what’s new in her2: current issues in her2 positive breast cancer kristine abueg, rn, msn, ocn®,...
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What’s New in HER2:Current Issues in HER2 Positive
Breast Cancer
Kristine Abueg, RN, MSN, OCN®, CBCN ®Oncology Clinical Trials
Kaiser Permanente, Roseville
Coordinator, 2011-2103Targeted and Biological Therapies
Special Interest Group
Today in a Nutshell• ErbB tyrosine kinase family receptor alterations
drive HER2+ breast cancer.• HER2+ mutation associated with poor outcomes.• Trastuzumab offers significant clinical benefit.• Current Challenges in HER2 breast cancer
– Effective Identification of appropriate populations– Overcoming trastuzumab resistance and recurrence
• Trastuzumab resistance and recurrence associated with alternative signaling pathways
• New agents in development target alternative signaling pathways
HER2 BIOLOGY….AS WE CURRENTLY UNDERSTAND IT
Part I
RH Gunby et al. Oncogenic Fusion Tyrosine Kinases As Molecular Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 2007; 7:594-611. Images created by Kristine Abueg.
HER1/EGFR
HER4HER 3HER 2
The Human Epidermal Growth Factor Receptor (HER) family of cell surface receptors
[ErbB = HER2]
Extracellular ( Receptor)Transmembrane Domain
Intracellular Kinase
Receptor Activation via two dimer formations.HER2 is the preferred dimer partner
Homodimerization Heterodimerization
Rowinsky. Oncologist. 2003;8(suppl 3):5-17. Yarden et al. Nature Rev Mol Cell Biol. 2001;2:127-137.Images created by Kristine Abueg
HER 3HER 2 HER 2 HER 2
Angiognesis Proliferation ↓ Apoptosis ↑Survival
P P
mTOR
PI3K
RafCell Signal Cascade
RAS
6
HER2 partnering results in the strongest signal
++
Signaling activity
+ ++
+
HER1:HER1
HER2:HER2HER3:HER3
HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4HER2:HER3
HER2:HER4
HER3:HER4
++++
+++
++
Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397.
HER2-positive clinical impact
• Associated with poor outcomes:– ↑ Distant metastases– ↑ Nodes + disease– ↑ Highest risk of recurrence– ↓Overall Survival– High grade tumors– Endocrine therapy resistance
• “Trastuzumab [and other HER2 targeted therapies] have changed the course of HER2 positive breast cancer (Mukohara, 2011)”
1. Antibody Dependent Cellular Toxicity (ADCC)– Attached trastuzumab
signals immune destruction
2. Prevents Intracellular Cell Signaling– Induces Apoptosis– Prevents Proliferation
Trastuzumab ‘s Dual-Kill Mechanism
Trastuzumab
Immune Cells
Cell Signaling Activation
Apoptosis
HER2
Immune Cells
Images created by Kristine Abueg
Pivotal Trastuzumab trials: Adjuvant
A: Doxorubicin (Adriamycin); C: Cylclophosphamide; T: Paclitaxel (Taxol); H: Herceptin (Trastuzumab)PFS: Progression Free Survival, OS: Overall Survival
BCIRG 006 (N=1073) (Slamon et al, 2011)
AC→Taxotere AC→Taxotere +H Taxotere +Carboplatin+ H
PFS 77% 83% 82%
OS 86% 92% 91%
HERA (N=3401) (Gainni, et al 2011)
Observation One year Trastuzumab
PFS 72.2% 78.6%
OS 89.3% 87.7%
Joint Analysis NCCTG 98331 and B-31 (Perez, et al 2011)
AC→T AC→TH
PFS 73% 86%
OS 89.4% 92.6%
Pivotal Trastuzumab trials: Adjuvant
A: Doxorubicin (Adriamycin); C: Cylclophosphamide; T: Paclitaxel (Taxol); H: Herceptin (Trastuzumab)PFS: Progression Free Survival, OS: Overall Survival
BCIRG 006 (N=1073) (Slamon et al, 2011)
AC→Taxotere AC→Taxotere +H Taxotere +Carboplatin+ H
PFS 77% 83% 82%
OS 86% 92% 91%
HERA (N=3401) (Gainni, et al 2011)
Observation One year Trastuzumab
PFS 72.2% 78.6%
OS 89.3% 87.7%
Joint Analysis NCCTG 98331 and B-31 (Perez, et al 2011)
AC→T AC→TH
PFS 73% 86%
OS 89.4% 92.6%
Pivotal Trastuzumab trials: Metastatic
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639-2648.
H0648g: First line Metastatic (Slamon, 2001)
AC AC + H Paclitaxel Paclitaxel + Herceptin
Overall survival
22.8 24.5 18.9 22.4
Time to progression
5.7 mos 7.6 mos 2.5 mos 6.7 mos
Cardiotoxicity 7% 28% 1% 11%
Pivotal Trastuzumab trials: Metastatic
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639-2648.
H0648g: First line Metastatic (Slamon, 2001)
AC AC + H Paclitaxel Paclitaxel + Herceptin
Overall survival
22.8 24.5 18.9 22.4
Time to progression
5.7 mos 7.6 mos 2.5 mos 6.7 mos
Cardiotoxicity 7% 28% 1% 11%
Pivotal Trastuzumab trials: Metastatic
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639-2648.
H0648g: First line Metastatic (Slamon, 2001)
AC AC + H Paclitaxel Paclitaxel + Herceptin
Disease Free Interval
22.8 24.5 18.9 22.4
Time to progression
5.7 mos 7.6 mos 2.5 mos 6.7 mos
Cardiotoxicity 7% 28% 1% 11%
Paradigm shift
• “Clearly, the results reported in this issue of the Journal are not evolutionary but revolutionary. The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow. However, trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer” Gabe Hortobayi, NEJM, 2005
Trastuzumab Side Effect Profilewww.herceptin.com
• Cardiomyopathy– Baseline and q3 mos LVEF (should be >50%)– S/S congestive heart failure
• Pulmonary Toxicity– Dyspnea, interstitial pneumonia, ARDS
• Neutropenia exacerbation• Infusion reaction (cytokine release syndrome)• GI: diarrhea, stomatitis• Risk to pregnancy
Trastuzumab: Key Patient Education
Schedule:– Weekly: Loading dose 4mg/kg over 90 min
followed by 2mg/kg over 30 min– Q3 week: Loading dose 8mg/kg over 90
followed by 6 mg/kg over 30 min
Trastuzumab regimens: AdjuvantAC→TH: Total regimen lasts 64 weeks• AC: Four cycles of Adriamycin® (doxorubicin) and Cytoxan® (cyclophosphamide) chemotherapy given
every 3 weeks; followed by• TH: Twelve cycles of Herceptin given weekly, along with 4 cycles of Taxotere® (docetaxel) given every 3
weeks OR 4 cycles of Taxol® (paclitaxel) given every 3 weeks OR 12 cycles of paclitaxel given weekly; followed by
• Fourteen cycles of Herceptin administered alone every 3 weeks to complete 52 total weeks (1 year) of Herceptin therapy
TCH: Total regimen lasts 52 weeks• TCH: Six cycles of Taxotere and Paraplatin® (carboplatin) chemotherapy given every 3 weeks, along with
18 cycles of Herceptin given weekly; followed by• Twelve cycles of Herceptin given every 3 weeks to complete 52 total weeks (1 year) of Herceptin
therapy
Herceptin monotherapy: Regimen lasts 52 weeks• Eighteen cycles of Herceptin administered every 3 weeks for 52 total weeks (1 year) of Herceptin
therapy• Herceptin is administered alone after receiving a full course of chemotherapy
Trastuzumab regimens: Metastatic
• Herceptin is administered alone or in combination with Taxol at an initial dose of 4 mg/kg
• Subsequent doses of 2 mg/kg given once weekly until disease progression or unacceptable toxicity occurs
7
Trastuzumab has offered significant benefit to our HEr2+ breast cancer population, however there is still some work to be done.
1. Identifying appropriate patients
2. Resistance
Challenge #1: Identification of appropriate populations
Objectives:1. Discuss current ASCO/NCCN guidelines for
HER2 testing.2. Discuss current controversies in HER2 testing
1. Accuracy2. Predictive value
3. Implications for patients and oncology professionals
In-Situ Hybridization (-ISH) “Quantitative” ratio of HER2 to normal genes (CEP17)
Invasive Breast Cancer Specimen
Immunohistochemistry (IHC)Subjective “scoring” of HER2 surface protein expression
IHC 1+
HER2/ CEP17 ≤ 2.0FISH neg = HER2-
No HER2 gene amplificationPaik, et al (2002).
HER2/ CEP17 > 2.0FISH positive = HER2+
HER2 gene amplificationAnti-HER2 therapy
IHC 3+Positive
IHC 0+HER2 Negative
IHC 2+Equivocal
IHC 1+HER2 Negative
Anti-HER2 therapy
Breast Specimen
Community Pathology Lab
“Reference” Pathology Lab
Study Findings
Mass, et al (2000) 18% lack of agreement
N9831 (Roche, et al 2002) 26-34% lack of agreement
NSABP B-31 (Paik, et al 2002) 21% lack of agreement
Testing Issue #1 How accurate are IHC and -ISH scoring?
Provocative Date leading to Re-examination of current practice patterns.
Clinical Implications• Validation of community labs• More stringent revision of ASCO/CAP guidelines
Wolff (2007); Raji (2007)
-ISH scores
1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4
-ISH Negative < 2.0 -ISH Positive ≥ 2.0Old guideline
-ISH - < 1.8 -ISH + ≥ 2.2Equivocal 1.8-2.2New guideline
Her 2 targeted Tx
Her 2 targeted TxRetest
Comparison of ASCO revisions
Paik, 2007
Testing Issue #2 How predictive areIHC and -ISH scoring?
HER2 neg patients still benefited from trastuzumab.
Study Findings
NSABP B-31 (Paik, et al 2002)
2007 Re-analysis
• Consistent benefit from trastuzumab in every subset
HERA trialSlamon, 2009
FISH score strength did NOT predict trastuzumab benefit
N9831Roche, et al, 2002
•FISH score strength did NOT predict trastuzumab benefit•FISH – still benefited from trastuzumab
Perez, et al (2010)
•FISH score strength did NOT predict trastuzumab benefit
Breast Specimen
Community Pathology Lab
“Reference” Pathology Lab
HER2-
HER2+
Clinical Implication:Expansion of HER2 “sensitive” definition?
• 2010 ASCO, Collins : Effect of trastuzumab on antibody-dependent cellular cytotoxicity (ADCC) in HER2 nonamplified (non-amp) breast cancer (BC) cells.– Demonstrated cell toxicity even when HER2 –
• Clinical trials on going: – trastuzumab in the IHC 1+– Trastuzumab in FISH negative
• Possible expansion of trastuzumab application• Possible revision of HER2 positive criteria
Wolff (2007); Raji (2007)
Despite trastuzumab’s significant survival benefit, a large proportion of HER-2 positive breast cancer will develop resistance, and ultimately recurrence and progression.
The key to understanding - and ultimately mitigating- this resistance lies in the HER2 signaling pathway.
• Steric hinderance (something getting in the way)
• Alternate signaling from other HER family member
• Alternate signaling from non-HER receptors
• Altered intracellular signaling
Resistance to trastuzumab: Proposed mechanisms
Trastuzumab
Cell Signaling Activation
HER2“other” HER3
P PP
Images created by Kristine Abueg
PART 2: New Anti-HER2 Agents
Objectives:1. Review of lapatinib mechanism, efficacy, side
effects, and patient management.
2. Investigational Agents1. Rationale for mechanism2. Published data & on-going trials
3. Implications for patients and oncology professionals
RH Gunby et al. Oncogenic Fusion Tyrosine Kinases As Molecular Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 2007; 7:594-611. Images created by Kristine Abueg.
HER1/ EGFR HER 3HER 2
LapatinibLapatinib
Anti-HER 2 AgentsAgent Mechanism
Trastuzumab Anti-HER2 MoAb
Lapatinib HER2/EGFR inhibitor
*Investigational Agents
*TDM-1 HER1 MoAb-chemo conjugate
*Pertuzumab Prevents HER2/HER3 binding
*Neratinib EGFR/HER2 inhibitor
*Everolimus P13K/PTEN/mTOR pathway
Neratinib
TDM-1Pertuzumab
Trastuzumab
Everolimus
Lapatinib Efficacy in Trastuzumab Resistant Disease• Trastuzumab “cleaves”
extracellular domain of HER2
• p95HER2 stimulates intracellular cell signaling
• Trastuzumab ineffective
• Lapatinib inhibits intracellular cell signalingCell Signaling Activation
p95HER2
Scaltriti, et al 2007; Mukohara 2011
Trastuzumab
Post- trastuzumab HER2
LapatinibLapatinib
Images created by Kristine Abueg
Lapatinib demonstrates prolonged progression free survival after trastuzumab failure
First Line 2nd line HER2+ after Trastuzumab/chemo
failure
1st line ER+/HER2+0
2
4
6
8
10
12
14
16
Capecitabine
Cape
cita
bine
Letr
ozol
e
Capecitabine + Lapatinib
Capecitabine + Lapatinib
Letrozole with Lapatinib
4.4 mos
8.4 mos
3 mos
8.2 mos
4.6 mos
6.75 mos
Johnston et al 2009, Schwartzerg, et al 2010. Cameron, et al 2008.Geyer, et al 2006
FDA Approved Indications: Lapatinib in Metastatic HER2+Disease
Scaltriti, et al 2007; Mukohara 2011
Lapatinib WITH Trastuzumab (Prior to Trastuzumab Resistance)
Trastuzumab monotherapy Trastuzumuab + Lapatinib combination
TrastuzumabTrastuzumab
LapatinibLapatinib
Images created by Kristine Abueg
Cell Signaling Activation Cell Signaling Activation
What is Lapatinib’s benefit prior to trastuzumab failure?
Surgery
Randomize
Lapatinib TrastuzumabConcurrent
Lapatinib + Trastuzumab
Sequential
Trastuzumab then Lapatinib
Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Trialwww.alttotrials.com; http://www.breastinternationalgroup.org
Options: Concurrent taxane chemotherapy
Ongoing data analysisClosed to “non-inferiority threshold”
Ongoing Adjuvant Trials
Combined targeting
AlttoAdjuvant Lapatinib
and/or Trastuzumab Treatment Optimisation
Trial
Lapatinib efficacy prior to trastuzumab failure?
Baseline
Lapatinib
Lapatinib + Paclitaxel
Trastuzumab
Trastuzumab + Paclitaxel
Lapatinib & Trastuzumab
Lapatinib + Trastuzumab +
Paclitaxel
Surgery
24.7% 51.3%29.5%
Pathological Complete Response
23% 21%2%
16% 9%3%
Baselga, 2010
DiarrheaNeutropenia
Skin 7% 7%3%
NEOAlttoNEOAdjuvant Lapatinib
and/or Trastuzumab Treatment Optimisation
Trial
Lapatinib: Ongoing NEOAdjuvant Trials
No significant cardiac toxicity in either arm
Lapatinib: Key Patient EducationDosing Instructions
– Empty Stomach: 1 hr before; 2 hrs after food– Take all at once (do not divide daily dose)– Metastatic with capecitabine: 1250 mg d1-d21
– Metastatic with letrozole: 1500 mg qD
Capecitabine 1500 mg/m2 BID d1-d14
Lapatinib 1250 mg qD d1-d21
Lapatinib 1500 mg qD continuously
Letrozole 2.5 mg qD continuously
Lapatinib Package Insert
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312247/table/TU1/
Lapatinib: Key Patient EducationInteractions
CYP3A4 inducers DECREASE Lapatinib
concentration.DECREASED Efficacy
• Alprazolam• Buspirone• Ca+ channel blockers• Dexamethasone• Erythromycine• Fentanyl• Simvastatine• St. John’s Wort
CYP3A4 inhibitorsINCREASE Lapatinib concentration.
INCREASED Toxicity• Grapefruit• Cimetidine• Amiodarone• Cyclosporines• Itraconazole• Ketaconazoles• Omeprazole• Clarithromycin
Lapatinib: Key Patient EducationCommon Side Effects
Recommend Frankel & Palmieri, 2010 CJON 14(2).• Gastrointestinal : Diarrhea (>20%)
– Generally mild– Baseline and ongoing assessment– BRAT diet; hydration– Loperamide (grade 2) and oncreotide (grade 3 or persistent)
• Dermatological: Rash (>50%)– Maculopapular or papulopustular rash– No documented correlation between severity and efficacy– Moisturize & Protect– Coverage >50% body surface or symptomatic – hold lapatinib, topical
corticosteroids and oral tetracyclines
Crown, et al 2009; Frankel and Palmieri 2010.
Lapatinib: Lab Monitoring
• Hepatic Parameters– AST or ALT > 3x Upper Limit of Normal– Total Bilirubin > 2x Upper Limit of Normal
• Cardiac Dysfunction– EKG changes: QT prolongation >480mSec– MUGA/ECHO changes: Ejection Fraction↓
but lower than with trastuzumab
Neratinib: Efficacy in Trastuzumab Resistant Disease
• Similar mechanism to lapatinib:– Trastuzumab “cleaves”
extracellular domain of HER2
– p95HER2 stimulates intracellular cell signaling
– Trastuzumab ineffective
• Neratinib blocks ErbB1, ErbB2, and ErbB4 & inhibits intracellular cell signaling
Post- trastuzumab HER2
Cell Signaling Activation
Scaltriti, et al 2007; Mukohara 2011
ErbB1Trastuzumab
NeratinibNeratinib
Images created by Kristine Abueg
p95HER2
Does Neratinib offer a benefit in metastatic breast cancer?
Baseline
Prior Trastuzumab
No prior Trastuzumab
24%
Burstein, 2009
Diarrhea (mild) 85%Nausea, fatigue, acneuform rash
26%
59% 78%23% 40%
Response Rate
40 week PFS
16 week PFS
Everolimus : Efficacy in Trastuzumab Resistant Disease
• Everolimus = mTOR inhibitor• Early Phase I/II data• mTOR + Trastuzumab
Post- trastuzumab HER2
Cell Signaling Activation
p95HER2
Marrow, et al (2011)
Clinical Benefit 34%
Partial Response 15%
Stable Disease >6mo 19%
PFS 4.1 mos
Trastuzumab
EveroliumusEveroliumus
Images created by Kristine Abueg
Antibody Drug Conjugate:TDM-1 (trastuzumab emtansine)
• Trastuzumab bound to cytotoxic chemotherapy
• Retains trastuzumab ADCC action
• Targeted chemotherapy delivery to cellIntracellular Chemo Delivery
Juntilla, 2010, Lewis, 2011,Scaltriti, et al 2007; Mukohara 2011
Trastuzumab
DM1
ApoptosisImages created by Kristine Abueg
Immune Cells
Immune Cells
TDM-1 efficacy, tolerability, and safety
HER2+ advanced disease
Docetaxel/Trastuzumab
TDM-1
58% 64%Overall Response
Hurvitz, et al Abstr 5001, ESMO, 2011. Perez, et al, Abstr LBA 3. ESMO, 2010
TDM4450gFirst line HER2 metastatic
9.5 months Not yet reachedMedian Duration
of Response
Docetaxel + Trastuzumab
TDM-1
Grade 3 or 4 89.4 46
Grade 3 Neutropenia 61 6
Thrombocytopenia 30 6.1
Alopecia 67 4
TDM-1 on-going clinical trials
• 2010 FDA submission for accelerate approval denied pending Phase III data completion
• 2nd line, Phase III (EMILIA) [closed to accrual]– TDM 1 vs. Capecitabine and Lapatinib
• 1st line, Phase II (MARIANNE) [closed to accrual]– TDM1/Pertuzumab vs. TDM1 vs. Docetaxel/Trastuzumab
• 3rd line, Phase II (THERESA) [pending]– TDM vs. Physician’s Choice
Heterodimerization Targeting:Pertuzumab (Omnitarg ®)
THREE ACTIONS• Blocks HER2/HER1 and
HER2/HER3 dimerization • Binds at separate site from
trastuzumab. Synergistic effect.
• Stimulates antibody-dependent cell-mediated cytotoxicity ADCC
Scaltriti, et al 2007; Mukohara 2011
Apoptosis
PertuzumabPertuzumab
Trastuzumab
Images created by Kristine Abueg
48
Among all possible dimers, the HER2:HER3 pair has the strongest mitogenic signaling
++
Signaling activity
+ ++
+
HER1:HER1
HER2:HER2HER3:HER3
HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4HER2:HER3
HER2:HER4
HER3:HER4
++++
+++
++
Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397.
Pertuzumab efficacy in the metastatic setting
Baseline
DocetaxelTrastuzumab
DocetaxelTrastuzumabPertuzumab
Baselga, 2012, Lenihan, 2011.
CLEOPATRA data
Series10.0
5.0
10.0
15.0
20.0
12.418.5
Prog
ress
ion
Free
Su
rviv
al
Pertuzumab efficacy in the metastatic setting
Baseline
DocetaxelTrastuzumab
DocetaxelTrastuzumabPertuzumab
46.3%
7.6 %
Baselga, 2012, Lenihan, 2011.
DiarrheaNeutropenia
Skin 24.2 %
CLEOPATRA data
66%
13.8%33.7%
No notable increase in cardiac effects.No notable increase in infusion reactions.
Most AE’s were grade 1-2 (ie mild)
Pertuzumab efficacy in the NeoAdjuvant Setting
HER2+ locally advanced
DocetaxelTrastuzumab
DocetaxelTrastuzumabPertuzumab
TrastuzumabPertuzumab
Docetaxel Pertuzumab
NeoSphere data Gianni (2012)
Series10%
10%20%30%40%50%
29.00%45.80%
16.80% 24.00%
Path
olog
ical
Com
plet
e Re
spon
se
Improved response with dual blockadeSome women with pCR WITHOUT chemo
Selected Pertuzumab on-going clinical trials
• FDA grants pertuzumab priority review for previously untreated HER2 positive metastatic breast cancer.
• Adjuvant, Phase III (B025126)– Chemo/Trastuzumab vs.
Chemo/Trastuzumab/Pertuzumab
• Metastatic, Phase II (M022324)– Capecitabine/Trastuzumab vs.– Capecitabine/Trastuzumab/Pertuzumab
Clinical Implications• HER2+ associated with significant mortality and
metastases.• Trastuzumab offers very significant survival
advantage. Consider expansion of indications?• New agents employing multiple blockades offer
increasing survival advantage.• Although PFS growing, ultimately vast majority of
metastatic patients will progress.• Next steps
– Ongoing vigilance for long term toxicity– Survivorship– Support clinical trial accrual
References• Baselga, J., (2010 Final Results of the NeoALTTO Trial (BIG01-06 / EGF106903): A Phase III, randomized, open-label, neo-adjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer, CTRC-AACR San Antonio Breast Cancer Symposium, S3-3l
• Burstein et (2010) Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. Journal of Clinical Oncology, 10; 28(8):1301-7.
• Cameron, D (2008) A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.” Breast Cancer Research and Treatment, vol 112, no3.pp533-543.
• Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease . J Clin Oncol. 1999;17:2639-2648.
• Crown, et al (2009) Pooled analysis of diarrhea events in patients with cancer treated with lapatinib Breast Cancer Research and Treatment, vol 113, no2.pp409-410.
• Geyer, eta l (2006) Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer (355), 2733-2743
• Johnston, S (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer, CJON 20 (27) 5538-5546.
• Junttila TT, Li G, Parsons K, Lewis Phillips G, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. August 21, 2010. doi:10.1007/s10549-010-1090-x.19.
• Lapatinib Package Insert. 2012. GSK.
• Lenihan, et al (2011) Pooled analyusis of cardiac safety in patients with cancer treated with pertuzumab Annals of Oncology,
• Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280-9290
• Morrow, PK, Wulf GM, Ensor, J et al (2011) Phase I/II study of trastuzmab in combination with everolimus (RAD001) in patients with HER2 overexpresing metastatic breast cancer who progressed on trastuzumab-based therapy. Journal of Clinical Oncology (29); 3126-3132.
• Mukohara T (2011), Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer. Cancer Science 102(1):108.
• Nahta, R & Esteva, F.J. (2006) Molecular mechanisms of trastuzumab resistance, Breast Cancer Research (8), 215.
• Paik, et al (2002) Real-world performance of HER2 testing - NSABP experience, Journal of the National Cancer Institute (94) 852-854.
• Perez, et al (2010) HER2 and chromosome 17 effect on patient outcomes in the N9831 Adjuvant Trastuzumab Trial.
• Piccart-Gebhart MJ. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. New England Journal of Medicine . 2005;353:1659-72.
• Raji, A. (2007) Human epidermal growth factor receptor 2 testing recommendation, Journal of Clinical Oncology (25), 4020-4021.
• Roche, et al (2002) Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831
• Romond EH, et al. (2005) Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. New England Journal of Medicine; 353:1673-84.
• Rowinsky. Oncologist. 2003;8(suppl 3):5-17. Yarden et al. Nature Review of Molecular & Cellular Biology. 2001;2:127-137.
• Scaltriti, et al (2007) Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer. Journal of the National Cancer Institute 99(8), 628-639.
• Slamon DJ, et al. (2001) Use Of Chemotherapy Plus A Monoclonal Antibody Against Her2 For Metastatic Breast Cancer That Overexpresses Her2. New England Journal of Medicine (344),783-792.
• Slamon, D. 2009 Abstract 62. San Antonio Breast Care Symposium: 3 rd analysis presentation at 65 months of follow-up: Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC -> T) with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC -> TH) with Docetaxel, Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast Cancer Patients: BCIRG 006 Study
• Schwartzerg, et al (2010) Lapatinib plus Letrozole as First-Line Therapy for HER-2 Hormone Receptor–Positive Metastatic Breast Cancer, The Oncologist (15), 122-129.
• Wolff, et al (2007) American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer, Archives of Pahtollgy and Laboratory Medicinem 131 , 18-34.