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Recent Update in Management of Breast Cancer:
Medical Oncology
Jin Hee Ahn, M.D., PhD.
23-April-2015
Department of Oncology, Asan Medical Center, UUCM, Seoul, Korea
2015 GBCC & 4th IBCS 1/37
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ER-positive breast cancer
Endocrine therapy…. and its potential new friends?
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Combining targeted and antiestrogen therapies in HR positive breast cancer
PI3K
AKT
PTEN
mTOR
RAS
RAF
MEK
MAPK
ER target gene transcription
P P
EGFR HER2
E
E
ER
E ER
E
ER
E
TKI
mTOR Inhibitors Everolimus Sirolimus Temsirolimus
Aromatase Inhibitor Nonsteroidal AIs
Anastrozole Letrozole
Steroidal AIs Exemestane
Selective Estrogen Receptor Modulators Tamoxifen Toremifene
ER Downregulator Fulvestrant
HDAC Inhibitor Entinostat
CDK 4/6 Inhibitor Palbociclib LEE011 LY2835219
Cell Cycle
Transcription Silencing
PI3K inhibitor BKM 120 GDC-0941 BYL 719
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BOLERO-2: Everolimus + Exemestaine increase the PFS & OS of ER+ HER2- MBC
Baselga J et al. NEJM 2012, 366: 520-529, Adv Ther 2013, 30: 870-84
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Phase II Randomized study: ER +, HER2 – MBC (1st line)
Primary endpoint: PFS
PALOMA-1 Trial
“Palbociclib”
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PALOMA1 trial: palbociclib + letrozole vs. letrozole median F/U: 29.6 mo
Finn RS et al. Lancet Oncol 2015; 16: 25
Median PFS: 10.2 vs. 20.2 months
(HR 0.488, 95% CI 0.319-0.748,P=0.0004)
Progression-Free Survival Overall Survival
Palbociclib + Letrozole
Letrozole
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Most common Treatment-Related AEs 10%
Palbociclib+ Letrozole (N=83) Letrozole (N=77)
Gr ½ (%) Gr 3 (%) Gr 4 (%) Gr ½ (%) Gr 3 (%) Gr 4 (%)
Neutropenia 19 48 6 1 1 0
Leukopenia 23 18 0 0 0 0
Anemia 23 4 1 0 0 0
Fatigue 22 2 0 14 0 0
Alopecia 22 0 0 3 0 0
Hot flush 18 0 0 10 0 0
Arthralgia 17 0 0 9 1 0
Thrombo-cytopenia
14 2 0 0 0 0
Nausea 14 1 0 1 0 0
Decreased appetite
8 1 0 0 0 0
Stomatitis 10 0 0 0 0 0
• Neutropenia was self-limited and not associated with infectious complications
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Timeline of approval of agents for HR-positive advanced breast cancer
Palbociclib (CDK 4/6 inhibitor)
(2015)
2015
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The PI3K/AKT/mTOR Pathway in Breast Cancer: Common Molecular Alterations
~40% of HR + breast cancer have PIK3CA mutations
Baselga J. Oncologist 2011; 16: Suppl 1: 12 Endocrine Rev. 2008; 29: 217-33.
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HER2-positive breast cancer
New standard treatment for HER+ MBC
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Molecular approaches to HER2 targeted therapy
Singh JC et al. BJC 2014, 111: 1888
1998
2005
2012 2013
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CLEOPATRA: Phase III trial of trastuzumab plus pertuzumab in the first-line setting
Baselga J et al. NEJM 2012; 366: 109
Study dosing q 3 week -Pertuzumab/placebo: 840 mg loading 420 mg maintenance -Trastuzumab: 8 mg/kg loading 6 mg/kg maintenance -Docetaxel: 75 mg/m2 100 mg/m2 escalation if tolerated
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CLEOPATRA: Phase III trial of trastuzumab plus pertuzumab in the first-line setting
Baselga J et al. NEJM 2012; 366: 109
PFS
Median follow-up period: 19.3 months
OS
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Swain et al, ESMO 2014, NEJM 2015; 372: 724-734
CLEOPATRA: Final OS Analysis (median f/u 50 months)
Median OS 56.5 vs. 40.8 months Difference: 15.7 months
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T-DM1 selectively delivers DM1 to HER2-positive tumor cells
LoRusso PM et al. Clin Cancer Res 2011
Antibody-drug conjugate: T-DM1
Highly potent DM1 is internalized within HER2+ cancer cells
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EMILIA study: Phase III trial of T-DM1 vs. Lapatinib+capecitabine after trastuzumab in HER2+ MBC
Sunil Verma et al. NEJM 2012; 367: 1783
• Primary end points: PFS by independent review, OS, and safety
• Secondary end points: PFS by investigator, ORR, duration of response,
time to symptom progression
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EMILIA study: Progression-Free Survival
Sunil Verma et al. NEJM 2012; 367: 1783
3.2 months
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EMILIA study: Overall survival
Sunil Verma et al. NEJM 2012; 367: 1783
OS = 5.8 months
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Cap + Lap
(n=488)
T-DM1
(n=490)
All-grade AE, n (%) 477 (97.7) 470 (95.9)
Grade ≥3 AE, n (%) 278 (57.0) 200 (40.8)
AEs leading to treatment discontinuation (for any
study drug), n (%)
52 (10.7)
29 (5.9)
AEs leading to death on treatment, n (%) 5 (1.0) 1 (0.2)
LVEF <50% and ≥15-point decrease from
baseline, %
7 (1.6)
8 (1.7)
EMILIA study: Adverse Events in the Safety Population
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TH3RESA Study Schema
• Co-primary end points: PFS by investigator and OS
• Secondary end points: ORR by investigator and safety
Krop IE et al, Lancet Oncol 2014, 15: 689-699
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TH3RESA Study: PFS
Krop IE et al, Lancet Oncol 2014, 15: 689-699
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TH3RESA Study: First Interim Analysis of OS
Krop IE et al, Lancet Oncol 2014, 15: 689-699
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Current ASCO guidelines
HER2 MBC
ER-/ER+ ER+
Taxane/trastuzumab/pertuzumab
Ado Trastuzumab Emtansine (T-DM1)
Lapatinib/Capecitabine Trastuzumab/Capecitabine Trastuzumab/Lapatinib Trastuzumab/Chemotherapy T-DM1 if not received earlier Pertuzumab if not received earlier
Letrozole +/- Lapatinib AI or tamoxifen +/- Trastuzumab
ER guidelines
* No OS advantage with hormone therapy plus anti-HERE2 therapy
Giordano et al. JCO 2014 (ASCO Guidelines)
(e.g. asymptomatic, low burden disease, patients at increased risk of toxicity from chemotherapy)
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Can resistance to anti-HER2 agents be overcome or modulated?
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Triple Negative Breast Cancer (TNBC)
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Molecular Heterogeneities of TNBC
Lehmann BD et al. J Clin Invest 2011, 121: 2750
SUBGROUPS
Basal-like 1
Basal-like 2
Immunomodulatory
Mesenchymal-like
Mesenchymal stem-like
Luminal AR
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Mayer et al. CCR 2014, 20: 782 BCRT 2011; 125: 627
Schematic illustration of overlap among TNBC, basal-like, and BRCA1-related tumors
(80%)
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How to Target Advanced TNBC ?
Impaired repair of DNA (Homologous Recombination Deficiency) * BRCA dysfunction
Methylation Somatic mutation Other epigenetic mechanisms
Blood vessel growth
Increased sensitivity to platinum chemotherapy ? PARP inhibitors?
Role of angiogenesis Inhibitors (Bevacizumab)?
High growth rate Increased sensitivity to chemotherapy ?
* DFCI 2014
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Platinum in unselected TNBC
Regimen N Overall RR PFS (mo) Dz-free-interval
(median)
Gemcitabine/
carboplatin1
1st line
2nd/3rd line
258
148
110
30% 4.1
4.6
2.9
15 months
15.9 months
13.8 months
Carboplatin or
cisplatin2
1st line / 2nd line
86 30%
32% / 20%
3.2 NA
1. ASCO 2011 (abstr) 2. ASCO 2011 (abstr)
ORR in BRCA ½ mutant 55% vs.
26% in BRCA ½ wild type
Highlights need for biomarkers of platinum response
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TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC
• Primary endpoint: ORR in ITT population
• Secondary endpoints: PFS, OS, ORR (crossover), toxicity
• Subgroup analyses: BRCA1/2 mutation, basal-like subgroups, HRD biomarkers
Tutt A, et al. SABCS 2014. Abstract S3-01.
Patients with ER-, PgR-/
unknown, and HER2- or
BRCA1/2+ metastatic or
recurrent LA BC
(N = 376)
Carboplatin AUC6 q3w
x 6 cycles (n = 188)
Docetaxel 100 mg/m2 q3w
x 6 cycles ( n = 188)
For both arms, crossover upon progression allowed
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TNT trial: Overall Response Rate
0
10
20
30
40
50
60
70
80
90
Resp
on
se a
t C
ycle
3 o
r 6 (
%)
All Pts (n = 376)
BRCA1/2 Mutation (n = 43)
No BRCA1/2 Mutation (n = 273)
31.4% 35.6%
P = .44
68.0%
33.3%
P = .03
28.1%
36.6%
P = .16
Carboplatin
Docetaxel
Crossover
Tutt A, et al. SABCS 2014. Abstract S3-01.
Survival, Mos Carboplatin Docetaxel
Median PFS 3.1 4.5
BRCA 1/2 mutated 6.8 4.8
BRCA 1/2 not mutated 3.1 4.6
Median OS 12.4 12.3
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A new modality for breast cancer? Immune checkpoint agents and immunomodulators
Pembrolizumab (Keytruda) [Anti PD-1 therapy]
• High affinity for the PD-1 receptor • Recently approved in the US for the pts with unresectable or metastatic melanoma
T-cell Targets for Immunotherapy
Mellman I et al. Nature 2011; 480
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Phase Ib KEYNOTE-012:
Pembrolizumab Holds Promise in TNBC, Early Studies Suggest
Pts with recurrent or metastatic ER/
PgR-/HER2-, PD-L1+ BC (N = 32)
Pembrolizumab
10 mg/kg q2w
Nanda R, et al. SABCS 2014. Abstract S1-09.
Individual Evaluable Pts
Confirmed CR (nodal disease)
Confirmed PR
SD
PD
100
80
60
40
20
0
-20
-40
-60
-80
-100 Ch
an
ge F
rom
Baselin
e i
n S
um
of
Lo
ng
est
Dia
mete
r o
f Targ
et
Lesio
n (
%)
Overall Response rate: 18.5% (5/27)
Stable disease: 25.9% (7/27)
Progressive disease: 44.4% (12/27)
3 responding pts on treatment for > 11 mos
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TNBC: Current and Future Potential Therapeutic Targets 36/37
Recent update of systemic therapy: SUMMARY
• ER + MBC
– mTOR inhibitor or CDK4/6 inhibitor with endocrine therapy to overcome endocrine
resistance
• HER2 + MBC
– Pertuzumab and T-DM1 lead to improved outcomes with favorable toxicity.
• TNBC
– Recent renewed interest in investigating the role of platinum in TNBC.
– BRCA 1/2 mutation status: important potential biomarker for platinum therapy.
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Thank you for your attention!
CDK 4 and 6 inhibitor
• Oral, highly selective inhibitor of CDK4/6 kinase
• Prevent cellular DNA synthesis by prohibiting progression
of the cell cycle from G1 to S phase
HER2 dimerization is essential for HER2 activity: Pertuzumab and trastuzumab bind to different regions
on HER2 and have synergistic activity
trastuzumab
Pertuzumab
More complete blockade of HER2 signal transduction
TIL (tumor infiltrating lymphocyte)
Higher levels in TNBC
Higher level of TIL = better survival in TNBC
Loi et al. JCO 2013
Lymphocyte-predominant BC
Pembrolizumab in Advanced TNBC : Toxicity
Nanda R, et al. SABCS 2014. Abstract S1-09.
Adverse Events in ≥ 5%, % N = 32
Any Grade Grade 3-5
Arthralgia 18.8 0
Fatigue 18.8 0
Myalgia 15.6 0
Nausea 15.6 0
ALT increased 6.3 0
AST increased 6.3 0
Diarrhea 6.3 0
Erythema 6.3 0
Headache 6.3 3.1 (1 patient)
Cross-talk between signal transduction and endocrine pathways
Endocrine Rev. 2008; 29: 217-33.
HER2 targeted therapy adds modestly to endocrine therapy
PFS Anastrozole + Trastuzumab > Anastrozole
Kaufman et al, JCO 2008
PFS Letrozole + Lapatinib > Letrozole
Johnston et al, JCO 2009
Addition of HER2-directed therapy improves PFS but not OS
Choice of Chemotherapy in TNBC
• HR deficiency characterizes breast cancers in BRCA 1/2 mutation carriers
– Due to loss of heterozygosity
at BRCA1 or BRCA2
• HR deficiency implicated in some sporadic TNBC
– Methylation
– Somatic mutation
– Other epigenetic mechanisms
Breast Cancer Genome Sequencing Results
Ellis MJ et al. Nature 2012; 486: 353
The genome wheels show point mutations, copy number changes, and chromosomal Translocations in aromatase inhibitor (AI) sensitive and AI-resistant breast cancers.
PI3K inhibitors in clinical development
SABCS 2014
Phase III trial: MARIANNE 1st line HER2+ MBC
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