Trastuzumab

SYMPOSIUM TRASTUZUMAB IN EARLY BREAST CANCER 29/05/2012 DR. R. RAJKUMAR

II YR POST GRADUATE DEPT OF MEDICAL ONCOLOGY MADRAS MEDICAL COLLEGE CHENNAI

QUESTION

• Trastuzumab:– A. Is indicated for all adjuvant

breast cancer treatment– B. Marginally improves overall

survival– C. Requires Her 2 neu

overexpression for efficacy– D. Is not yet approved for breast

cancer treatment

ANSWER

• Trastuzumab requires Her 2 neu overexpression for efficacy– Trastuzumab is indicated only for

breast cancers that overexpress Her 2 neu, is associated with a significant improvement in overall survival in the adjuvant setting, and is FDA approved for adjuvant and metastatic breast cancer

Cobleigh, MA et.al., J Clin Oncol 1999 Sep; 17(9): 2639-48Slamon, DJ et.al., N Eng J Med 2001 Mar 15; 344(11): 783-92Romond, EH et.al., N Eng J Med 2005; 353: 1673-1684

ANSWER

1. AGREE2. DON’T AGREE3. DON’T KNOW4. AGREE FOR THE TIME BEING

ANTI HR+ & ANTI HER2+ CROSS TALK

1. AGREE2. DON’T AGREE3. DON’T KNOW

ANTI HR+ & ANTI HER2+ CROSS TALK

QUESTION 1. IT CAN BE OVERWHELMED2. NO WAY3. DON’T KNOW

HER 2 & TOP II ᾀ CO - AMPLIFICATION

QUESTION CHOICE OF CHEMOTHERAPY

1. ANTHARCYCLINE BASED2. TAXANE BASED3. COMBINATION4. NONE

HER 2 & TOP II ᾀ CO AMPLIFICATION

QUESTION

1. 50%2. 73%3. 35%4. 30%

• Localized to chromosome 17q• Tyrosine kinase transmembrane growth factor

receptor• Member of EGFR gene family• In 85% of 120 publications (> 20,000 patients

total),abnormal HER2 expression has been linked with adverse outcome in breast cancer

HER2 Gene: Background

Ross and Fletcher. Semin Cancer Biol. 1999;9:125.Pegram and Slamon. Semin Oncol. 2000;27(suppl 9):13.Data on file, Genentech BioOncology.

Normal (1x)~ 25,000-50,000 HER2 receptors

Overexpressed HER2 (10-100x)

up to ~ 2,000,000

HER2 receptors

Excessive cellular division

HER2 Overexpression in Breast Cancer

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):Slamon DJ, et al. Science. 1987;235:177-182.

HER2 is overexpressed in ~ 25% of breast cancers

HER2 Overexpression Shortens Survival

HER2 oncogeneamplification

HER2 oncoproteinoverexpression

Shortened survivalMedian Survival From First DiagnosisHER2 overexpressing

3 yrsHER2 normal

6-7 yrs

Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ, et al. Science. 1989;244:707-712.

OVEREXPRESSION AMPLIFICATION

(PROTEIN) (DNA)

Methods for Testing HER2 Status

IHC FISH

Methods for Testing HER2 Status

ASCO/College of American Pathologists Guidelines for HER2 Testing in Breast Cancer

Positive for HER2 is either immunohistochemistry (IHC) HER2 3+ (defined as uniform intense membrane staining of >30% of invasive tumor cells) or FISH amplified (ratio of HER2 to CEP17 of >2.2 or average HER2 gene copy number >6 signals/nucleus for those test systems without an internal control probe)

Equivocal for HER2 is defined as either IHC 2+ or FISH ratio of 1.8–2.2 or average HER2 gene copy number 4–6 signals/nucleus for test systems without an internal control probe

Negative for HER2 is defined as either IHC 0–1+ or FISH ratio of <1.8 or average HER2 gene copy number of <4 signals/nucleus for test systems without an internal control probe

HER2 TESTING CHALLENGES• Unclear which patients benefit most from targeted

therapy[1-3]

• Determination of HER2 status reliant on testing infrastructure – ie, central vs local testing, FISH vs IHC

• Potential benefit from adding trastuzumab for treatment of patients with tumors < 3+ IHC and FISH negative

• Disparate results with local vs central testing– Patients in NCCTG 9831 (adjuvant chemotherapy ±

trastuzumab) were assessed for HER2 by local testing– Central testing identified subset of patients who were

protein negative and gene negative with HR of 0.51 for DFS (P = 0.13)

Disease-free-Survival According to Local Immunohistochemistry for HER2 and Central FISH for Patients Treated with Adjuvant Chemotherapy with/without Trastuzumab in the HERA Trial

_____________________McCaskill-Stevens W, Procter M, Azambuja E, Dafni U,

Leyland-Jones B, Ruschoff J, Dowsett M, Jordan B, Dolci S,Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart

M,for the HERA Study Team

Prospective testing for

eligibility before randomization

Local IHC 3+ → central IHC 3+

Local IHC 2+ → central FISH+

Local FISH + → central FISH+

HER2 STATUS TESTING

central FISH+ = FISH Ratio ≥ 2.0

Central FISH results are available for:

1131 pts. prospectively (eligibility screening)

940 pts. retrospectively (assay banked specimens)

2071 (61%) total out of the 3401 patients

Biology of Her2 RTKs

HER family, also known as ErbB family– HER1, HER2, HER3, HER4– Transmembrane receptor kinases with extracellular

domain– Receptor-specific growth factor ligands identified for

all but HER2 Activated HER molecules– dimerize upon ligand binding– Result in signal transduction and cell growth

Slamon D, et al. N Engl J Med. 2001;344:783-792. Valabrega G, et al. Ann Oncol. 2007;18:977-984. Pegram MD, et al. Semin Oncol. 2000;27(suppl 11):21-25. 3.

HER2-Targeted Agents

Trastuzumab Development History

Phase III

Human HER2 gene

cloned

trastuzumabFDA

approval 9/25/98

Phase II

Phase I IND for rhuMAb HER2

muMAb 4D5

1992 1993 1994 19971995 1996

19981985 199119901981 1987

Association of HER2 with poor clinical

outcome

Murine HER2/neu gene cloned

• Targets HER2 protein

• High affinity (Kd = 0.1 nM) and specificity

• 95% human, 5% murine– Decreases potential

for immunogenicity– Increases potential for

recruiting immune effector mechanisms

HER2 epitopes recognized by hypervariable murine

antibody fragment

Human IgG-1

Trastuzumab:Humanized Anti-HER2 Antibody

Baselga. Satellite Symposium, 23rd Annual San Antonio Breast Cancer Symposium 2000.

Trastuzumab: Mechanism of Action

1. Trastuzumab mediates ADCC

Once bound to the Fc domain of trastuzumab, the NK cells release substances…

…that perforate the tumour cell membrane and promote cell death

Nahta R, Esteva FJ. Breast Cancer Res 2006; 8: 215Clynes RA, et al. Nat Med 2000; 6: 443-446

Gennari R, et al. Clin Cancer Res 2004; 10: 5650-5655Arnould L, et al. Br J Cancer 2006; 94: 259-267

2. Trastuzumab preventsformation of p95HER2

Formation of the active p95 fragment, through proteolytic cleavage of the extracellular domain of HER2…

…is prevented by trastuzumab

Molina MA, et al. Cancer Res 2001; 61: 4744-4749Nahta R, Esteva FJ. Cancer Lett 2006; 232: 123-138

3. Trastuzumab blocks HER2-activated cell proliferation

Trastuzumab interrupts this process

HER2 signalling induces cell proliferation

Nahta R, Esteva FJ. Cancer Lett 2006; 232: 123-138Fry MJ. Breast Cancer Res 2001; 3: 304-312

Gershtein ES, et al. Clin Chim Acta 1999; 287: 59-67Yakes FM, et al. Cancer Res 2002; 62: 4132-4141Longva KE, et al. Int J Cancer 2005; 116: 359-367

4. Trastuzumab inhibits HER2-regulated angiogenesis

Trastuzumab inhibits this process

HER2 signalling induces angiogenesis

Izumi Y, et al. Nature 2002; 416: 279-280 Nahta R, Esteva FJ. Cancer Lett 2006; 232: 123-138

Wen XF, et al. Oncogene 2006; 25: 6986-6996Klos KS, et al. Cancer 2003; 98: 1377-1385

Trastuzumab: 1 target4 mechanisms of action

Prevention of formation of p95HER2

Inhibition of cell proliferation

Activation of ADCC

Inhibition ofHER2-regulated angiogenesis

HER2

HerceptinTumourcell

+

ADCC is a key mechanism of Herceptin’s antitumour activity in vivo

ADCC

FcgRIII

NK cell

• Once bound to HER2, the Herceptin Fc domain recruits immune cells to target and destroy the tumour

Lapatinib Blocks Signaling Through Multiple Receptor Combinations

Downstream signaling cascade

Downstream signaling cascade

1 + 11 + 1 2 + 22 + 2 1 + 21 + 2Blocks signaling through

ErbB1 and ErbB2 homodimers and heterodimers

Might also prevent signaling through heterodimers between these receptors and other ErbB family members

Potentially blocks multiple ErbB signaling pathways

Herceptin® in the adjuvant

setting: rationale

• HER2 overexpression is an early event in breast cancer development and is associated with aggressive disease

Herceptin® offers

• A new mechanism of antitumour activity

• Proven clinical benefits in the metastatic setting,including increased survival when used in combination with chemotherapy

• Greater benefit when used earlier in metastatic disease

• A favourable safety profile and good tolerability

HER2 and Adjuvant• Benefit estimates for use of trastuzumab

available in Adjuvant! Version 9.0– HER2 included as a variable

• HER2 expression prognostic for breast cancer – Modest independent relative risk of 1.5

• Trastuzumab now included as adjuvant therapy option– Projections of benefit for trastuzumab only for

3 years because of short follow-up on current trials

Adjuvant! Limitations• Many estimates are based on as yet

incomplete evidence and as yet strongly debated assumptions

• For example– No impact of HER2 status on estimates of

hormonal therapy efficacy– No impact of HER2 status on estimates of

efficacy of adjuvant anthracyclines and/or taxanes

Adjuvant! Version 9.0

Adjuvant! Projection for Trastuzumab

Four major ongoing Herceptin® adjuvant trials

• The extensive Herceptin® adjuvant trial programme will

– investigate complementary strategies

– establish the efficacy and role of Herceptin® in the adjuvant setting

– establish the safety profile of Herceptin®

– determine the optimal duration of adjuvant Herceptin® therapy

Herceptinâ in the adjuvant setting: major trials

Four main trials are currently investigating Herceptin® in the adjuvant setting

• HERA (Herceptin® Adjuvant) Trial• NSABP (National Surgical Adjuvant

Breast Project) trial B31• Intergroup trial N9831• BCIRG (Breast Cancer International

Research Group) trial 006

CURRENT CLINICAL DATA ON ADJUVANT THERAPY FOR HER2-POSITIVE BREAST CANCER

Comparison of the four large Herceptin® adjuvant trials

Trial

Target accrual

Patient

selection

Accrual phase (years)

Follow-up phase (years)

Primary endpoint

NSABP B31 2,700 Node+, IHC 3+ or

FISH+

4.75 15 OS

Intergroup N9831

3,000 Node+, IHC 3+ or

FISH+

4.5 15 DFS

BCIRG 006 3,000 Node+ and – FISH+

NA NA DFS

HERA Trial 3,192 Node+ and – IHC 3+ or

FISH+

4 10 DFS

North American Trastuzumab Adjuvant Trials in Breast Cancer

4 cycles

AC

T HD every 3 wks

Trastuzumab

T HD every 3 wks

4 cycles

4 cycles52 wks

NSABP B-31

NCCTG 9831

4 cycles

AC

T LD/wk

Trastuzumab

T LD/wk Trastuzumab

T LD/wk

12 wks

52 wks

64 wks

Romond EH, et al. N Engl J Med. 2005;353:1673-1684.

NSABP TRIAL B31: TREATMENT PLAN

Doxorubicin 60mg/m2

Cyclophosphamide 600mg/m2

Paclitaxel 175mg/m2 q3w

Herceptin®

– loading dose 4mg/kg on week 1

– maintenance dose 2mg/kg x 51 weeks

NSABP TRIAL B31:PRIMARY OBJECTIVES Stage I: (n=1,000)

– evaluation of cardiac safety

Stage II: (n=1,700; total=2,700)

– evaluation of efficacy

• survival: primary endpoint

• disease-free survival (DFS): secondary endpoint

NSABP TRIAL B31: SECONDARY OBJECTIVES

Prognostic and predictive value of phosphorylated HER2 receptor

Prognostic and predictive value of shed extracellular domain (ECD)

Concordance between different HER2 assays, i.e. IHC versus FISH

Change in HER2-phosphorylated receptor, ECD level or HER2 overexpression upon relapse

NSABP TRIAL B31: KEY INCLUSION CRITERIA

Histologically/cytologically proven invasive adenocarcinoma of the breast

At least one positive axillary node

Axillary dissection AND either total mastectomy OR lumpectomy

HER2 overexpression (IHC 3+ or FISH positive)

Known hormone receptor status (ER/PgR)

No more than 84 days since prior surgery for breast cancer

No prior chemotherapy, radiotherapy or hormonal therapy for breast cancer

Normal cardiac, renal and hepatic function

Disease-Free Survival

Romond EH, et al. N Engl J Med. 2005;353:1673-1684.

0 1 2 3 4 5

50

60

70

80

90

100

0 1 2 3 4 5

50

60

70

80

90

100B-31 N9831

HR: 0.45; 2P = 1 x 10-9

74%

87%85%

66%

78%

87%86%

68%

Years From Randomization

Pat

ien

ts (

%)

Patients Events Treatment872 171864 83

AC TAC TH

HR: 0.55; 2P = .0005

AC T (n = 807)AC TH (n = 808)

AC TAC TH

Years From Randomization

0 1 2 3 4 5

50

60

70

80

90

10

0

0 1 2 3 4 5

50

60

70

80

90

10

0

DISEASE-FREE SURVIVAL

B-31 N9831

Years Years

AC->T+H 864 83AC->T 872 171 AC->T 807 90

AC->T+H 808 51

N Events N Events

HR=0.45, 2P=1x10-9 HR=0.55, 2P=0.0005

AC->T+H AC->T+H

AC->T AC->T

NSABP B-31: CARDIOTOXICITY DATA

Tan-Chiu E, et al. J Clin Oncol. 2005;23:7811-7819. Reprinted with permission from the American Society of Clinical Oncology.

Per

cen

tag

e

Arm 2: AC T + Hn = 850, 31 CHFs,no cardiac deaths

4.1%

Arm 1 evaluable cohortArm 2 evaluable cohort

Arm 1: AC T n = 814, 4 CHFs,1 cardiac death

0.8%

6

4

2

00.5 1.0 1.5 2.0 2.5

Years After Day 1 Cycle 5

3.0

HR: 5.9

Years After Day 1 Cycle 5

Cum Inc Arm 1, %

Cum Inc Arm 2, %

No. at Risk

0.5 0.3 2.6 1472

1.0 0.5 3.6 1202

1.5 0.5 3.9 983

2.0 0.5 4.1 775

2.5 0.8 4.1 595

3.0 0.8 4.1 405

Intergroup trial N9831: treatment plan Herceptin®

– 4mg/kg loading dose (90 minutes i.v. infusion) followed by 4mg/kg weekly (90 minutes i.v. infusion or 30 minutes i.v. infusion based on toxicity)

Doxorubicin 60mg/m2 every 3 weeks

Cyclophosphamide 600mg/m2 every 3 weeks

Paclitaxel 80mg/m2 weekly

Intergroup trial N9831: objectives

Primary

– disease-free survival

– cardiotoxicity

Secondary

– overall survival

– evaluation of whether sHER1 or sHER2 levels at baseline are prognostic for disease-free and overall survival

– concordance of IHC (HercepTest®) with FISH

(VysisTM

); disease-free survival; and overall survival

Intergroup trial N9831: inclusion criteria

• Operable, histologically confirmed adenocarcinoma of the breast

• Node-positive disease• Hormonal status known (ER/PgR)• HER2 overexpression (IHC 3+ or FISH positive)• No prior chemotherapy

– hormonal therapy allowed for up to 4 weeks but discontinued prior to enrolment

• No more than 84 days from mastectomy or axillary node dissection

• LVEF normal

Intergroup trial N9831: exclusion criteria

• Locally advanced tumours• Prior history of breast cancer• Prior chemotherapy or radiotherapy

for breast cancer• Cardiac disease including:

– myocardial infarction– history of congestive heart failure– medication for arrythmia or angina

pectoris

• Prior anthracycline or taxane therapy for any malignancy

Herceptin®

q3w x 1 yearHerceptin®

q3w x 2 years

Observation*

Stratification

Randomisation

Primary management (surgery, [neo]adjuvant chemotherapy

± adjuvant radiotherapy)

*Observation group to receive the same follow-up as the Herceptin® treatment groups

HERA TRIAL: STUDY DESIGN

HERA: Trastuzumab in HER2-Positive

Early-Stage Breast Cancer

Piccart-Gebhart MJ, et al. N Engl J Med. 2005 ;353:1659-1672.

Women with HER2-positive invasive

early-stage breast cancer, who

received surgery and adjuvant or

neoadjuvant chemotherapy ±

radiotherapy

(N = 3401)

Observation*(n = 1698)

Trastuzumab8 mg/kg loading dose,6 mg/kg every 3 weeks

for 1 year(n = 1703)

Interim follow-up:median 2 years

*All patients given the option to switch to trastuzumab May 2005 after positive interim data review.

• Compare disease-free survival (DFS) in patients with HER2-overexpressing breast

cancer who received Herceptin® versus

those who did not receive Herceptin®

– in patients treated for 1 year– and those treated for 2 years

HERA TRIAL: PRIMARY OBJECTIVES

HERA TRIAL: SECONDARY OBJECTIVES

Overall survival, relapse-free survival and distant DFS– 1 year of Herceptin® versus observation – 2 years of Herceptin® versus observation

Safety and tolerability – Herceptin® versus observation

Incidence of cardiac dysfunction – Herceptin® versus observation

Treatment duration (efficacy and safety) – 1 year versus 2 years of Herceptin®

HERA TRIAL: STUDY SIZE AND DURATION

Sample size: 3,192 (1,064 per arm)

Target population: women with HER2-positive primary breast cancer (IHC 3+ or FISH positive)

Study duration– recruitment 48 months

– follow-up until 10 years after last patient enrolled

Number of centres: ~600

HERA TRIAL: KEY INCLUSION CRITERIA

Invasive, non-metastatic, operable primary breast cancer –histologically confirmed and adequately excised

Axillary node positive, or node negative with tumour size >1cm

Known hormone receptor status (ER/PgR or ER alone)

Completed 4 cycles of approved (neo)adjuvant chemotherapy

Baseline LVEF >55% (echocardiography or MUGA scan)

Completed radiotherapy if indicated

Centrally confirmed HER2 overexpression (IHC 3+ or FISH positive) in invasive component of primary

HERA TRIAL: KEY EXCLUSIONCRITERIA

Clinical T4 tumour, including inflammatory breast cancer

Cumulative dose of doxorubicin >360mg/m2 or epirubicin

>720mg/m2

(Neo)adjuvant chemotherapy with peripheral blood/bone marrow stem cell support

Supraclavicular lymph node involvement

Any prior malignant neoplasms (including primary invasive breast cancer), except– curatively treated basal/squamous cell carcinoma of skin– curatively treated in-situ cervical carcinoma

HERA: Trastuzumab in HER2-Positive Early-Stage Breast Cancer (cont’d)

1703 1127 140

1698 930 114

HR: 0.63 (95% CI: 0.53-0.75; P < .0001)

3-year DFS: 80.6% vs 74.0%

DFS (Censored)

Pat

ien

ts (

%)

100

80

60

40

20

012 360 186 24 30

Observation

1-year trastuzumab

Months From Randomization

Pat

ien

ts A

live

(%)

1703 1190 146

1698 1042 126

100

80

60

40

20

012 360 186 24 30

OS (Censored)

Observation

1-year trastuzumab

Months From Randomization

HR: 0.63 (95% CI: 0.45-0.87; P < .0051)

3-year OS: 92.4% vs 89.2%

Smith IE, on behalf of HERA. ASCO 2006. Clinical Science Symposium.

HERA: DFS Benefit in Subgroups

All

Any, neoadjuvant chemotherapyNodal status

0 pos, no neoadjuvant chemotherapy

3387

3581100

872

2032307

n0.54

0.530.52

0.77

0.640.43

HR

No anthracycline or taxaneAdjuvant chemotherapy regimen

Anthracycline, no taxane

NegativePos + no endocrine therapy

972953

0.510.53

1674 0.51

Pos + endocrine therapy467 0.49

1234 0.68

FavorsTrastuzumab

Favors Observation

Anthracycline + taxaneReceptor status/endocrine therapy

0 1 2

1-3 pos, no neoadjuvant chemotherapy³4 pos, no neoadjuvant chemotherapy

HR: 1-Year Trastuzumab vs Observation


HERA TRIAL: UNIQUE FEATURES

Investigating the role of Herceptin® independently from chemotherapy regimen

Investigating 2 years of Herceptin® treatment

3-weekly schedule from the start

– more convenient

– gives similar exposure to Herceptin® as weekly administration of lower doses

New model of partnership between academia and pharmaceutical industry

HERA: Cardiac Safety

*Observation, n = 1678; trastuzumab, n = 1708.†Observation, n = 1545; trastuzumab, n = 1600.‡Many were single observations, not confirmed at subsequent time points.

Patients, n (%)

Observation 1-Yr Trastuzumab

Cardiac death* 1 (0.1) 0 (0)

Severe CHF* 1 (0.1) 10 (0.6)

Symptomatic CHF* (including severe) 3 (0.2) 36 (2.1)

Confirmed significant LVEF decline* 9 (0.5) 51 (3.0)

Any type of cardiac endpoint* 10 (0.6) 61 (3.6)

At least 1 significant LVEF decline†‡ 35 (2.3) 118 (7.4)


BCIRG 006

Slamon D. SABCS 2005. General Session 1.

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6

1-Yr Trastuzumab

N = 3222

1-Yr Trastuzumab

AC T

AC TH

TCH

N+or High-Risk N-

Stratified by nodes and hormone receptor status

HER2+(Central FISH)

BCIRG TRIAL 006: OBJECTIVES

• Primary – disease-free survival

• Secondary– overall survival– safety– cardiac toxicity– quality of life – prognostic value of HER2 overexpression

BCIRG TRIAL 006: TREATMENT PLAN

• Doxorubicin 60mg/m2

• Cyclophosphamide 600mg/m2

• Docetaxel 100mg/m2

• Platinum salt

– carboplatin AUC 6

– cisplatin 75mg/m2

• Herceptin®

– 6mg/kg every 3 weeks

BCIRG trial 006: key inclusion criteria

• Histologically proven breast cancer• Definitive surgical treatment• Node-positive/negative disease• HER2 overexpression (FISH positive)• Normal renal, hepatic and cardiac function• No prior systemic therapy or radiotherapy

for breast cancer

Absolute DFS benefits(from Year 2 to 4):

AC TH vs AC T: 6%TCH vs AC T: 5%

81%

87%

86%

77%

83%

82%87%

93%

92%

Slamon D. SABCS 2006. Abstract 52.

BCIRG 006 DISEASE-FREE SURVIVAL: 2ND INTERIM ANALYSIS

AC T

AC TH

TCH

Patients Events1073 192 AC T1074 128 AC TH1075 142 TCH

HR (AC TH vs AC T): 0.61 (0.48-0.76; P < .0001)HR (TCH vs AC T): 0.67 (0.54-0.83; P = .0003)

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Year From Randomization

Dis

ease

Fre

e (%

)

Su

rviv

al (

%)

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

BCIRG 006 Overall Survival: 2nd Interim Analysis

Slamon D. SABCS 2006. Abstract 52.

97%

99%

98%

93%

97%

95%92%

91%

86%AC T

AC THTCH

Patients Events1073 80 AC T1074 49 AC TH1075 56 TCH

HR (AC TH vs AC T): 0.59 (0.42-0.85; P < .004)HR (TCH vs AC T): 0.66 (0.47-0.93; P = .017)

Year From Randomization

BCIRG 006: EFFICACY RESULTS

Both AC TH and TCH arms

– Statistically significantly improved DFS compared with AC T (HR: 0.61 with AC TH and 0.67 with TCH)

At this time

– No statistically significant difference between AC TH and TCH

– Insufficient information to evaluate overall survival (secondary endpoint)

Slamon D. SABCS 2006. General Session 1.

SECOND INTERIM ANALYSIS OF ADVERSE EVENTS FOR PHASE III BCIRG 006

Adverse events less common and safety better in anthracycline-free TCH arm of BCIRG 006

– Significantly lower rates of sensory neuropathy and myalgias

– No leukemias

– More grade 3/4 thrombocytopenia and anemia

Benefit of anthracyclines in adjuvant treatment of breast cancer now questioned

Slamon D, et al. SABCS 2006. Abstract 52.

Normal Amplified Deletion

Topo IIα non-coamplified

Most recent analysis

Coamplified

HER2Core region

17 q 12 17 q 21.1 17 q 21.2

Topo IIα regionN = 2990

1788 pts (60%)

145 pts (5%)

1057 pts (35%)

2990 of 3222 patients analyzed

HER2 and Topo IIα in BCIRG 006

Slamon D, et al. SABCS 2006. Abstract 52.

HER2/neu Overexpression: Predictive of Response

Topoisomerase IIα gene (Topo IIα)

Located close to HER2/neu on the 17q chromosome

Integrally involved in the antitumor action of anthracyclines

Topo IIα is essential for DNA replication and recombination

Anthracyclines target Topo IIα enzyme

The Topo IIα Gene

Functions

Resolves topological problems in DNA

Is critical in RNA transcription from DNA

Makes transient protein-bridged DNA breaks on one or both DNA strands during replication

Plays critical roles in segregation, condensation, and superhelicity

Implications for HER2-Negative and HER2-Positive Breast Cancers• Superior efficacy benefits for anthracyclines

(when present) derives from their effects on Topo IIα amplification and/or overexpression

• To date, Topo IIα amplification occurs only in 35% of the 25% of breast cancer patients with HER2 amplification, ie, a subset of a subclass (tested in > 4500 patients)

• Data support their preferential use in a HER2-negative breast cancer population that is ~ 75% of all breast cancers

• For HER2-positive breast cancers, trastuzumab and lapatinib appear to replace the gained efficacy of anthracyclines in the 1/3 of patients with coamplification of HER2 and Topo IIα without risking their known and well-established toxicities

105

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 < 50% / ER negative

No TaxolTaxol

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 < 50% / ER positive

No TaxolTaxol

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 >= 50% / ER negative

No TaxolTaxol

Years

Pro

po

rtio

n

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

DFS: Her2 CB11 >= 50% / ER positive

No TaxolTaxol

ER Neg ER Pos

HE

R2

NE

GH

ER

2 P

OS

HER2 is Predictive of Paclitaxel BenefitBy Estrogen ReceptorDisease Free Survival

n = 1322

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

paclitaxel

No paclitaxel

n=390 (29%)

n=144 (11%)

n=703 (53%)

n=79 (6%)

YearsHayes D.F., et al. N Engl J Med. 357:1496-506, 2007

FINHER TRIAL

Patients with node-positive or node-

negative disease; tumor > 20 mm and PgR-

negative

(N = 1010)

Docetaxel100 mg/m2 3 cycles,

followed by 3 cycles CEF(n = 502)

Joensuu H. SABCS 2006. Abstract 2.

Vinorelbine25 mg/m2 8 cycles, then

3 cycles CEF (n = 507)

CEF + docetaxel or vinorelbine

(n = 115)

First randomization

Trastuzumabonce wkly for 9 wks;first dose 4 mg/kg

then 2 mg/kg with CEF + docetaxel or vinorelbine

(n = 116)

Second randomization

Patients with HER2amplification

(n = 232)

At 36 months of median follow-up, the following was observed in the trastuzumab arm

– 58% improvement in DFS

– A trend for improvement in OS

– No major increase in cardiotoxicity

Established short duration trastuzumab as an option for patients unable to complete a 1-year course

FINHER TRIAL: EFFICACY

Joensuu H, et al. N Engl J Med. 2006;353:809-820..

ECOG TRIAL E2198: INCLUSION CRITERIA

• Histologically confirmed stage II or IIIa adenocarcinoma of the breast

• HER2 overexpression (IHC 2+/3+)• Axillary node dissection AND mastectomy or

lumpectomy within 12 weeks prior to enrolment• No prior chemotherapy, hormonal therapy (at

least one year since tamoxifen therapy) or radiotherapy

• No history of cardiac disease

ECOG TRIAL E2198: OBJECTIVES

• Evaluate the incidence of cardiotoxicity associated with paclitaxel plus Herceptin® in women with HER2-positive breast cancer

• Assess the long-term safety of Herceptin® in this patient population

ECOG TRIAL E2198: CARDIOTOXICITY

LVEF >10%

LVEF < normal

LVEF grade 3/4

Post paclitaxel + Herceptin®

9.5 (18/189) 2.1 (4/189) –

Post AC 12.5 (16/128) 5.5 (7/128) 8

HER2+ BC Tumors 1 cm after completion of anthracycline based therapy with LVEF 50%

RANDOMIZE

(paclitaxel) trastuzumab (trast for 1 yr)

(paclitaxel) lapatinib (lap for 1 yr)

(paclitaxel) trastuzumab+ lapatinib(trast + lap for 1 yr)

(paclitaxel) trastuzumab (12 weeks),6-week wash out , lapatinib (34 weeks)

N = 8,000Treatment Schema 1: No taxane: all neoadjuvant/adjuvant chemo before targeted therapy.

Treatment Schema 2: Taxane included: targeted therapy after neoadjuvant/adjuvant anthracycline-based chemo, and concurrent with weekly paclitaxel.

BIG 2.06/N063D Adjuvant HER2+

“ALL OVER THE

MAP”

AC-TH

TCH

Docetaxel/cyclophos + trastuzumab*

FAC/FEC then trastuzumab

Endocrine Rx +/- trastuzumab*

Vinorelbine/trastuzumab*

AC/EC then trastuzumab

Trastuzumab alone*

Chemo then “short course” trastuzumab*

Vin/trastuz. then FEC

Adjuvant Regimens Prescribed for HER2+ Disease

*not based on phase III data

PRECLINICAL RATIONALE FOR HERCEPTIN TREATMENT BEYOND PROGRESSION IN HER2-POSITIVE

BREAST CANCER

HERCEPTIN TREATMENT BEYOND PROGRESSION ENHANCES

EFFICACY OF COMBINATION CHEMOTHERAPY

• HER2 remains overexpressed and active in progressive disease

• HER2 may contribute to an even more aggressive tumour growth if Herceptin treatment is discontinued

• Inhibition of HER2 signalling may sensitise tumours to chemotherapy in tumours progressing on Herceptin alone

HERCEPTIN TREATMENT BEYOND PROGRESSION ENHANCES EFFICACY OF COMBINATION

THERAPY WITH TARGETED AGENTS

• Herceptin synergistically enhances the antitumour effect of Avastin in tumours progressing on Herceptin

• Herceptin synergistically enhances the antitumour effect of pertuzumab in tumours progressing on Herceptin

• Lapatinib enhances the antitumour effect of Herceptin

Scheuer et al 2006; Friess et al 2006; Scaltriti et al 2008

TREATMENT OPTIONS AFTER PROGRESSION ON

TRASTUZUMAB

Treatment Options After Trastuzumab Trastuzumab use after disease recurrence has not been

evaluated in clinical studies

In a retrospective evaluation[1]

– Response rate was 26% when trastuzumab was used in the second-line setting vs 43% in the first-line setting

– In another review, TTP was extended from 7.1 months to 10.2 months in patients who continued trastuzumab

A phase III study of lapatinib plus capecitabine compared with capecitabine alone provides evidence for lapatinib therapy following progression on trastuzumab[2]

1. Extra JM, et al. SABCS 2006. Abstract 2064.2. Geyer C, et al. N Engl J Med. 2006;355:2733-2743.

PERTUZUMAB

Baselga J, et al. ASCO 2007. Abstract 1004.

Monoclonal antibody to HER2

– Recognizes different epitope than trastuzumab

– Inhibits homo- and heterodimerization of HER2

– Potentially useful for patients who have progressed on trastuzumab

Interim phase II study results combining trastuzumab and pertuzumab indicate combination is well tolerated

– Overall response rate is 18.2% in this pretreated population

– Results suggest new HER2 monoclonal antibodies are promising in HER2-positive breast cancer

PERTUZUMAB AND TRASTUZUMAB BIND TO DISTINCT EXTRACELLULAR HER2 EPITOPES

Hubbard SR. Cancer Cell. 2005;7:287-288.

Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex

PertuzumabDimerization domain

TrastuzumabIII

II

I

Inhibits HER2 dimerization with other HER family receptors (particularly HER3)

Activates ADCC

Inhibits multiple HER-mediated signaling pathways

Activates ADCC

Inhibits HER-mediated signaling pathways

Prevents HER2 domain cleavage

III

II

I

IV

IV

ESTABLISHED CHEMOTHERAPY RESISTANCE MECHANISMS

Impaired drug uptake

Active drug efflux, eg by ABC transporters (P-glycoprotein, MDR2, BCRP, MRP1-6 etc)

Enhanced drug metabolism, eg by P450 enzymes

Alterations of intracellular target, eg tubulin

Upregulation of DNA repair in tumour cells

Upregulation of signalling pathways, eg anti-apoptotic genes (bcl-2, XIAP etc)

Hypothetical mechanisms of resistance to Herceptin (1)

• Selection of HER2-negative cells in a heterogeneous tumour– Outgrowth of HER2-negative tumours from an

originally mixed tumour cell population

• Defective interaction of Herceptin with HER2– Masking of Herceptin-binding epitope of HER2– Alterations in Herceptin-binding epitope of HER2– Loss of HER2 ECD by shedding or alternative

initiation of translation on HER2 gene

Kunitomo et al 2004; Nagy et al 2005; Tanner et al 2004; Stephens et al 2004;

Stephens et al 2005; Anido et al 2006HER2, human epidermal growth factor receptor 2; ECD, extracellular domain

Hypothetical mechanisms of resistance to Herceptin (2)

• Changes in downstream signalling proteins which eventually disconnect growth regulation from HER2– PIK3CA mutations resulting in constitutively active

PI3-kinase– Loss of PTEN function leading to persistent

signalling activity via the PI3K/Akt survival pathway– Changes in cyclin-dependent kinase inhibitor

p27kip1

Berns et al 2007; Nagata et al 2004; Crowder et al 2004; Pandolfi 2004; Kute et al 2004; Nahta et al 2004

IN VITRO STUDIES ARE NOT PREDICTIVE OF IN VIVO

RESISTANCE• In vitro resistance was observed in cell

lines exposed to Herceptin• In vitro resistance models tend to focus on

just one biological feature • In vitro resistance represents intrinsic

insensitivity or artificial manipulation of cells

• Conclusions from in vitro resistance models cannot be translated to clinical settings– ADCC is a key mechanism of Herceptin efficacy

in vivo

Gennari et al 2004; Arnould et al 2006; Musolino et al 2008; Gianni 2008

ADCC, antibody-dependent cellular cytotoxicity

Highly potent cytotoxic agent

Cytotoxic agent: DM1

Monoclonal antibody: Trastuzumab

Target expression: HER2

Systemically stable

Linker: SMCCT-DM1

Average drug:antibody ratio ≅ 3.5:1

Trastuzumab-DM1: Novel Antibody-Drug Conjugate

Trastuzumab

MCCDM1

P

P

P

P

Cell growth, proliferation, survival, metastasis, angiogenesis

Akt/PKB

mTOR

S6K1

PI3-K

Lapatinibphase III

Gefitinibphase II

Everolimusphase III

EGFR HER2

4E-BP1

elF-4E

Protein synthesis

Neratinibphase III

Pertuzumabphase III

Trastuzumab

T-DM1 phase III

P

P

P

P

PTEN

VEGFRSunitinibphase II

Bevacizumabphase III VEGF

Targeted Agents for HER2+ Breast Cancer

CP1270832-139

Clinical Significance of Polysomy 17 in the HER2+ NCCTG N9831

Intergroup Adjuvant Trastuzumab Trial

Reinholz MM, Jenkins RB, Hillman D, Lingle WL, Davidson N, Martino P, Kaufman P,

Kutteh L, and Perez EA. NCCTG, ECOG, SWOG, CALGB

Reinholz et al: SABCS 2007 (abstract #36)

CP1270832-140

Adjuvant Trastuzumab May Benefit Pts with Normal HER2 Breast Tumors (n=103)

40

50

60

70

80

90

100

0 1 2 3 4 5

Time (years)

Per

cent

AC→T+H

HER2 FISH ratio < 2.0

AC→T N Events DFS 3 yr 5 yrAC→T 74 19 82.0 63.7AC→T+H 82 11 91.0 80.8

40

50

60

70

80

90

100

0 1 2 3 4 5

Time (years)

Perc

ent

AC→T+H

AC→T

IHC 0,1,2+ and HER2 FISH ratio <2.0

N Events DFS 3 yr 5 yr

AC→T 44 14 82.6 60.9AC→T+H 59 9 90.2 81.2

40

50

60

70

80

90

100

0 1 2 3 4 5

Time (years)

Perc

ent

AC→T+H

AC→T

IHC 0,1,2+

N Events DFS 3 yr 5 yr

AC→T 142 20 88.2 67.6AC→T+H 191 19 89.1 82.3

p = 0.12p = 0.26

p = 0.14

•p-value for interaction = 0.38 (HER2 copy ≥ 4 only)

RR of ACTH/ACT for DFS (NSABP B-31)

0.00 0.25 0.50 0.75 1.00 1.25 1.50

FISH- & IHC <3 (174)

IHC <3 (299)

IHC 3+ (1488)

FISH- (207)

FISH+ (1588)

RR

Cat

ego

ries

(N

)

Interaction p=0.60 for FISHInteraction p=0.26 for IHC

Note: RR adjusted for ER and nodal status

HER2 Amplification and Polysomy

• Retrospective tissue analysis of CALGB 9840 patient subset

• Polysomy 17 may be associated with increased response to trastuzumab

• More study warranted to evaluate this response marker

• Counting centromeres may not correlate with degree of HER2 amplification

Kaufman PA, et al. ASCO 2007. Abstract 1009.

Response Rate, % P Value

Paclitaxel Paclitaxel + Trastuzumab

Polysomy 17 and FISH ratio < 2 (n = 38) 26 63 .043

CEP 17 < 2.2 and FISH ratio < 2 (n = 103) 36 36 NS

• Common clinical scenarios: – FISH neg and IHC 1+/2+ = 40% of cases– FISH ratio 1-2 = 25%-40% of cases– Polysomy 17 = 8%-27% of cases

• Does give one pause…– Retest negatives?– Consider trastuzumab if the FISH – ratio = 1-2, or if polysomy 17?

This Situation is Quite Common

ANTI HR + & ANTI HER2 + CROSS TALK

• TAMOXIFEN – Oldest targeted agent (1896/1960)

• TRASTUZUMAB- Newest targeted agent (1998)

CROSS TALK

• Endocrine resistance presents major problem

• 70% Percent ER positive• develop endocrine resistance

eventually

The ER Pathway

Estrogen

ER

ER

ER

DNA

Transcription of genes

CoA

Nucleus

Cell Surface

Cytoplasm

Roop R., Ma C., Future Oncology, In press.

Steroid receptor coactivators and ER-dependent gene transcription

TATA

ERE

Estradiol-bound ERTranscription

HistoneAcetylaseActivity

P/CAFCBP

SRCFamily AIB1

A/B C D E/F

AF-1DBD AF-2/HBD

estrogen

tamoxifen

transcription

CorepressorsN-CoR/SMRTCoactivators

COOHNH2

SERM sensitive

A/B C D E/F

AF-1DBD AF-2/HBD

estrogen

tamoxifen

transcription

Corepressors

Coactivators(AIB1,etc.)

COOHNH2

SERM resistant

A/B C D E/F

PSer118

AF-1DBD AF-2/HBD

estrogen

tamoxifen

transcription

N-CoRSMRT

NH2 COOH

HER2/neu

MAPK

PI3K-Aktsrc

JNK

Coactivators(AIB1,etc.)

Non-classic Effects of ER

Estrogen

ER

ER

AKTMAP

K

AdP

ER

ER P

C

TF

ERp

ER

TF

ERE

RER

DNA

Transcription of genes

CoA

Cytoplasm

Nucleus

Cell Surface

RTK: FGFR, IGF-1R, EGFR, HER2

Roop R, Ma C. Future Oncology, In press.

Cross-talk between signal transduction and endocrine pathways

Adapted from Johnston 2005

SOSRAS

RAF

Basaltranscriptionmachineryp160

ERE ER target gene transcription

ER CBPPP P P

ER

Pp90RSK

AktP

MAPKP

Cellsurvival

Cytoplasm

Nucleus

ER

PI3-KP

P

PPP

P

Cellgrowth

MEKP

Plasmamembrane

AI

HER2

IGFRGrowth factorEstrogen

Trastuzumab

P

Ras

p8

5

p110 ERE

E

ERE

P

P

P

Transcription

ErbB ErbB

ER-Responsive Element

P

MAPKAkt

Ligand

Crosstalk with TK pathways

• Endocrine resistance– Cross talk with growth factor (GF) pathways

• EGFR, HER2, AKT, MAPK, PI3K• Ligand independent pathway

– GF pathways also cause ER independent endocrine resistance

– Novel targeted agents to inhibit these pathways

• Goal of restoring endocrine sensitivity

Her2 and Endocrine Resistance

• ER+ and Her2+ breast cancer = 10%– Less than you expect by chance

• Interaction between Her2 and ER expression• ERE exist on promoter region of HER2 gene

• Her2 pathway facilitates endocrine resistance– Increases ER phosphorylation– Disrupt interaction of ER and co-repressors– AKT and MAPK pathways (both activated by

ER and HER2)

Adjuvant Endocrine Therapy Study TransATAC: Time to Recurrence by HER2 Status

HER2+HER2

n=839HR=2.30P=0.001

40 1 2 3 5 6

35

30

15

10

5

0

25

20

40 1 2 3 5 6

35

30

15

10

5

0

25

20

n=877HR=3.23P<0.0001

HER2+HER2

HR = hazard ratio.Update of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48.

Tamoxifen Patients

Years

Anastrozole Patients

Years

Pat

ien

ts (

%)

• HER2+ status was significantly associated with reduced time to recurrence for both tamoxifen and anastrozole

TransATAC: Time to Recurrence by HER2 Status

Patients Events HR

1526 149 0.66

190 45 0.92

1786 200 0.72

ANA better

TAM better

HR (ANA:TAM) and 95% CI

HER2–

HER2+

Combined

0.5 1.0 2.0

Update of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48.

• HER2+ statuswas associated with substantially reduced benefit in time to recurrence with adjuvant anastrozole compared with tamoxifen

TANDEM

• Combination ER/HER2 blockade (TANDEM)– 207 patients postmenopausal ER+/HER2+– Anastrazole +/- trastuzumab for metastatic

disease– PFS prolonged for combination

• 4.8 vs. 2.4 months

– Clinical Benefit Rate 40.7 vs. 20.3– Increased SAE’s (28% vs. 16%)

• Mostly GI toxicities, arthralgias

TANDEMKaufman, B., et. al., J Clin Oncol, 27:5529-5537 (2009).

De Laurentiis et al. Clin. Cancer Res. 11:4741, 2005

ER+/HER2+ br ca is less responsive to endocrine therapy

N=1,925

ER+/PR tumors are resistant to tamoxifen (ATAC)

From Cui et al. JCO 23:7721, 2005

ER+/PR+

ER+/PR+

Negative PR is a marker of high HER1/HER2levels and tamoxifen resistance

Arpino et al. JNCI 97:1254, 2005

ER+/PR+

ER+/PR+

ER+/PR

ER+/PR

Negative PR is a marker of high HER1/HER2levels and tamoxifen resistance

Arpino et al. JNCI 97:1254, 2005

Randomized Phase II Trial of Tamoxifen ± Gefitinib in MBC (ZD1839IL/0225)

Tamoxifen +Gefitinib20 mg/day 250 mg/day

Tamoxifen +Placebo20 mg/day

Randomize

Primary Endpoint• TTP

Secondary• ORR & CBR

Exploratory• IHC study of

downstream effectors of erbB family and ER & co-activators (AIB1)

274 Pts

Strata 1•No prior Tam•Prior Tam > 1yr

Strata 2•Prior AI

PI CK Osborne, Baylor College MedicineStudy Chair: Kent Osborne, Baylor College Medicine.

EG

FRH

ER

2

Tam-S Tam-R

Knowlden et al. Endocrinology 144:1032, 2003

10% ‘conversion rate’ to HER2 overexpression in breast cancersthat recur (early) on adjuvant tamoxifen (Gutierrez et al. J. Clin.Oncol. 23:2469, 2005)

Tamoxifen-resistant breast tumors acquireErbB receptor overexpression

Osborne and Schiff J. Clin. Oncol. 23:1616, 2005

Neoadjuvant aromatase inhibitors (AI) are betterthan tamoxifen against ER+/HER2+ breast cancer

Gefitinib blocks HER2 signaling and restores letrozole-

mediated growth inhibition of breast cancer cells

Shin et al. Submitted

HER2

Akt

Ser473 P-Akt

MAPK

P-MAPK

ERa

Ser118 P-ERa

Ser167 P-ERa

P-TyrIP:HER2

LY294002U0126

Gefitinib

+- - --- - - +

- -+

0

5

10

15

20

25

30

35

40

Colo

nie

s (1

0-1)

AD - + + + +- - + - +Letrozole

- - - + +Gefitinib

Is EGFR/HER2 signaling upregulated after escape from estrogen depletion?

Estrogen depletion upregulates EGFR transcription (EGFR gene contains a 96-bp intron fragment that is repressed by estradiol)– Wilson and Chrysogelos, J. Cell Biochem. 85:601, 2002

ER+ breast cancer cells selected for resistance to fulvestrant show EGFR and P-MAPK levels– McClelland et al., Endocrinology 142:2776, 2001

Resistance to fulvestrant does not occur if selection is done in the presence of gefitinib or MAPK inhibitors

MCF-7/aromatase cells that become resistant to letrozole overexpress HER2 and P-MAPK; resistance is reversed by gefitinib or MEK inhibitors– Jelovac et al. Cancer Res. 65:5380, 2005; Sabnis et al. ibid

65:3903, 2005

Serum HER2 converts to positive at disease progression

in patients with breast cancer on hormonal therapy

Lipton et al. Cancer 104:257, 2005

Letrozole 29/111 (26%)Tamoxifen 32/129 (25%)

EGFR

Interaction of with ER less studied than HER2

Like HER2 can activate downstream pathways

– MAPK

Can form heterodimers with HER2 receptors

– Gefitinib prevented heterodimer formation/phosphorylation

– Reversed tamoxifen resistance MCF-7 cell line

Clinical data

56 postmenopausal patients ER+ and EGFR+

– Gefitinib + Anastrazole or placebo

– 4-6 weeks prior to surgery

– Primary endpoint cell cycle inhibition (Ki67)

– Combination arm showed higher Ki67 reduction

– 5.6% relative difference P=0.0054

– Tumor response rates were similar

– Showed that combination is tolerable

Polychronis, A., et. al., Lancet oncology 6:383-91 (2005).

IGF-1 Pathway

TK receptor

TK activity on transmembrane subunit

Has homology with the insulin receptor

– IGF-1R and IR can form hybrid receptors

– IGF-1R and IR can bind each other’s ligands

IGF-1R expressed in ~45% of breast cancers (by IHC)

Belinsky, M.G., et. al., Cell Cycle 7:19, 2949-2955 (2008).

IGF-1 system and Endocrine Resistance

Crosstalk with ER pathway similar to other TK

IGFR inhibitors + endocrine therapy

– Negative trials (two monoclonal Ab)

– At least two ongoing (one small molecule TKI, one monoclonal Ab)

Data too sparse to make any judgments

FGF Pathway

Fibroblast growth factor pathway TKR

FGF1-FGF4 (4 different genes)

– Alternate splicing results in many isoforms

– At least 18 ligands that can bind FGF receptors

– Activates downstream pathways similar to other TKI

FGF pathway

PI3K

MAPK

AKT

Ras

FGFR(1-4)

Cytoplasm

TF pGene ExpressionGrowth Invasio

n

Cell Surface

Roop R, Ma C., Future Oncology, In press.

18 different ligands

FGF and endocrine resistance

Amplification of FGFR1 in 10% breast CA

– FGFR1 amplified cell line resistant to tamoxifen

FGFR1 amplified ER+ tumors usually PR-

– Tend to have higher Ki67

– ? Role in luminal B breast cancers

FGFR3 activation in cell lines decreased sensitivity to endocrine therapy

FGFR4 transcription predicts Tamoxifen sensitivity clinically

PI3K

Activated by TK or G-protein

Divided into 3 subclasses (I-III)

– Subclass I divided Ia and Ib

Heterodimers p110 and p85

– Three isoforms p110 exist (α, β, δ)

PI3K activation

– Activates AKT and interacts with mTOR

PI3K/AKT/mTOR Pathway

p85

p110RAS

MAPK

PIP3

PIP2

RTK: FGFR, IGF-1R, EGFR, HER2

PTEN

AKT

PDK1

mTOR-C2

mTOR-C1

Downstream Target Proteins

growth, Invasion

Roop R., Ma C., Future Oncology, In press.

Increased PI3K Pathway Activity Promotes endocrine resistance (LTED cells)

Ways PI3K can be overactivated

– PIK3CA (encodes p110α) mutated 30-40% time

– Loss of PTEN

– Amplification PIK3CB (encodes p110β)

– Mutations in AKT

PI3K Inhibition

Cell line experiments

– ER+ and PIK3CA or PIK3CB silenced (RNAi)

– Apoptosis and growth inhibition

– PIK3CA ≥ PIK3CB

– Combined PIK3CA and PIK3CB greatest

– Apoptosis dependent on estrogen depletion

– ER negative cell line had no effect

Clinical trials PI3K

A few clinical trials underway

– Endocrine therapy + BKM120 or BEZ235

– Letrozole + XL147 or XL765

Data is very early for this class of drugs

mTOR

Downstream of PI3K pathway

Rational target for treating endocrine resistance

Phase III letrozole +/- temsirolimus (metastatic)

– negative

Phase II trial neo-adjuvant letrozole +/- everolimus

– positive

TAMRAD – phase II tamoxifen +/- everolimus

– positive

ONCOGENES AND SIGNALING MOLECULES THAT BEEN ASSOCIATED WITH ANTIESTROGEN RESISTANCE

Ha-Ras Cox-2 IGF-II

Src Heregulin FGF-1/4

Erk (MAPK) VEGF p38Mapk

Cyclin D1 AIB-1 (SRC-1)IGF-I receptor

and IRS-1

Cyr61 (ligand for avb3)

Activated Akt p130Cas

High ER and PR+ predict good response to tamoxifen

Negative PR and high EGFR/HER2 predict early escape

ER+/HER2+ tumors are initially more responsive to AIs than tamoxifen

EGFR/HER2 overexpression occurs at the time of escape from hormonal therapy

Blockade of EGFR/HER2 is one of many approaches to enhance hormonal therapy action

We need new clinical paradigms to elucidate the preferential mechanisms of escape from endocrine therapy as well as to prioritize combinatorial molecular strategies

Summary/Conclusions

In summary

Her2+ Her2-

Agressive Non agressive Agressive Non agressive

RH+ Trastuzumab+ CT

Trastuzumab + Hormono PolyCT Hormono

RH-Trastuzumab

+ CT Trastuzumab +/- CT

PolyCT Sequentiel MonoCT, PolyCT?

190

LESSONS LEARNEDSO FAR

HER = human epidermal growth factor receptor; ER = oestrogen receptor; PgR = progesterone receptor.Berger et al. Cancer Res. 1988;48:1238; Chazin et al. Oncogene. 1992;7:1859; Hynes and Stern. Biochim Biophys Acta. 1994;1198:165; O’Reilly et al. Br J Cancer. 1991;63:444; Paik et al. J Clin Oncol. 1990;8:103; Press et al. J Clin Oncol. 1997;15:2894; Slamon et al. Science. 1987;235:177; van de Vijver et al. N Engl J Med. 1988;319:1239.

Prognosis for Patients With HER2+ Breast Cancer• HER2 positivity is an independent predictor of poor prognosis• HER2 positivity predicts response and survival• HER2 positivity also correlates with other clinical pathologic variables

– Short disease-free interval– Larger tumour size– Positive nodal status– Ductal rather than lobular histology– Ploidy– High S-phase fraction– High nuclear grade– Mutated p53– Decreased ER and PgR expression

All HER2/neu Might Not Be Created Equal . . .

Activation mediates multiple processes

Extracellular domain

Trastuzumab binding site

Intracellular domain

Lapatinib binding site

HER2 receptors

Multiple Approaches to Targeting the HER Pathways

Truncated HER2 continues to mediate multiple

processes

Truncation of HER2

Multiple Approaches to Targeting the HER Pathways (cont’d)

Adjuvant Node+, HER2+Unresolved Clinical Questions• Concurrent vs sequential trastuzumab• Which chemotherapy regimen?• Anthracycline or not?• Duration of trastuzumab?• Endocrine therapy plus trastuzumab only?• Trastuzumab alone?

Node negative

Nodepositive

Traditionalapproach

HER-2+Virulent

ER-, PR-HER-2-

Basal-like Virulent

ER++Luminal AIndolent

ER+Luminal BVirulent

New Approach

Indolent ER and PR-Positive Breast Cancer

E2

ER

P

PR

Breast Cancer•Tamoxifen and Aromatase Inhibitor- responsive

More Virulent ER+ Breast CancerTAM

AIB1An estrogen response

coactivatorPR

+

Her-1

Her-2

ER

Schiff R, J Natl Cancer Inst 2003;95:353 - 361

IGFR

Cancer stem cells: are we missing the target?

Jones et al. JNCI 96:583, 2004

Courtesy of Jenny Chang, MD

Cancer stem cells: are we missing the target?

Jones et al. JNCI 96:583, 2004

Stem Cell

Self-renewal

Wntfamily

Notchfamily

Hedgehogfamily TGFβ

family

EGFfamily

FGFfamily

Growth Hormone

/Insulin-like GF

Progesterone

Estrogen

Prolactin

Breast Stem Cell Survival

Modified from Clarke et al 2005

Jones, Mary A. DOR: 01/31/25MR#:555690 Dx: Breast cancerReceptor status: ER-, Her2-, PR-, AR-

Activated pathway: Insulin-like growth factor receptor, AKT, mTOR Basal-like Breast Cancer

Breast Cancer Lab Report of the Future

Percentage of patients that have had this pathway activated in breast cancer: 16%

Jones, Mary A. DOR: 01/31/25MR#:555690 Dx: Breast cancerReceptor status: ER-, Her2-, PR-, AR-

Activated pathway: Insulin-like growth factor receptor, AKT, mTOR Basal-like Breast Cancer

Breast Cancer Lab Report of the Future

Potential therapies:RAD0001ImatinibAnti-IGFR antibodyMetforminExercise, low fat diet

Percentage of patients that have had this pathway activated in breast cancer: 16%

Breast Cancer MortalityWill the Progress Continue?

20102020

2030

Clinical Trials in Breast CancerSubtypes

Queen-size pantyHose – onesize does not fitall !

I don’t know if heavier than air flight is possible, but I’m committed to living my life dedicated to its possibility. - Wilbur Wright

The Future Is Possible

QUESTIONS ???

Trastuzumab

Health & Medicine

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