Newest Approach to Breast Cancer

Kevin R. Fox, MDMacDonald Professor of Medicine

Abramson Cancer CenterUniversity of Pennsylvania

To follow:

• Early stage breast cancer– Genomic testing to predict response– Controversies in HER2 positive disease

• Advanced breast cancer– New chemotherapies– Agents targeting HER2– MTOR inhibition– Whither bevacizumab?– PARP inhibitors

Genomic evaluation in early stage disease

2000 Adjuvant Overview: Mortality Reduction

Tam Chemo Combined<50

ER+ 25% 25% 45%ER- 0% 35% 35%

>50ER+ 25% 10% 35%ER- 0% 20% 20%

NSABP B-20

RANDOMIZE

Node negativeER positivebreast cancer

Tamoxifen

Chemo + Tam

B-20 Chemotherapy BenefitBy Recurrence Score Category

Low Risk (RS < 18)

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 Risk Patients (RS < 18) Tam + Chemo Tam

p = 0.76N Events

218 11135 5

10 yr96%95%

Paik S, et al: SABCS 2004

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

Int Risk (RS 18 - 30) Tam + Chemo Tam

p = 0.71

N Events89 945 8

89%90%

Interm. Risk (RS 18–30)

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

DRFS

High Risk Patients (RS ≥ 31) Tam + Chemo Tam

p = 0.001

N Events117 1347 18

60%

88%

High Risk(RS ≥ 31)

Interaction p = 0.0368

Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+

RANDOMIZEn = 1477

tamoxifen x 5 yrs CAF x 6, thentamoxifen

CAF x 6, with concurrent tam

Superior Disease-Free Survival (DFS) and Overall Survival (OS)

over 10 Years

(n = 361)(n = 550) (n = 566)

Albain, SABCS 2007, Abstract #10Albain, et al. Breast Cancer Res Treat 2005

0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

sur

viva

l

0 2 4 6 8 10

Years since registration

Tamoxifen (n=55, 15 events)CAF-T (n=91, 26 events)

Stratified log-rank p = 0.97 at 10 years

Low risk (RS < 18)

Disease-Free Survival by TreatmentNo benefit to CAF over time if low RS

Strong benefit if high RS

0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

sur

viva

l

0 2 4 6 8 10

Years since registration

Tamoxifen (n=47, 26 events)CAF-T (n=71, 28 events)

Stratified log-rank p = 0.033 at 10 years

High risk (RS ≥31)

Disease-Free Survival by Treatment

0.00

0.25

0.50

0.75

1.00

Dis

ease

-free

sur

viva

l

0 2 4 6 8 10

Years since registration

Tamoxifen (n=46, 22 events)CAF-T (n=57, 20 events)

Stratified log-rank p = 0.48 at 10 years

Intermediate risk (RS 18-30)

Disease-Free Survival by Treatment

Albain, SABCS 2007, Abstract #10

CAF Benefit Greatest in Higher RS for Both Nodal Subsets,

with No Benefit in Lower RS

Recurrence Score

0.2

.4.6

.81

Five

Yea

r Pro

babi

lity

of a

n Ev

ent

0 20 40 60 80 100

Tam, 4+ nodes (n=54)CAF-T, 4+ nodes (n=86)Tam, 1-3 nodes (n=94)CAF-T, 1-3 nodes (n=133)

Linear model for Recurrence Score and interactions with treatmentFive-Year Probability of Death or Disease Recurrence

Chemo benefit 4+ nodes

Chemo benefit 1-3 nodes

Albain, SABCS 2007, Abstract #10

20 yr RFS: 36% 27% P =.00420 yr OS: 34% 25% P =.04

CMF Obs.

Observationn=179

12 X CMF, q28dn=207Cyclophosphamide - 100 mg/m2 PO days 1-14Methotrexate - 40 mg/m2 IV days 1 and 8Fluorouracil - 600 mg/m2 IV days 1 and 8

R

Median follow-up: 19.4 years

Milan TrialAdjuvant Cyclophosphamide, Methotrexate and Fluorouracil in Node-Positive Breast Cancer

Bonnadonna et al. NEJM (1995) 332:901-906

RFS1.00.90.80.70.60.50.40.30.20.10.0

5 10 15 20Years After Mastectomy

Prob

abilit

y of R

elaps

e-Fr

ee S

urviv

al

P =0.004 (unadjusted)P <0.001 (adjusted)

CMF

Control

OS1.00.90.80.70.60.50.40.30.20.10.0

5 10 15 20Years After Mastectomy

Prob

abilit

y of O

vera

ll Sur

vival

P =0.04 (unadjusted)P =0.03 (adjusted)

CMF

Control

Appropriate for node-positive patients?

Do any reasonable alternatives exist?

The use of trastuzumab in early stage breast cancer patients-

what constitutes the “right” chemotherapy?

Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg); doxorubicin dose 60mg/m2; cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2

q3w=every 3 weeks; qw=weekly

NCCTG N9831 Schema

RANDOMIZE

Radiation and/or hormonal therapy as indicated

Paclitaxel qw x 12Arm A: AC q3w x 4

Paclitaxel qw x 12Arm B: AC q3w x 4 H qw x 52

AC q3w x 4Paclitaxel qw x 12

+H qw x 12

Arm C: H qw x 40

Disease-Free Survival: A vs CFrom the Joint Analysis

1009080706050403020100

0 1 2 3 4Years

AC → TEvents=261

AC → T + H → HEvents=134

%

Hazard ratio=0.48Stratified logrank 2P=3x10-12

Number of patients followedA 1162 689 374 193 59C 1217 766 427 238 74

HERA TRIAL DESIGN

Women with HER-2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) ± radiotherapy

StratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy,

age, regionRandomization

Trastuzumab8 mg/kg 6 mg/kg3 weekly x 2 years

Trastuzumab8 mg/kg 6 mg/kg3 weekly x 1 year

Observation

DISEASE-FREE SURVIVAL

% alive and

disease free

Months fromMonths from randomizationrandomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 878716941694 14721472 10671067 629629 303303 102102

EventsEvents22--yryr

DFSDFS %% HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54 [0.43, 0.67][0.43, 0.67] <0.0001<0.0001220220 77.477.4

1 year trastuzumab1 year trastuzumab

ObservationObservation

100100909080807070606050504040303020201010

00

No. No. at riskat risk

Months fromMonths from randomizationrandomization00 55 1010 1515 2020 2525

16931693 14281428 994994 580580 280280 878716941694 14721472 10671067 629629 303303 102102

EventsEvents22--yryr

DFSDFS %% HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54 [0.43, 0.67][0.43, 0.67] <0.0001<0.0001220220 77.477.4

1 year trastuzumab1 year trastuzumab

ObservationObservation

100100909080807070606050504040303020201010

00

No. No. at riskat risk

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Carboplatin75 mg/m2 AUC 6

1 Year Trastuzumab

N=3,222

1 Year Trastuzumab

ACT

ACTH

TCH

Her2+(Central FISH)

N+or highrisk N-

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

Slamon D., SABCS 2005

BCIRG 006

Stratified by Nodes and Hormonal Receptor Status

Disease Free Survival%

Dis

ease

Fre

e0.

50.

60.

70.

80.

91.

0

0 1 2 3 4 5Year from randomization

77%

86%

80%

73%

84%

80%86%

93%

91%

Patients Events1073 147 AC->T1074 77 AC->TH1075 98 TCH

HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002

Disease Free Survival - 2nd Interim Analysis

Absolute DFS benefits(from years 2 to 4):

AC→TH vs AC→T: 6%TCH vs AC→T: 5%

% D

isea

se F

ree

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Patients Events1073 192 AC->T1074 128 AC->TH1075 142 TCH

81%

87%

86%

77%

83%82%

87%

93%

92%

HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003

Year from randomization

Overall Survival – 2nd Interim Analysis

HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] P=0.004HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017

% S

urvi

val

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Patients Events1073 80 AC->T1074 49 AC->TH1075 56 TCH

97%

99%98%

93%

97%95% 92%

91%

86%

Year from randomization

Advanced Breast Cancer

New, and final (?) chemotherapies…

Copyright © American Society of Clinical Oncology

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

Survival for patients presenting with metastatic breast cancer

Andre F, et al. J Clin Oncol 22: 3302, 2004

ER-positive

ER-negative

Survival curves for ER-positive and ER-negative metastatic breast cancers

Median survival 4 years Median survival ≈ 1 year

Capecitabine +/- Ixabepilone in Triple-Negative MBC

a ORR and PFS computed on all randomized pts in 046 and pts randomized to the measurable disease strata in

048b All randomized

046 / 048: Pooled Subset Analysis

4.2(95% CI:3.6-4.4)

31%(24-38)

10.3(95% CI:9.1-11.8)

1.7(95% CI:1.5-2.4)

15%(10-20)

9.0(95% CI:6.7-10.6)

Ixa + Cape Cape

(N = 213 for OS)a

(N = 191 for ORR and PFS)b(N = 208 for ORR and PFS)a

(N = 230 for OS)b

Median PFS ORR Median OS

HR = 0.63 (95% CI, 0.52 to 0.77)P < 0.0001

HR = 0.87 (95% CI, 0.71 to 1.07)P < 0.1802

8

7

6

5

4

3

2

1

0

1020

304050

6070

8090

100 20

1816

14

1210

86

4

20

Med

ian

PFS

(mon

ths)

Resp

onse

Rat

e (%

)

Med

ian

OS

(mon

ths)

Rugo H, et al. SABCS 2008 Poster Presentation. Available at: http://www.abstracts2view.com/sabcs/view.php?nu=SABCS08L_982.

Abstract 1004; Twelves

Therapies Targeting HER2

Targets in trastuzumab-resistant cancers

p85p110

PI3-Kinase

Akt-Kinase

BAD BAD

mTOR

RAD 0014E-BP1/PHAS-1

p70S6-kinase

G1

S

Translation(cyclin D1)

+

IGFR

LAP

TRAST PERTT-DM1

HER2EGFR VEGFR

BEV

PTEN

Emerging data supports co-targeting the HER2pathway in trastuzumab-resistant cancers

Targets in trastuzumab-resistant cancers

p85p110

PI3-Kinase

Akt-Kinase

BAD BAD

mTOR

RAD 0014E-BP1/PHAS-1

p70S6-kinase

G1

S

Translation(cyclin D1)

+

IGFR

LAP

TRAST PERTT-DM1

HER2EGFR VEGFR

BEV

PTEN

Emerging data supports co-targeting the HER2pathway in trastuzumab-resistant cancers

Targets in trastuzumab-resistant cancers

p85p110

PI3-Kinase

Akt-Kinase

BAD BAD

mTOR

RAD 0014E-BP1/PHAS-1

p70S6-kinase

G1

S

Translation(cyclin D1)

+

IGFR

LAP

TRAST PERTT-DM1

HER2EGFR VEGFR

BEV

PTEN

Emerging data supports co-targeting the HER2pathway in trastuzumab-resistant cancers

p85

GF

p110

PI3-Kinase

Akt-Kinase

BAD BAD

mTOR

MTOR inhibitor4E-BP1/PHAS-1

p70S6-kinase

G1

S

Translation(cyclin D1)

+

Possible Downstreammarkers of mTOR inhibition

Effects of mTOR inhibition on signaling pathways

Feedback loop

? Se

nsit

ize

to u

pstr

eam

GF

inhi

bito

rs

Phase 1 trial of RAD001 in Trastuzumab-resistant HER2+ MBC

Treatment until progression or unacceptable toxicity

Paclitaxel continuation after 6 cycles: optional

Open-label, multicenter, Phase I, dose-escalation study of everolimus in combination

with trastuzumab and paclitaxel

Paclitaxel: 80 mg/m2 (Days 1, 8, and 15, q28 days)

Trastuzumab: 2 mg/kg/week (Day 1: 4mg/kg)

ARM 1: DailyEverolimus 5 mg (starting dose)

10 mg/day

ARM 2: Weekly Everolimus 30 mg (starting dose)

50 mg and 70 mg/week

Phase 1 trial of RAD001 in Trastuzumab-resistant HER2+ MBC

Best Overall Response (PFS – wks)

Overall(N=27)

5 mg Daily (N=6)

10 mg Daily

(N=11)

30 mg Weekly (N=10)

Complete Response 1 (5%) 1 (42+) 0

Partial Response 8 (36%) 4* (24, 2933, 39)

1 (16+) 3 (24+, 30, 36)

Stable Disease 11 (50%)

6 (8+, 9+, 10+, 24+, 24+, 32+)

5 (16, 24+, 41, 41, 48+)

Disease Control(CR/PR/SD≥16 Weeks)

17(77%)

5(24, 29

33, 39, 42+)

4(16+, 24+, 24+,

32+)

8(16, 24+, 24+,30, 36,

41, 41, 48+)

Progressive Disease 2 0 1 1

Not Evaluable 2 1 1Not yet available 3 3

% based on evaluable patients (22 in total = 5 + 8 + 9)*Including two patients with unconfirmed CR Andre JCO 2010

Efficacy in Patients With Taxane- and Trastuzumab-resistant Tumors

Best Overall Response (PFS - weeks)

Overall(N=11)

5 mg Daily (N=5)

10 mg Daily (N=3)

30 mg Weekly (N=3)

Complete Response 1 (11%) 1 (42+) 0

Partial Response 4 (44%) 3 (29, 33, 39)

0 1 (30)

Stable Disease 4 (44%) 2 (8+, 24+) 2 (16, 48+)

Disease Control(CR/PR/SD>16 Weeks)

8(89%)

4(29, 33, 39, 42+)

1(24+)

3(16, 30, 48+)

Progressive Disease 0 0 0 0Not Evaluable 1 1Not yet available 1 1

% based on evaluable patients (9 pts evaluables = 4 + 2 +3) Andre JCO 2010

BOLERO-3 : Trastuzumab-resistantVinorelbine + Trastuzumab ± Everolimus

aAfter a loading dose of 4 mg/kg on day 1, cycle 1 (1 cycle = 28 days)

Everolimus 10.0 mg PO dailyVinorelbine 25mg/m2 weeklyTrastuzumab 2 mg/kga IV on days 1, 8, 15, 22Placebo PO dailyVinorelbine 25mg/m2 weeklyTrastuzumab 2 mg/kga IV on days 1, 8, 15, 22

Assessment q8wk

PFSResponseSurvivalSafety

RANDOMIZATION

• Patients with HER2-overexpressing, unresectable locally advanced, recurrent, or metastatic breast cancer; resistant to trastuzumab

N = 572

Screen < 14 days prior to day 1

More on M-TOR inhibition

Johnston JCO 2009

ITT HER2+ HER2-let

(n=644)let + lap (n=642)

let (n=108)

let + lap (n=111)

let (n=474)

let + lap (n=478)

PFS (months)

10.8 11.9 3.0 8.2 13.4 13.7HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P =.188

ORR28% 30% 15% 28% 32% 33%

P =.262 P =.021 P =.726

CBR51% 56% 29% 48% 56% 58%

P =.096 P =.003 P =.761

OS (months)NR NR 32.3 33.3 NR NR

NR HR 0.74; P =.113 NR

Letrozole ± Lapatinib in HR-positive MBC

• Preplanned stepwise exploratory Cox proportional hazard analysis for PFS:

– HER2- population: HR for treatment = 0.77; P = .010

≥6 months since discontinuation of tamoxifen or none

<6 months since discontinuation of

tamoxifenlet (n=370) let + lap

(n=382)let (n=104) let + lap

(n=96)

Median PFS (months)

15.0 14.7 3.1 8.3HR 0.94; P = .522 HR 0.78; P = .117

CBR 64% 62% 32% 44%

Johnston JCO 2009

Hormone-sensitive Hormone-refractory

Letrozole ± Lapatinib in HR-positive, HER2-negative MBC

Suggests that HER2 may be a viable target in cancerswith acquired hormone-resistance (even if they were HER2-negative at diagnosis)

BOLERO-2: Addition of everolimus to exemestane improves PFS in HR+ MBC

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months

Log rank P value = 3.3 x 10 -15

0 126 18 24 30 36 48 6042 54 7266 78

80

60

40

20

100

0

Prob

abili

ty o

f Ev

ent

(%)

Everolimus + Exemestane (E/N=114/485)Placebo + Exemestane (E/N=104/239)

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

Whither bevacizumab?

PARP Inhibition

DNA DAMAGE DNA DAMAGE

BRCA1 or BRCA2 Carrier Normal tissues

BRCA1 or BRCA2 Carrier Tumor tissue

HR NHEJ SSA BER NER etc HR NHEJ SSA BER NER etc

Tumour specific lethality

x xx

Tutt A et al. Cold Spring Harb Symp Quant Biol. 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115.

Targeting BRCAness for tumor selective killing

• Olaparib• Phase I trial

– Dose escalation– Established favorable toxicity profile– Proof of principal with responses seen only in BRCA1

and BRCA2 mutation carriers• Fong et al, NEJM 2009

• Phase II studies– Ovarian cancer: Audeh et al, Lancet 2010– Breast cancer: Tutt et al, Lancet 2010

PARP inhibitors in BRCA1/2 mutation carriers

• To assess the efficacy and tolerability of oral olaparib in BRCA1/ BRCA2 mutation carriers with breast cancer

• Proof-of-concept phase II study, single-arm, international multicenter

Confirmed BRCA1 or BRCA2 mutationAdvanced refractory breast cancer

(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy

Olaparib 400 mg po bid28-day cycles; 27 patients

Cohort 1 (enrolled first)

Olaparib 100 mg po bid28-day cycles; 27 patients

Cohort 2*

*Withdrawal rate in cohort 2 monitored and compared with cohort 1. If significantly greater withdrawal rate in cohort 2 dose escalation was triggered

Study Design and Eligibility

Olaparib 100 mg bid

(n=27)

6 (22)* 0

6 (22)12 (44)9 (33)

Overall Response Rate, n (%)Complete Response, n (%)Partial Response, n (%)

Stable disease, n (%)Progressive disease, n (%)

11 (41)* 1 (4)

10 (37)12 (44)4 (15)

Olaparib400 mg bid

(n=27)

ITT cohort

Objective tumor response rate (RECIST)

Favorable toxicity profile: mild nausea, fatigue

• Secondary mutations with functional restoration of BRCA proteins

• Identified in BRCA1 and BRCA2 mutation carriers with cisplatin resistant recurrent ovarian cancer– Sakai et al Nature, 2008, Swisher et al Cancer Res, 2008;

Sakai et al Cancer Res, 2009

• Identified in BRCA2 mutation carrier with progression through PARP inhibition– Edwards et al, Nature 2008

Resistance?

• The concept of “BRCA-ness”– Basal phenotype of breast cancer– Ovarian cancer

• Phase II trial in triple negative breast cancer– 120 patients randomized to carboplatin/gemcitabine

and BSI PARP inhibitor – iniparib– 201 compared to carboplatin/gemcitabine alone– Significant improvement in progression free and overall

survival with PARP inhibitor– No increased toxicity– Phase III trial has completed accrual and results

are…….

More than BRCA1/2?

O’Shaughnessy, NEJM 2011

Negative

Trial did not meet its primary endpoint

• The concept of “BRCA-ness”– Is this wrong?– Increasingly recognized that there are multiple

molecular subtypes of triple negative breast cancer– Did it work in BRCA1 mutation carriers? Will we ever

know?

• Iniparib used as a chemosensitizer• Second and third line apparently did meet

primary endpoint• Lessons:

- ? Make sure you have your group well defined- Or at least get DNA on everyone

Why did the iniparib study fail?

• Olaparib– Development suspended in BRCA1/2

related cancers– Studies planned in sporadic ovarian

cance• Iniparib - has never been developed in

mutation carriers• Veliparib – Abbott compound

– Combination with temazolamide -activity in BRCA1/2 mutation carriers

• Merck and Pfizer – early phase studies - ?development

• All PARP inhibitors are not alike

Future of PARP inhibitors?

Concluding comments

• Oncotype testing in node-positive patients?

• Optimum chemotherapy for HER2 positive patients with early-stage breast cancer?

• Trastuzumab DM-1• MTOR inhibition• Whither bevacizumab?• PARP inhibitors?