABP/N9831NSABP/N9831AC→THAC→TH

39639688

2.9 2.9 yy

0.480.48<0.0000<0.0000

11

0.650.65<0.0007<0.0007

12.8 @ 4 12.8 @ 4 yy

3.2 @ 4 y3.2 @ 4 y

HERAHERA 340340 2 y2 y 0.640.64 0.660.66 6.3 @ 3 y6.3 @ 3 y 2.7 @ 3 y2.7 @ 3 yMultiple→HMultiple→H 11 <0.0001<0.0001 <0.0115<0.0115

BCIRG 006BCIRG 006AC→DHAC→DH 322322 2 y2 y

0.610.61<0.0001<0.0001

0.590.590.0040.004

6 @ 3 y6 @ 3 y 4 @ 3 y4 @ 3 yAC→DHAC→DH 322322

222 y2 y

BCIRG 006BCIRG 006DCaH (aka DCaH (aka TCH)TCH)

0.670.670.00030.0003

0.660.660.0170.017

5 @ 3 y5 @ 3 y 2 @ 3 y2 @ 3 y

TCH)TCH)FinHerFinHerD/V+H→CEFD/V+H→CEF

232232 3 y3 y 0.420.420.010.01

0.410.410.070.07

11.7 @ 3 11.7 @ 3 yy

6.6 @ 3 y6.6 @ 3 y

Perez E et al. ASCO 2007; Smith I et al. Lancet 2007; Slamon D et al. SABCS 2006; Joensuu H et al. NEJM 2005; Spielmann M. et al SABCS2007

RESISTANCE TO THERAPY

LEVEL OF CROSS TALK FOR ONE PATHWAY

The 6 degrees of separation in drug resistance.

Trusolino L , and Bertotti A Cancer Discovery 2012;2:876-880

©2012 by American Association for Cancer Research

I IHER2 HER3

Pertuzumab

III

II

III

II

HER2 HER3

DimerizationIV

III

IVIII

E t ll l

DimerizationarmsTrastuzumab

TDM1

RTKRTKIntracellular

ExtracellularTDM1

RAS PI3K PTENRTKactivationRAF

MEK

PI3K

AKT

PTEN

TranscriptionNucleus

MAPK mTORTKI

32

Transcription

Cell proliferation Cell survivalOlson. J Clin Oncol. 2012;30:1712-4.

Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopesp p

Pertuzumab-HER2 Complex

Trastuzumab-HER2 Complexp p

Pertuzumab Dimerization d i

III

Idomain

TrastuzumabIII

IIIII

II

IV IVIV IV

Inhibits HER2 dimerization with other HER family receptors (particularly HER3)

Activates ADCC Inhibits multiple HER mediated signaling

Activates ADCC Inhibits HER-mediated signaling pathways Prevents HER2 domain cleavage

Hubbard SR. Cancer Cell. 2005;7:287-288.

Inhibits multiple HER-mediated signaling pathways

CLEOPATRAPlacebo

Trastuzumab 6mg/kg q

CLEOPATRA

Trastuzumab 6mg/kg q 3 weeks

Docetaxel 75 mg/m2 q 3 k

RANHER2 MBC

P t b 420 3

weeksNDOM

HER2+ MBC1st linen =808

1:1

Pertuzumab 420 mg q 3 weeks

Trastuzumab 6mg/kg q

I ZE

3 weeksDocetaxel 75 mg/m2 q 3

weeksweeks

Baselga NEJM 2011

CleopatraCleopatra

Baselga NEJM 2011

CleopatraCleopatra

Baselga NEJM 2011

SMART BOMBSMART BOMB

Trastuzumab-DM1: Novel Antibody-Drug ConjugateConjugate

Monoclonal antibody: Trastuzumab

Target expression: HER2

Trastuzumab

Cytotoxic agent: DM1

Highly potent cytotoxic agent MCCDM1

Systemically stable

Linker: SMCCT-DM1Average drug:antibody ratio 3.5:1

MCC (Non-reducible thioether bond to a linker molecule)Meeream M., et al. J clin Oncol. 2008; 26 (May 20 suppl; abstract

EMILIA (TDM4370g) Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBCLapatinib/Capecitabine in HER2 MBC

Stratification:World RegionNumber of Previous Chemotherapy

PD or unacceptable toxicityType of prior regimensLocally advanced breast cancerPresence of visceral disease

Patients with HER2+ locally advanced or metastatic breast cancer

T-DM1 3.6 mg/kg q3w(n = 495)

following treatment with a taxane and trastuzumab

(N = 980)

Lapatinib 1250 mg daily+Capecitabine 1000 mg/m2 2x/dayDays 1-14 every 3weeks(n = 496)

Primary endpoint: PFS by IRF, OS, safetySecondary endpoints: QoL (FACT B), DOR, PFS by investigator

assessmentJ Clin Oncol 30, 2012 (suppl; abstr LBA1)

40

Verma et al. N Engl J Med. 2012 (Published online on October 1)

Endocrine Therapy Resistance

Aromatase Inhibitors

Tamoxifen

Everolimus

a o eFulvestrant

Johnston S R Clin Cancer Res 2010;16:1979-1987

BOLERO-2BOLERO 2

PlaceboExemestane

RAN

Postmenopausal ER/PR+ Advanced

Breast Cancer NDOM

Breast Cancer

Progression on nonsteroidal AI in the

2:1

EverolimusExemestane

I ZE

adjuvant or metastatic setting

n =724

Baselga NEJM 2011

Bolero2Bolero2

• Insert exemestane + mTOR Bolero2 trialInsert exemestane mTOR Bolero2 trial

Baselga NEJM 2011

BOLERO-2

Baselga NEJM 2011

WHY???WHY???

• WHY are we still dealing with failures???WHY are we still dealing with failures???• WHY do not we cure 100% of patients

with breast cancer?with breast cancer?

Russens et al, JCI, 2011

STUDY DESIGNS FOR ARRAY-BASED GENE EXPRESSIONSTUDUES

Russens et al, JCI, 2011

Planned approachesFuture DirectionsMolecular Characterization

Courtesy of N. Wagley g

NEW SUBTYPES OF BREAST CANCER

Russens et al, JCI, 2011

MULTILEVEL APPROACH FOR DYNAMIC CLASSIFICATION

Russens et al, JCI, 2011