emerging medical treatments and future directions stefano iacobelli cancer clinic & laboratory...
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Emerging Medical Treatments and
Future Directions
Stefano Iacobelli
Cancer Clinic & Laboratory of Molecular Oncology
On behalf of the Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)
Breast Cancer Facts
Over 1 million new breast cancer cases are reported each year
~ 10% of new diagnosed BC patients are locally advanced or metastatic disease, and 20-60% of the remaining patients develop systemic relapse
~ 40% of the patients will die of breast cancer
Reason: Development of drug resistance in metastatic disease
Metastatic breast cancer remains an incurable disease
Gueth U et al. Oncology 2009 However…
Advances in Medical Treatment
1980 1985 1990 1995 2000 2005
Capecitabine
Bevacizumab
Paclitaxel
CMF
Gemcitabine
Albumin-Bound Paclitaxel
Trastuzumab
Lapatinib
Doxorubicin
EpirubicinMitoxantrone
Vinorelbine
Docetaxel
HER2+
Aromatase Inhibitors
Tamoxifen
ER+ or PR+
Ixabepilone
Fulvestrant
The use of newer therapeutic agents has been associated with improved
survival in MBC over time
Chia SK et al. Cancer 2007
HER-2
VEGF (R)
PARP
Three Key Clinical Advances
All In Targeted Therapies
Molecular Targets andTherapies Being Developed for Breast
Cancer
Normanno N et al. Endocr Rel Cancer 2009
However
In advanced breast cancer, primary resistance toTrastuzumab is frequent (60–70% of pts with Trastuzumabmonotherapy; 30–50% of pts with Trastuzumab pluschemotherapy)
Eventually, all advanced breast cancer patients becomeresistant to Trastuzumab within months or years
CNS is a frequent metastatic site and Trastuzumab isineffective for CNS MTS ( CSF levels 300-fold lower than inthe serum)
Trastuzumab represents the foundation of
treatment of HER2+ Breast Cancer
Altered Target Steric hindrance of receptor by cell surface proteins (MUC4)1
Truncated form of receptor (p95)2
Mutations in HER23
Increased circulating HER2 ECD
Alternativepathway signaling
IGF1R overexpression4
VEGF overexpression5
AlternativeHER signaling
HER1/HER3 heterodimers or HER1/HER1 homodimersIncreased levels of ligand (heregulin, EGF, TGFα)6
Costitutiveactivation ofdownstreameffectors
Reduced level of PTEN7
Reduced p27kip1 8
Increased AKT activity9
Molecular mechanisms of Trastuzumab resistance
9 Berns K et al. Cancer Cell 2007
1 Nagy P et al. Cancer Res 2005
2 Scaltriti M et al. J Natl Cancer Inst 2007
3 Prempree C et al. JCO 24: 611s, 2006
4 Nahta R et al. Cancer Res 2005
5 du Manoir JM et al. Clin Cancer Res 2006
6 Motoyama AB et al. Cancer Res 2002
7 Nagata Y et al. Cancer Cell 2004
8 Nahta R et al. Cancer Res 2004
Targeting HER2-beyond trastuzumab
Newer mAbs targeting the HER receptor family
- PERTUZUMAB- ERTUMAXOMAB
TKIs to HER2- receptor family- LAPATINIB- NERATINIB- JNJ-28871063
Trastuzumab-DM1
IHC 3+
FISH +
Different sites of action of various drugs acting on the HER-2 receptor signaling
pathway
Vora T et al. 2009
Pertuzumab
Humanized monoclonal antibody targeting the HER2 extracellular domain II
The combination of Pertuzumab with Trastuzumab has been shown to induce greater ADCC, receptor down-regulation and growth inhibition of tumor cells
Spiridon CI et al. Clin Cancer Res 2002
Prevents HER2 heterodimerization
Potent inhibitor of HER-mediatedsignalling pathways
Response N=66
CR 5 (7.6%)
PR 11 (16.7%)
ORR 16 (24.2%)
SD > 6 mos 17 (25.8%)
Phase II Trial of Pertuzumab and Trastuzumab in Patients With HER2–Positive Metastatic Breast
Cancer That Progressed During Prior Trastuzumab Therapy
Trastuzumab weekly (4 mg/kg loading dose, then 2 mg/kg every week) or every 3 wks (8 mg/kg loading dose, then 6 mg/kg every 3 wks)Pertuzumab every 3 weeks (840 mg loading dose, then 420 mg every 3 wks)
median PFS 5.5 months(range, 0.9 to 17.0 months)
- Grade 1 or 2 diarrhea (64%) fatigue (33%) nausea (27%)
- Only four G3 treatment-related event(2 cases of diarrhea, 1 central line infection, and 1 pruritic rash).
- no clinically significant cardiac events
Toxicities
Baselga J, J Clin Oncol 2010
CLEOPATRA: Phase III study of Trastuzumab + Pertuzumab in HER2+
MBC
1:1 randomisation
UntreatedHER2+ MBC
n=800
Herceptin + docetaxel + placebo
Herceptin + docetaxel + pertuzumab
An international Phase III randomised, double-blind, placebo-controlled study (approximately 250 sites worldwide)
End points:
Progression-free survival
Overall survival
Quality of life
Biomarker analysisExpected to be completed by March 2012
Ertumaxomab Ertumaxomab is a trifunctional, bispecific mAb targeting HER2 and CD3
It binds to HER2 positive tumor cells, T cells and fcγ receptor positive accessory immune cells (macrophages, dendritic cells and NK cells)
This tri-cell structure causes co-stimulation of T-cells resulting in the release of cytokines and lytic enzymes (e.g. perforin) and phagocytosis of tumor cells by the fcγ receptor positive cells
Zeidler RBr J Cancer 2000
Phase I Trial of the Trifunctional Anti-HER2 Anti-CD3 Antibody Ertumaxomab in MBC
Kiewe P et al. Clin Cancer Res 2006
6-h infusion
17 patients with HER2 positive MBCToxicities
Strong Th1 immune response
Doses up to 100 μg can be safely infused with close monitoring of pts. The observed clinical responses (ORR, 5/15) are encouraging and indicate antitumor efficacy
Infusion Reactions
Lapatinib inhibits EGFR and HER2
LAPATINIB GEFITINIB ERLOTINIB
ErbB1 3.0 ± 0.2* 0.4 ± 0.1* 0.7 ± 0.1*
ErbB2 13 ± 1* 870 ± 90* 1000 ± 100*
ErbB4 347 ± 16‡ 1130 ± 370‡ 1530 ± 270‡
*Kiapp (nM); ‡cKi
app (nM); gefitinib and erlotinib are ErbB1 inhibitors
N
N
O O
NH
O O
NH
S
O
N
N
NH
Cl
OO
O
F
N
O
N
N
O O
NH
Cl F
The slowoff-rate, bound EGFR structure, and dual ErbB1 and Erb2 inhibitionprofile differentiate Lapatinib from the other agent
PI3K/Akt pathwayPI3K/Akt pathwayMAPK pathway MAPK pathway (Ras/Raf/(Ras/Raf/MEK/ERK)MEK/ERK)
Lapatinib Acts Intracellularly, Directly Inhibiting Downstream Signals
Ligands
ErbB2Other ErbB
ProliferationProliferation Cell cycle, SurvivalCell cycle, Survival
PI3K/Akt pathwayMAPK pathway (Ras/Raf/MEK/ERK)
Lapatinib
Treatment continued until progression
Patients with ErbB2-positive locally advanced or metastatic breast cancer
that progressed after prior anthracycline, taxane and
trastuzumab(N=399)
RANDOMISATION
Lapatinib 1250 mg po qd continuously +
capecitabine 2000 mg/m2/d po days 1–14 q 3 wk
Capecitabine 2500 mg/m2/day
po days 1–14 q 3 wk
po = oral; qd = once daily; q 3 wk = once every 3 weeks
EGF 100151: Phase III, randomised, controlled study of lapatinib plus capecitabine vs
capecitabine alone
Cameron et al. Breast Can Res Treat 2008; Geyer et al. N Engl J Med 2006
Outcome Lapatinib +capecitabine (N=198)
Capecitabine
(N=201)
Hazard ratio(95% CI)
Odds ratio
(95% CI)
p-value
Median TTP (weeks [months])*
27.1 (6.2) 18.6 (4.3)0.57 (0.43,
0.77)– 0.00013
ORR (%) 23.7 13.9 –1.9 (1.1,
3.4)0.017
EGF 100151 study: Lapatinib plus capecitabine: significantly longer TTP in difficult to treat
population
Cameron et al. Breast Can Res Treat 2008
EGF100151 StudyMost Frequent Adverse Events All
Grades
L = Lapatinib; C = capecitabineCameron et al. Breast Can Res Treat 2008
Lapatinib inhibits p-Akt in a dose- and time-dependent manner in PTEN-null MDA-MB-468 BC cells
Low (1+) High (3+) Negative (0)
Phase II trial of Lapatinib alone in IBC
Cancer Res 2007
Scaltriti et al. J Natl Cancer Inst 2007
Lapatinib is active against tumours expressing p95ErbB2 variant
An estimated 30% of BCs overexpressing HER2 co-espress p95HER2
Preclinical evidence demonstrated that Lapatinib retains activity in models expressing p95HER2
Pedersen K et al. Mol Cell Biol 2009
EGF 104900: Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory MBC
HER2+ MBC pretreated with Trastuzumab,
Anthra, Taxane(n=296)
Lapatinib1500 mg/day
p.o.(n=148)
Lapatinib 1000 mg/day
+Trastuzumab
4 2 mg/kg IV qw(n=148)
Primary endpoint: PFS based on RECIST criteriaSecondary endpoints: ORR, CB, OS, QoL, safety Blackwell KL et al. J Clin Oncol 2010
R
Crossover if PD after4wk therapy (N = 73)
EGF 104900: Survival Analyses
The median PFS was 8.1 vs 12 wkslapatinib alone vs combination armHR 0.73 (95% CI, 0.57 to 0.93; P.008)
Improvement in PFS for the combination arm
Blackwell KL et al. J Clin Oncol 2010
Neratinib (HKI-272)
Oral, pan-HER (ie, HER1, HER2, and HER4) TKI
Rabindran SK et al. Cancer Res 2004
In a phase I study, MDT was 320 mg/day. Common AEs were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), and vomiting (29%)
Advanced HER2 + BC (N=136)
Neratinib 240 mgPrior trastuzumab
treatment(n = 66)
Neratinib 240 mgNo prior
trastuzumab treatment(n = 70)
Phase II study of Neratinib in pts with Advanced HER2 positive Breast Cancer
Primary end point: 16-week PFS rate
Burstein HJ et al. J Clin oncol 2010
Efficacy analysis and safety
Tumor Responses
Diarrhea was the most frequent grades 3 to 4 AE
Burstein HJ et al. J Clin oncol 2010
JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain BarrierBT474 ErbB2-overexpressing
breast carcinoma model
Drug plasma and tissue distribution ofJNJ-28871063 and lapatinibin nude mice bearing A431 Xenografts
L
J
N87 intracranial model5 x104 cells were injected intracranially, and animals (n=10) were treated with vehicle or 200 mg/kgJNJ-28871063 daily for 50 days
mTTP
mTTP
JNJ-28871063 significantly extended survival by 31.3%
Emanuel SL et al. Mol Pharmacol 2008
Trastuzumab-DM1 (Tmab-MCC-DM1) Immunotoxin: Ab delivery of the toxin; internalization via endocytosis induces toxin release inside the tumor
T-DM1 combines biological activity of trastuzumab with targeted delivery of DM1
DM-1: maytansine (potent microtubule destabilizing agent)
Activity in trastuzumab resistant cancer cell lines
• SK-OV-3 (Her2 2 +): ovarian carcinoma• Calu-3 (Her2 3 +): lung adenocarcinoma• BT-474-EI (Her2 3 +): breast tumor cells• MKN7 (Her2 2 +): gastric carcinoma
In a phase I study, T-DM1 was well-tolerated at the MDT of 3.6 mg/kg IV q21, with no cardiac toxicity. Grade 3-4 toxicities were thrombocytopenia and neutropenia. ORR was 44%.
Lewis Phillips GD et al. Cancer Res 2008Beeram M et al. ASCO 2008 (Abstr 1028)
Trastuzumab-DM1* q3w
ORR,safety/
Tolerability,
PFS
*3.6 mg/kg as 30- to 90-min continuous infusion.
Vukelja S, et al. SABCS 2008. Abstract 33. Vogel C, et al. ASCO 2009. Abstract 1017.
EndpointsProgression
within 60 daysof HER2-directed
therapy
Trastuzumab only
(n = 45)
Trastuzumab
+ Lapatinib
(n = 67)
HER2+
(IHC 3+ or FISH+)
MBC
(N = 112)
A phase II study of Trastuzumab-DM1in pts with HER2 positive MBC
Trastuzumab-DM1 in HER2-Positive MBC: Treatment History
Vogel C, et al. ASCO 2009. Abstract 1017.
Previous Chemotherapy and Anti-HER2 Therapy
Patients (N = 112)
Chemotherapeutic agents, median n (range)
3 (1-12)
Previous anthracycline, n (%) 78 (69.6)
Previous taxane, n (%) 94 (83.9)
Median duration of previous trastuzumab therapy, mos (range)
17.8 (1-152)
Previous lapatinib therapy, n (%) 67 (59.8)
Median duration of previous lapatinib therapy, mos (range)
6.0 (1-24)
Vogel C, et al. ASCO 2009. Abstract 1017.
Response Summary
Assessment
IRF(N = 112)
Investigator (N = 112)
Best objective response, n (%)
CR 0 3 (2.7)
PR 28 (25.0) 40 (35.7)
SD 54 (48.2) 43 (38.4)
PD 21 (18.8) 22 (19.6)
Unknown 9 (8.0) 4 (3.6)
ORR, n (%) 28 (25.0) 43 (38.4)
Clinical benefit,* n (%)
39 (34.8) 50 (44.6)
* CR, PR, or SD for ≥ 6 mos.
Trastuzumab-DM1 in HER2+ MBC:
Antitumor Activity
Response SummaryAssessment
IRF Investigator
Pts previously treated with trastuzumab and lapatinib
(n = 67) (n = 67)
ORR, n (%) 16 (23.9) 24 (35.8)
Clinical benefit,* n (%) 24 (35.8) 30 (44.8)
Pts with centrally confirmed HER2+
(n = 75) (n = 75)
ORR, n (%) 24 (32.0) 36 (48.0)
Clinical benefit,* n (%) 33 (44.0) 41 (54.7)
Subgroups analysis
Trastuzumab-DM1 in HER2-Positive MBC: PFS
Vogel C, et al. ASCO 2009. Abstract 1017.
0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10
Pro
po
rtio
n E
ven
t F
ree
14PFS (Mos)
IRF (N = 112) median: 4.9
INV (N = 112) median: 4.9
12
Median Follow-up 9.5 months
Trastuzumab-DM1 in HER2-Pos MBC: AEs
Any AE, n (%) Grade 1 or
2Grade 3 Grade 4 All Grades
Fatigue 72 (64.3) 5 (4.5) 0 73 (65.2)
Nausea 55 (49.1) 1 (0.9) 0 56 (50.0)
Headache 43 (38.4) 0 0 43 (38.4)
Pyrexia 39 (34.8) 1 (0.9) 0 39 (34.8)
Epistaxis 36 (32.1) 2 (1.8) 0 38 (33.9)
Thrombocytopenia NR 5 (4.5) 3 (2.7) NR
Constipation 33 (29.5) 0 0 33 (29.5)
Eye disorders 31 (27.7) 0 1 (0.9) 32 (28.6)
Cough 30 (26.8) 0 0 30 (26.8)
Diarrhea 29 (25.9) 0 0 29 (25.9)
Hypokalemia 22 (19.6) 9 (8.0) 0 27 (24.1)
Dyspnea 23 (20.5) 2 (1.8) 1 (0.9) 24 (21.4)
Pain in extremity 24 (21.4) 0 0 24 (21.4)
Vogel C, et al. ASCO 2009. Abstract 1017.
P<0.0001
Response Rates for Novel HER2-Targeting Agents after Progression
on Trastuzumab
Angiogenesis Inhibitors
Monoclonal Antibodies
- BEVACIZUMAB
Primarly antiangiogenic multitargeted TKIs
- PAZOPANIB- AXITINIB- SUNITINIB
HR = 0.51
+/- Bevacizumab 10 mg/kg q2w
First-line T herapy of MBC with Bevacizumab Added to Paclitaxel Improved PFS
Miller K et al. N Engl J Med 2007
Three prior Phase III trials (E2100, AVADO, and RIBBON-1) have established a consistent improvement in PFS with the combination of Bevacizumab with various cht as first-line treatment for MBC A previous Phase III study (AVF2119) in pts with heavily pre-treated MBC, in which bevacizumab was combined with Capecitabine, did not meet the primary end-point of PFS, but resulted in a significant increase in ORR RIBBON-2 was designed to evaluate the clinical benefit of combining Beva with various cht used to treat MBC in II line
RIBBON-2: A randomized phase III trial of Bevacizumab with cht for II line HER2neg MBC
Brufsky A et al. SABCS 2009
Bevacizumab15 mg/kg q3w or 10 mg/kg q2w
Brufsky A et al. SABCS 2009
RIBBON-2 is the first positive phase III study of bevacizumab in second-line MBC
A Phase II study of GW786034 (pazopanib) in pts with recurrent or metastatic breast cancer
Taylor SK et al. ASCO 2009Background
Pazopanib is an oral small molecule tyrosine kinase inhibitor of VEGFR1, 2, and 3, PDGFRα and β, and KIT A phase I study reached doses up 2000 mg/d DLT in 1/3 patients at 200 mg/d (grade 3 fatigue) Activity was seen with daily doses of > 800 mg
Elegibility
Metastatic or recurrent BC Up to 2 lines of cht If HER2 positive, must be trastuzumab refractory If ER+, must be hormone refractory No prior bevacizumab
Primary Endpoint- Anti-tumor efficacy: RR (RECIST)
This trial did not meet the criteria to go to stage 2 based on ORR
Pazopanib appears to have similar activity of other VEGF inhibitors in advanced pretreated breast cancer, bevacizumab and sunitinib (CBR 26%, TTP 5.3 months, vs. bevacizumab, CBR 16%, TTP 2.4 mo.; and sunitinb, CBR 17%, TTP 2.3 mo.)
These results suggest that there is minor cytotoxic as well as clear cytotoxic activity of pazopanib in advanced breast cancer, and it may be useful in studies of combination therapy
Pazopanib was well tolerated (G>3 Leuko-neutropenia; hypertension; AST, ALT)
Cobleigh et al. Semin Oncol 2003
Taylo SK et al. ASCO 2009
Burstein et al. JCO 2008
A randomized, phase II study of axitinib (AG-013736) in combination with docetaxel compared to DOC plus placebo in MBC
Rugo HS et al. ASCO 2007 Abstr 1003
Axitinib (AG-013736) a potent TKI targeting all VEGFR isoforms, PDGFR and c-KIT1
Previous phase I study identified appropriate doses of docetaxel and axitinib2 (DOC 80 mg/m2 q3w with axitinib 5 mg twice daily )
1Sloan B et al. Curr Opin Investig Drugs 2008 2Rugo HS et al. ASCO 2005 Abstr 1067
Docetaxel 80 mg/mq q3w+
Axitinib 5 mg twice dailyn=112
Docetaxel 80 mg/mq q3w+
Placebon=56
Pts with MBC not pretreated with
cht for metastatic
diseasen=168
Randomized 2:1
Primary Endpoint: TTP
Outcome
Docetaxel+
Axitinib(n=112)
Docetaxel+Placebo(n=56)
CR (%) 0.9 0
PR 39.3 23.2
SD 8.9 16.1
PD 33.9 42.9
Unknown 17 17.9
ORR, n (%) 40.2 23.2
Median TTP, mos 8.2 7
P value
0.038
0.052
Toxicities
Docetaxel and axitinib associated with a higher incidence of grade 3/4 febrile neutropenia, fatigue, stomatitis, hypertension, and thromboembolic events
Results
Axitinib has promising anti-tumor activity for pts with breast cancer
A Phase III Trial of Sunitinib (SU) Vs. Capecitabine (C) in Pts with Previously Treated HER2-Negative Advanced Breast Cancer (ABC)
HER2 negative ABC resistant to
Anthra and Taxane(n=464)
Sunitinib 37.5 mg daily(231)
Capecitabine 1250 mg/mq x2 /die d1-14 q21
(233)
Randomized 1:1
mPFS 2.8 vs. 4.2 mos for SU vs. C (p<0.001)ORR 9.1 vs. 12.9
Sunitinib is not superior to Cap given as monotherapy. Cap was better tolerated than SU. Sunitinib cannot be
recommended as monotherapy on this dosing schedule
.
Barrios C et al. SABCS 2009 Abs 46
Trial stopped for futility
Poly (ADP-ribose) polymerase (PARP)
PARP1-Inhibitors
AZD2281 Olaparib
BSI-201
PARP1 structure
PARP inhibition
and tumor-selective synthetic lethality
Peralta-Leal A et al, Free Radic. Biol. Med. 2009
CELLSURVIVAL
Tumor-selective
cytotoxicity
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient ABC
Tutt A et al. ASCO 2009, Abst # CRA 501
Confirmed BRCA1 or BRCA2 mutationAdvanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure of ≥ 1 prior chemotherapyFor advanced disease
Cohort 1 (enrolled first)
Olaparib 400 mg po bid (MDT)
28-day cycles; n = 27
Cohort 2*
Olaparib 100 mg po bid (MDT)
28-day cycles; n = 27* Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg bid cohort were permitted to crossover to receive the 400 mg bid dose
MDT determined during Phase I evaluation
- Median 3 prior cht treatments- In higher dose cohort, two thirds had BRCA1 mutation
Primary End-point: ORR by RECIST
ITT cohortOlaparib
400 mg bid(n=27)
Olaparib100 mg bid
(n=27)
Overall Response Rate, n (%) 11 (41)* 6 (22)*
Complete Response, n (%) 1 (4) 0
Partial Response, n (%) 10 (37) 6 (22)
Olaparib in Mutation Carriers: RESULTS
Tutt A et al. ASCO 2009, Abst # CRA 501
Phase II trial of BSI-201 in combination with gemcitabine/carboplatin in metastatic TNBC
O'Shaughnessy J et al. ASCO 2009 Abs 3Metastatic TNBC
Prior chemon = 120
RANDOMIZE
Gemcitabine 1000 mg/mq d 1, 8Carboplatin AUC 2 d 1, 8
BSI-201 5.6 mg/kg IV d 1, 4, 8, 11Gemcitabine 1000 mg/mq d1, 8Carboplatin AUC 2 d 1, 8
RESTAGINGEvery 2 cycles
* Pts randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression
21-daycycle
Striking early results Need confirmation in phase III trial Presumption is that PARPi interferes with chemo-induced DNA repair
O'Shaughnessy J et al. ASCO 2009 Abs 3
Resistance to PARP-Inhibitors
With the development of any active agent, resistance is sure to come
Many potential mechanisms
In a BRCA2-deficient cell line, resistance to PARP inhibition has been associated with restoration of BRCA2 function
Edwads et al, Nature 2008
Baselga J et al. SABCS 2009
Swaby et al. ASCO 2009, Abstr 1004
Phase I/II Neratinib + Trastuzumab in Trastuzumab-treated MBC
Conclusions
The list of the most promising agents in MBC is far from being complete
Novel molecules are being discovered and developed constantly
To better optimize BC therapy in the future, clinical trials testing new agents will need to meet rigorous patient selection criteria, and secure the collection of appropriate biological material.
Rationale for Targeting HER2 in Breast Cancer
Rosen LS et al. Oncologist 2010Spector NL et al. J Clin Oncol 2009Bacus SS et al. Oncogene 2002Xia W et al. Cancer Res 2006Yakes FM et al. Cancer Res 2002
20 to 25% of BCs exhibit HER2 gene amplification or protein overexpression
HER2 overexpression in BC predicts for a poor clinical outcome
It deregulates downstream signaling pathways, which impact on tumor cell growth and survival.
Concomitant up-regulation of the PI3K-AKT survival pathway and of NFkB that protects against apoptotic stimuli (eg, chemotherapy). Survivin also is regulated by HER2.
Blockage of HER2 leads to the inhibition of these survival pathway with tumor cell apoptosis