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/CME
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Newest Approach to Breast Cancer
1. Newest Approach to
Breast Cancer
Kevin R. Fox, MD
MacDonald Professor of Medicine
Abramson Cancer Center
University of Pennsylvania
2. 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
5. NSABP B-20
R
Node negative A
ER positive N Tamoxifen
D
breast cancer
O
M
I
Z Chemo + Tam
E
6. B-20 Chemotherapy Benefit
By Recurrence Score Category
Interm. Risk (RS 18–30)
Low Risk (RS <
1.0 1.0
10 yr
0.9
0.8
18) 96% 0.9
0.8
95% 89%
0.7 0.7
0.6 0.6 N Events 90%
DRFS
DRFS
0.5 0.5 89 9
N Events p = 0.71
0.4 0.4 45 8
218 11
0.3
135 5
p = 0.76 0.3
0.2 0.2
Low Risk Patients (RS < 18)
Int Risk (RS 18 - 30)
0.1 Tam + Chemo 0.1 Tam + Chemo
Tam Tam
0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Years Years
1.0
0.9
0.8
88%
0.7
High Risk 0.6
N Events
60%
DRFS
0.5
(RS ≥ 31) 0.4
117
47
13
18 p = 0.001
0.3
0.2
High Risk Patients (RS ≥ 31)
Interaction p = 0.0368
0.1 Tam + Chemo
Tam
0.0
0 2 4 6 8 10 12
Years Paik S, et al: SABCS 2004
7. Phase III SWOG 8814 (TBCI 0100)
Postmenopausal, N+, ER+
RANDOMIZE
n = 1477
tamoxifen x 5 yrs CAF x 6, with CAF x 6, then
(n = 361)
concurrent tam tamoxifen
(n = 550) (n = 566)
Superior Disease-Free Survival
(DFS) and Overall Survival (OS)
over 10 Years Albain, SABCS 2007, Abstract #10
Albain, et al. Breast Cancer Res Treat
2005
8. Disease-Free Survival by Treatment
No benefit to
1.00
CAF over time
Disease-free survival
0.75
Low risk (RS < 18)
if low RS
0.50
Stratified log-rank p = 0.97 at 10 years
0.25
Strong benefit Tamoxifen (n=55, 15 events)
CAF-T (n=91, 26 events)
0.00
if high RS 0 2 4 6
Years since registration
8 10
Disease-Free Survival by Treatment Disease-Free Survival by Treatment
1.00
1.00
Intermediate risk (RS 18-30)
High risk (RS ≥31)
Disease-free survival
Disease-free survival
0.75
0.75
0.50
0.50
Stratified log-rank p = 0.48 at 10 years
Stratified log-rank p = 0.033 at 10 years
0.25
0.25
Tamoxifen (n=47, 26 events) Tamoxifen (n=46, 22 events)
0.00
CAF-T (n=71, 28 events) CAF-T (n=57, 20 events)
0.00
0 2 4 6 8 10 0 2 4 6 8 10
Years since registration Years since registration
Albain, SABCS 2007, Abstract #10
9. CAF Benefit Greatest in Higher RS
for Both Nodal Subsets,
with No Benefit in Lower RS
Five-Year Probability of Death or Disease Recurrence
Linear model for Recurrence Score and interactions with treatment
1
Tam, 4+ nodes (n=54)
Five Year Probability of an Event
CAF-T, 4+ nodes (n=86)
Tam, 1-3 nodes (n=94)
.8
CAF-T, 1-3 nodes (n=133)
.6
Chemo benefit 4+ nodes
.4
Chemo benefit 1-3 nodes
.2 0
0 20 40 60 80 100
Recurrence Score
Albain, SABCS 2007, Abstract #10
10. Milan Trial
Adjuvant Cyclophosphamide, Methotrexate and
Fluorouracil in Node-Positive Breast Cancer
1.0
Probability of Relapse-Free Survival
12 X CMF, q28d 0.9 RFS
n=207 0.8
Cyclophosphamide - 100 mg/m2 PO days 1-14 0.7
Methotrexate - 40 mg/m2 IV days 1 and 8 0.6
Fluorouracil - 600 mg/m2 IV days 1 and 8 0.5
0.4 CMF
0.3 P =0.004 (unadjusted)
0.2 P <0.001 (adjusted) Control
0.1
R 0.0
5 10 15 20
Observation Years After Mastectomy
1.0
n=179
OS
Probability of Overall Survival
0.9
0.8
Median follow-up: 19.4 years 0.7
0.6
0.5
CMF Obs. 0.4 CMF
20 yr RFS: 36% 27% P =.004 0.3
0.2 P =0.04 (unadjusted) Control
20 yr OS: 34% 25% P =.04 0.1 P =0.03 (adjusted)
0.0
5 10 15 20
Bonnadonna et al. NEJM (1995) 332:901-906
Years After Mastectomy
12. The use of trastuzumab in early
stage breast cancer patients-
what constitutes the “right”
chemotherapy?
13. NCCTG N9831 Schema
Arm A: AC q3w x 4 Paclitaxel qw x 12
R
A
N
D
O Arm B: AC q3w x 4 Paclitaxel qw x 12 H qw x 52
M
I
Z
E Paclitaxel qw x 12
Arm C: AC q3w x 4 + H qw x 40
H qw x 12
Radiation and/or hormonal therapy as indicated
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
14. Disease-Free Survival: A vs C
From the Joint Analysis
100 AC → T + H → H
90 Events=134
80
70 AC → T
Events=261
60
% 50
40
30 Hazard ratio=0.48
20 Stratified logrank 2P=3x10-12
10
0
0 1 2 3 4
Years
Number of patients followed
A 1162 689 374 193 59
C 1217 766 427 238 74
15. HERA TRIAL DESIGN
Women with HER-2 POSITIVE invasive
breast cancer IHC3+ or FISH+ centrally confirmed
Surgery + (neo)adjuvant chemotherapy (CT) ± radiotherapy
Stratification
Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy,
age, region
Randomization
Trastuzumab Trastuzumab
8 mg/kg 6 mg/kg 8 mg/kg 6 mg/kg Observation
3 weekly x 2 years 3 weekly x 1 year
17. BCIRG 006
4 x AC 4 x Docetaxel
60/600 mg/m2 100 mg/m2
ACT
Her2+ 4 x Docetaxel
(Central FISH) 4 x AC
60/600 mg/m2 100 mg/m2
N+ ACTH
or high
risk N- 1 Year Trastuzumab
6 x Docetaxel and Carboplatin
N=3,222 75 mg/m2 AUC 6
Stratified by Nodes TCH
and Hormonal
Receptor Status
1 Year Trastuzumab
Slamon D., SABCS 2005
28. Survival curves for ER-positive and ER-negative
metastatic breast cancers
ER-
negative
ER-
positive
Median survival 4 years Median survival ≈ 1 year
Andre F, et al. J Clin Oncol 22: 3302, 2004
29. Capecitabine +/- Ixabepilone in
Triple-Negative MBC
046 / 048: Pooled Subset Analysis
Ixa + Cape Cape
(N = 213 for OS)a (N = 208 for ORR and PFS)a
(N = 191 for ORR and PFS)b (N = 230 for OS)b
Median PFS ORR Median OS
8 100 20
HR = 0.63 (95% CI, 0.52 to 0.77) 18 HR = 0.87 (95% CI, 0.71 to 1.07)
7 90
P < 0.0001 P < 0.1802
Median PFS (months)
Median OS (months)
80 16
Response Rate (%)
6
70 14
5
60 12
4 50 10
4.2
3 (95% CI: 40 8 10.3
3.6-4.4) (95% CI: 9.0
30 6
2 9.1-11.8) (95% CI:
31%
1.7 20 (24-38) 4 6.7-10.6)
1 (95% CI: 15%
10 2
1.5-2.4) (10-20)
0 a ORR
0
and PFS computed on all randomized pts in 046
and pts randomized to the measurable disease strata in
048
b All randomized
Rugo H, et al. SABCS 2008 Poster Presentation. Available at: http://www.abstracts2view.com/sabcs/view.php?nu=SABCS08L_982.
38. Targets in trastuzumab-resistant cancers
T-DM1 TRAST PERT BEV
IGFR EGFR HER2 VEGFR
p110
p85
LAP
RAD 001
PTEN PI3-Kinase 4E-BP1/PHAS-1 G1
+ Translation
(cyclin D1)
Akt-Kinase mTOR
S
p70S6-kinase
BAD BAD
Emerging data supports co-targeting the HER2
pathway in trastuzumab-resistant cancers
39.
40.
41.
42.
43.
44.
45.
46. Targets in trastuzumab-resistant cancers
T-DM1 TRAST PERT BEV
IGFR EGFR HER2 VEGFR
p110
p85
LAP
RAD 001
PTEN PI3-Kinase 4E-BP1/PHAS-1 G1
+ Translation
(cyclin D1)
Akt-Kinase mTOR
S
p70S6-kinase
BAD BAD
Emerging data supports co-targeting the HER2
pathway in trastuzumab-resistant cancers
47. Targets in trastuzumab-resistant cancers
T-DM1 TRAST PERT BEV
IGFR EGFR HER2 VEGFR
p110
p85
LAP
RAD 001
PTEN PI3-Kinase 4E-BP1/PHAS-1 G1
+ Translation
(cyclin D1)
Akt-Kinase mTOR
S
p70S6-kinase
BAD BAD
Emerging data supports co-targeting the HER2
pathway in trastuzumab-resistant cancers
48. Effects of mTOR inhibition on signaling pathways
GF
? Sensitize to upstream
p110 Possible Downstream
p85
markers of mTOR inhibition
GF inhibitors
MTOR inhibitor
PI3-Kinase 4E-BP1/PHAS-1 G1
+ Translation
(cyclin D1)
Akt-Kinase mTOR
S
Feedback loop p70S6-kinase
BAD BAD
49. Phase 1 trial of RAD001 in
Trastuzumab-resistant HER2+ MBC
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: Daily ARM 2: Weekly
Everolimus 5 mg (starting dose) Everolimus 30 mg (starting dose)
10 mg/day 50 mg and 70 mg/week
Treatment until progression or unacceptable
toxicity
Paclitaxel continuation after 6 cycles: optional
50. Phase 1 trial of RAD001 in
Trastuzumab-resistant HER2+ MBC
Best Overall Overall 5 mg Daily 10 mg 30 mg Weekly
Response (N=27) (N=6) Daily (N=10)
(PFS – wks) (N=11)
Complete Response 1 (5%) 1 (42+) 0
Partial Response 8 (36%) 4* (24, 29 1 (16+) 3
33, 39) (24+, 30, 36)
Stable Disease 11 6 (8+, 9+, 10+, 5 (16, 24+,
(50%) 24+, 24+, 32+) 41, 41, 48+)
Disease Control 17 5 4 8
(CR/PR/SD≥16 (77%) (24, 29 (16+, 24+, 24+, (16, 24+, 24+,30, 36,
33, 39, 42+) 32+) 41, 41, 48+)
Weeks)
Progressive Disease 2 0 1 1
Not Evaluable 2 1 1
Not yet available 3 3
% based on evaluable patients (22 in total = 5 + 8 + 9)
*Including two patients with unconfirmed CR Andre JCO 2010
51. Efficacy in Patients With Taxane- and
Trastuzumab-resistant Tumors
Best Overall Overall 5 mg Daily 10 mg 30 mg Weekly
Response (N=11) (N=5) Daily (N=3)
(PFS - weeks) (N=3)
Complete Response 1 (11%) 1 (42+) 0
Partial Response 4 (44%) 3 0 1
(29, 33, 39) (30)
Stable Disease 4 (44%) 2 (8+, 24+) 2 (16, 48+)
Disease Control 8 4 1 3
(CR/PR/SD>16 (89%) (29, 33, 39, 42+) (24+) (16, 30, 48+)
Weeks)
Progressive Disease 0 0 0 0
Not Evaluable 1 1
Not yet available 1 1
% based on evaluable patients (9 pts evaluables = 4 + 2 +3) Andre JCO 2010
52. BOLERO-3 : Trastuzumab-resistant
Vinorelbine + Trastuzumab ± Everolimus
R
A Everolimus 10.0 mg PO daily Assessment
N
D Vinorelbine 25mg/m2 weekly q8wk
O
M
Trastuzumab 2 mg/kga IV on days 1, 8, PFS
I 15, 22
Z Response
Placebo PO daily
A Survival
T Vinorelbine 25mg/m2 weekly
I
Trastuzumab 2 mg/kga IV on days 1, 8, Safety
O
N 15, 22
N = 572
• Patients with HER2-overexpressing,
unresectable locally advanced, recurrent,
or metastatic breast cancer; resistant to
trastuzumab
Screen < 14 days
prior to day 1
aAfter a loading dose of 4 mg/kg on day 1, cycle 1 (1 cycle = 28 days)
55. Letrozole ± Lapatinib in HR-positive MBC
ITT HER2+ HER2-
let let + lap let let + lap let let + lap
(n=644) (n=642) (n=108) (n=111) (n=474) (n=478)
PFS 10.8 11.9 3.0 8.2 13.4 13.7
(months) HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P =.188
28% 30% 15% 28% 32% 33%
ORR
P =.262 P =.021 P =.726
51% 56% 29% 48% 56% 58%
CBR
P =.096 P =.003 P =.761
NR NR 32.3 33.3 NR NR
OS (months)
NR HR 0.74; P =.113 NR
Johnston JCO 2009
56. Letrozole ± Lapatinib in HR-positive,
HER2-negative MBC
• Preplanned stepwise exploratory Cox proportional hazard analysis
for PFS:
– HER2- population: HR for treatment = 0.77; P = .010
≥6 months since <6 months since
discontinuation of discontinuation of
tamoxifen or none tamoxifen
let (n=370) let + lap let (n=104) let + lap
(n=382) (n=96)
Median PFS 15.0 14.7 3.1 8.3
(months) HR 0.94; P = .522 HR 0.78; P = .117
CBR 64% 62% 32% 44%
Hormone-sensitive Hormone-refractory
Suggests that HER2 may be a viable target in cancers
with acquired hormone-resistance (even if they were
HER2-negative at diagnosis)
Johnston JCO 2009
57.
58.
59.
60.
61. BOLERO-2: Addition of everolimus to
exemestane improves PFS in HR+ MBC
HR = 0.36 (95% CI: 0.27–0.47)
100 Log rank P value = 3.3 x 10 -15
Probability of Event (%)
EVE + EXE: 10.6 Months
80 PBO + EXE: 4.1 Months
60
40
20
Everolimus + Exemestane (E/N=114/485)
Placebo + Exemestane (E/N=104/239)
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Time (weeks)
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
73. Targeting BRCAness for tumor selective
killing
BRCA1 or BRCA2 Carrier BRCA1 or BRCA2
Normal tissues Carrier Tumor tissue
DNA DAMAGE DNA DAMAGE
HR NHEJ SSA BER NER etc HR NHEJ SSA BER NER etc
x x x
Tumour specific lethality
Tutt A et al. Cold Spring Harb Symp Quant Biol. 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115.
74. PARP inhibitors in BRCA1/2 mutation
carriers
• 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
75. Study Design and Eligibility
• 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 mutation
Advanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy
Cohort 1 (enrolled first) Cohort 2
*
Olaparib 400 mg po bid Olaparib 100 mg po bid
28-day cycles; 27 patients 28-day cycles; 27 patients
*Withdrawal rate in cohort 2 monitored and compared with cohort 1. If significantly
greater withdrawal rate in cohort 2 dose escalation was triggered
77. Resistance?
• 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
78. More than BRCA1/2?
• 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……. O’Shaughnessy, NEJM 2011
80. Why did the iniparib study fail?
• 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
81. Future of PARP inhibitors?
• 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
82. 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?