recent update in management of breast cancergbcc2016.gbcc.kr/gbcc2014/upload/pfile_01_1_ed01-1...
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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
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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!
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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
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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
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TIL (tumor infiltrating lymphocyte)
Higher levels in TNBC
Higher level of TIL = better survival in TNBC
Loi et al. JCO 2013
Lymphocyte-predominant BC
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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)
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Cross-talk between signal transduction and endocrine pathways
Endocrine Rev. 2008; 29: 217-33.
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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
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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
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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.
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PI3K inhibitors in clinical development
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SABCS 2014
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Phase III trial: MARIANNE 1st line HER2+ MBC
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