controversias y estrategias terapéuticas prometedoras en el cáncer de mama her2 positivo francisco...
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Controversias y estrategias terapéuticas prometedoras en el cáncer de mama HER2 positivo
Francisco J. Esteva, MD, PhDProfessor of Medicine
Department of Breast Medical OncologyMD Anderson Cancer Center
Houston, Texas
Francisco J. Esteva, MD, PhDProfessor of Medicine
Department of Breast Medical OncologyMD Anderson Cancer Center
Houston, Texas
Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness
Adapted from Hudis. N Engl J Med. 2007;357:39
Akt
SOS
RAS
RAF
MEK
VEGF
MAPK
P
P
PP
Receptor specificligands HER1, HER2,
HER3*, or HER4HER2
HER1(EGFR)
HER2HER4
HER3
Tyrosine kinasedomains
Plasmamembrane
PI3K
Cell proliferationCell survivalCell mobility and invasiveness
Cytoplasm
NucleusTranscription
Adapted from Esteva FJ and Hortobagyi GN. Sci Am 2008
HER2 Targeted Therapies
• Monoclonal Antibodies– Trastuzumab*– Pertuzumab– Trastuzumab-DM1
• Small Molecule TKIs– Lapatinib*– Neratinib
• Vaccines
*FDA-approved for breast cancer
YY
• First-line therapy as a single agent – Vogel et al. 2002
• Second-line therapy as a single agent– Cobleigh et al. 1999
• First-line therapy in combination with chemotherapy– Slamon et al. 2001, Marty et al.
2005• Adjuvant therapy in combination or
following chemotherapy– Romond et al. 2005, Piccart-
Gebhart et al. 2005
Trastuzumab Improves Outcomes in Women with HER2+ Breast Cancer
Capecitabine + Lapatinib Locally Advanced or Metastatic Disease
HER2 + stage IIIB or IIIC or metastatic disease
Randomization
Geyer et al. N Engl J Med. 2006;355(26):2733-2743.
Capecitabine 2000 mg/m2 PO BID days 1 - 14
Lapatinib 1250mg PO q day x 21 days
Capecitabine 2000 mg/m2 PO BID days 1 - 14
Results: Improved Time to Progression in patientsTreated with Cape/Lapatinib c/w Cape alone
Geyer et al. N Engl J Med. 2006;355:2733-2743.
Key Inclusion CriteriaKey Inclusion Criteria
• Stage IV invasive, measurable breast cancer• HER2+ by FISH or IHC (score, 3+)• No prior treatment for MBC• No prior HER2 inhibitor, other than adjuvant
trastuzumab• >12 months since adjuvant trastuzumab
• If neo/adjuvant taxane given, progression must have occurred 12 mo after completion of this treatment
• No CNS metastases or leptomeningeal involvementEsteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
An Evaluation of the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2+ Metastatic Breast Cancer
An Evaluation of the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2+ Metastatic Breast Cancer
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Diarrhea Incidence by Maximum Severity Grade
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Pharmacokinetics• The pharmacokinetic interaction between lapatinib and paclitaxel
observed at higher doses also occurs at lower doses• Additional data will be required to estimate the magnitude of this
interaction
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Efficacy Data: Response Rate
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Case Discussion
• 45 y/o female diagnosed with stage II left breast cancer (IDC ER/PR+), s/p mastectomy/reconstruction, FAC x 6, adjuvant tamoxifen
• After taking tamoxifen for 5 years, a routine chest x-ray showed pulmonary metastases. Biopsy: MBC, ER+, HER2+
• Treatment: letrozole -> exemestane -> trastuzumab (single agent)
Response to Trastuzumab
August 2001 December 2001
Progression on Trastuzumab
December 2001 January 2003
Lapatinib 1,500 mg PO (n=148)
Lapatinib 1,000 mg PO+ Trastuzumab 4mg/kg IV
load, then 2 mg/kg IV weekly(n=148)
R
HER2+ MBC,Previous
antrhacycline, taxane,
Trastuzumab (N=296)
LapatinibLapatinib +
TrastuzumabOdds Ratio P Value
Response Rate 6.9 10.3 1.5 0.46
Clinical Benefit Rate
12.4 24.7 2.2 0.01
Treatment Beyond Trastuzumab Progression in HER2+ MBC
O’Shaughnessy J, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015)
Patient Characteristics
ITT Population Lapatinib n = 148
Lapatinib + Trastuzumab n = 148
Median Age (Years) 51 52
% ECOG 0/1/2 47/49/4 54/41/5
Median Prior Chemotherapy Regimens
4 5
Median Prior Trastuzumab Regimens for MBC
3 3
> 6 Prior Treatment Regimens
28% 34%
HER2(+) 98.6% 99.3%
% HR(-) 51 51
O’Shaugnessy J, et al. J Clin Oncol. 2008;26(15S): Abstract 1015.
Cu
mu
lati
ve %
Alive w
ith
ou
t P
rog
ressio
n
Subjects At Risk
148148
LL+T
5373
2142
1327
58
02
0
20
40
60
80
100
0 10 20 30 40 50 60Time from Randomization (wks)
L N = 145
L+T N = 146
Progressed or Died, n 128 127
Median, wks 8.1 12.0
Hazard ratio (95% CI) 0.73 (0.57, 0.93)
P value 0.008
6 Mo PFS
13%
28%
Progression-Free SurvivalLapatinib + trastuzumab vs. Lapatinib in HER2+ MBC progressing on or after trastuzumab
O’Shaughnessy J, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015)
Trastuzumab and Lapatinib Resistance in Breast Cancer: Clinical Considerations
• Less than a third of patients with HER2+ MBC respond to single-agent trastuzumab or lapatinib
• Most responding patients develop progressive disease within one year.
• Approximately 15% of patients with early-stage breast cancer develop metastatic disease regardless of trastuzumab adjuvant therapy
Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107
MAPK PI3K
p27-cdk2cyclin D1
Alterations in downstream molecules: PTEN downregulation, increased Akt signaling, reduced p27kip1
HER-2
Increased receptor signaling: HER members, IGF-IR
Potential Molecular Mechanisms of Trastuzumab ResistanceY
Disrupted antibody-receptor interaction
Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107
p
p
pp
p
p
p
p
pp
p
p
p
p
pp
p
p
PI3-kinasep85
PKB(AKT)
mTOR/FRAP
p70S6K
ProliferationSurvival
DifferentiationCell metabolism
p
p110
PTEN
0
20
40
60
80
100
12-9 6-0
PTEN IRS
Res
po
nse
rat
e (%
) n=30 n=17*
CR+PRSD+PD
0
20
40
60
80
100
12-4 3-0
PTEN IRSR
esp
on
se r
ate
(%)
n=38
n=9**CR+PRSD+PD
Nagata Y et al. Cancer Cell 2004;6:117-127
Patients with PTEN deficient breast tumors have a poor response rate to Trastuzumab-based therapy
0 1 2 3 40
250
500
750RAD+HCPRADHCPDMSO
(N=7)
weeks
tum
or
size
(m
m3)
0 1 2 3 4 5 60
250
500
750TCN+HCPTCNHCPDMSO
* *
* p<0.05
(N=7)
weeks
tum
or
size
(m
m3)
Trastuzumab + RAD001 Trastuzumab + Triciribine
Combined treatment with PI3K inhibitors and Trastuzumab Significantly Inhibits the Growth of
PTEN AS- treated, BT 474 Xenografts
Agents tested in vivo: Perifosine, Edelfosine, Triciribine, KP-372-1, A838, RAD001
Lu CH, et al. Clin Cancer Res 2007
P
P
P
P
P P
P
P
TOR
PI3K
PTEN
src
Rapamycin
Trastuzumab
Akt
Her2/neu
Simultaneous Targeting of Her2 signaling at two levels:
Rationale for combining Rad001 and Trastuzumab
Phase I / II: Everolimus + Trastuzumab in HER2+ Patients With Resistance to Trastuzumab
Best Response N (%)N = 47
Complete response (CR) -
Partial response (PR) 7 (15%)
Stable disease ≥ 24 weeks (SD)
9 (19%)
Overall response rate 7 (15%)
Clinical benefit rate 16 (34%)
Median time to progression3.4 months
(Range 1-14)
Most frequent grade 3 / 4 adverse events (> 10%)
Lymphopenia, hyperglycemia,
mucositis
Everolimus 10 mg qdayand
Trastuzumab 6 mg/kg q3wk
Everolimus 10 mg qdayand
Trastuzumab 6 mg/kg q3wk
• Pts had ≤ 2 prior trastuzumab regimens and 1 prior lapatinib- based regimen for MBC
Morrow PK, et al. J Clin Oncol 28:7s, 2010 (abstr 1014)
Baseline PET scan (8/1/07)
PET scan after C2 (8/29/07)
SUV=9.1SUV=5.5
CT at Baseline (7/30/07) CT after Cycle 2 (9/20/07) CT after C12 (4/16/08)
PD after x 12 cycles (best response: SD)
Trastuzumab/RAD001Protocol 2005-0471 (Pt#10)
Molecular targets and therapeutic approaches to overcome trastuzumab and lapatinib resistance
Adapted from Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107
mTOR
Pertuzumab: a HER dimerization inhibitor
Prevents pairing with other HER
family members, including
HER3, HER1, and
HER4
0
5
10
15
20
25
30
0 0.1 1 10 100
Trastuzumab + 2C4 (ug/mL)
% A
nn
exin
V +
7-A
AD
Cells
0 0.1 1 10 0.1 1 10 0.1 1 10 PARPTrastuzumab 2C4 Trastuzumab + 2C4
Full length 116kD
89 kD
24 kD
Combination of Trastuzumab and Pertuzumab: Increased Apoptosis in vitro
Nahta. Nahta R, Hung MC, Esteva FJ. Cancer Res 2004;64:2343-6
Antitumor activity of trastuzumab and/or pertuzumab in NSCLC (Calu-3) and breast cancer (KPL-4) xenograft tumor models.
Scheuer W et al. Cancer Res 2009;69:9330-9336
©2009 by American Association for Cancer Research
HER2 A Good ADC Target• Tumor expression >>> Normal-tissue expression• Absolute Expression levels very high• Internalized without down regulation
Austin et al. (2004) Mol Biol Cell 15, 5268-82.
Trastuzumab-DM1– Binds to HER2 with affinity similar to trastuzumab– Provides intracellular delivery of anti-microtubule agent DM1
• Binds to tubulin competitively with vinca alkaloids, 20-100 times more potently than vincristine2-4
– Combines trastuzumab mediated inhibition of HER2 signaling with selective delivery of potent cytotoxic
Burris H A et al. J Clin Oncol 2011;29:398-405
Phase II study of trastuzumab-DM1 for the treatment of HER2+ breast cancer after prior HER2-directed therapy
Efficacy based on centrally assessed HER2 status and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) expression levels of HER2
Burris H A et al. J Clin Oncol 2011;29:398-405
Phase II study of trastuzumab-DM1 for the treatment of HER2-positive breast cancer after prior HER2-directed therapy
Ongoing and Planned Randomized Trials of Trastuzumab, Pertuzumab and T-DM1 in HER2+ Metastatic Breast Cancer
Combination Trial
Trastuzumab/Docetaxel +/- Pertuzumab CLEOPATRA (phase III)*
Trastuzumab/Docetaxel vs. T-DM1 Randomized phase II*
Trastuzumab/taxane vs.T-DM1 vs.T-DM1 + Pertuzumab
MARIANNE (phase III)*
T-DM1 vs. Capecitabine/Lapatinib EMILIA (phase III)**
*first-line**second-line after trastuzumab
Liang, et al. Cancer Cell 18:423-435, 2010
Trastuzumab& Erythropoietin
Liang, et al. Cancer Cell 18:423-435, 2010
Trastuzumab & Epo = Resistance
Liang, et al. Cancer Cell 18:423-435, 2010
Trastuzumab & Epo = Resistance
SRC is a Key Modulator of Trastuzumab Response
Zhang S., et al. Nat Med 2011
SRC Trastuzumab treatment plus SRC inhibition overcomes multiple resistance mechanisms in vitro
Zhang S., et al. Nat Med 2011
Trastuzumab plus SRC inhibition overcomes trastuzumab resistance in vivo
Zhang S., et al. Nat Med 2011
Trastuzumab plus saracatinib combinatorial treatment overcomes trastuzumab resistance in vivo
Zhang S., et al. Nat Med 2011
Zhang S., et al. Nat Med 2011
• Incorporate prospective tissue collection in clinical trials to assess molecular changes in breast cancer tissue
– Characterize mechanisms of action and resistance
– Identify patients most likely to benefit
• Preclinical and clinical development of novel combination targeting receptors and pathways
• Integrate non-invasive methods to monitor response to treatment
• Characterize the potential toxicity of long-term pathway blockade (especially important in adjuvant setting)
Future Directions
Thank you for your attention!