what’s new in her2: current issues in her2 positive breast cancer

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: 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

http://www.herceptin.com/hcp/

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


HER2“other” HER3

P PP


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


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

citab

ine

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


Lapatinib WITH Trastuzumab (Prior to Trastuzumab Resistance)

Trastuzumab monotherapy Trastuzumuab + Lapatinib combination

TrastuzumabTrastuzumab

LapatinibLapatinib


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

http://www.alttotrials.com/

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




ErbB1Trastuzumab

NeratinibNeratinib


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



p95HER2

Marrow, et al (2011)

Clinical Benefit 34%

Partial Response 15%

Stable Disease >6mo 19%

PFS 4.1 mos

Trastuzumab

EveroliumusEveroliumus


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


Apoptosis

PertuzumabPertuzumab

Trastuzumab


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



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



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

Stay in touch!

Biotherapy.vc.ons.org

•[email protected]•[email protected]

mailto:[email protected]

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: 3rd 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.

what’s new in her2: current issues in her2 positive breast cancer

Documents

receptor heterodimers

her2 mutation

her2 breast cancer

receptor recycling

receptor overexpression

current receptor activation

mitogenic signal

her3 heterodimers