Download - 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
Smith IE, on behalf of HERA. ASCO 2006. Clinical Science Symposium.
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)
Smith IE, on behalf of HERA. ASCO 2006. Clinical Science Symposium.
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
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 ???