newest approach to breast cancer
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Kevin R. Fox, M.D., Director, Rena Rowan Breast Center, Perelman Center for Advanced Medicine at Penn Medicine - Newest Approach to Breast Cancer Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CMETRANSCRIPT
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?