HER 2 Positive Breast Cancer

HER – 2 Positive Breast
Cancer : Current Therapy
John T. Cole M.D.
HER 2 Positive Breast Cancer
Disclosures - None
HER-2 Positive Breast Cancer
Objectives
1. Clinical relevance of HER-2 in Breast Cancer
2. Biology of HER-2
3. Therapy for HER-2 positive Breast Cancer
- Adjuvant therapy
- Neo-adjuvant therapy
- Advanced disease
HER-2 Positive Breast Cancer - Biology
• HER 2 – neu (ERB-B2) is a member of the
epidermal growth factor family (HER 1-4)
• The ERB-B receptors are activated by several
effector molecules including EGF, neuregulin,
amphiregulin, TGF alpha, and others
• HER 2 cannot bind ligand but dimerizes
readily with other family members when they
bind ligand
HER-2 Positive Breast Cancer - Biology
• The HER-2 receptor must dimerize with
another EGF family member receptor to
activate the intracellular activity of HER2
• The intracellular tyrosine kinase activity leads
to the activation of multiple pathways
promoting growth and survival
Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab
Hudis C. N Engl J Med 2007;357:39-51
HER 2 Positive Breast Cancer - Risk
• HER-2 over-expression occurs in approx 20%
of BRCA and is a marker of increased risk
( Slamon et al. Science 244:707-712;1989)
• HER-2 Status is clearly important from a
therapeutic perspective
• Overexpression can be measured by immunohistochemistry (IHC), Fluorescent in situ
hybridization (FISH), or by gene expression
Relapse-free Survival (Panel A) and Overall Survival (Panel B) among Women with Breast Cancer, According to
HER2 Amplification Status on FISH
Pritchard K et al. N Engl J Med 2006;354:2103-2111
Fig. 4-Effect of HER 2 positivity on distant DFS for T1, N0 Tumors
Data derived from
Finnish Cancer
Registry case 1991-92
Joensuu, H. et al. Clin Cancer Res 2003;9:923-930
Copyright ©2003 American Association for Cancer Research
Disease-free survival in patients with pT1a-b, pN0, M0, HER2-positive (HER2+) status and of a
matched, HER2-negative comparison group (HER2−).
Curigliano G et al. JCO 2009;27:5693-5699
©2009 by American Society of Clinical Oncology
HER 2 Positive Breast Cancer
HER 2 Positive Breast Cancer: IHC
HER 2 Positive Breast Cancer: FISH
Breast Cancer – Molecular Classification
Sorlie et al
Breast Cancer – Molecular Classification
Sorlie et al, PNAS 2001
MD Anderson HER 2 Discordance -Study diagram.
Niikura N et al. JCO 2012;30:593-599
©2012 by American Society of Clinical Oncology
HER 2 Positive Breast Cancer
Therapy
HER 2 Positive Breast Cancer:
Trastuzumab (Herceptin)
• Trastuzumab is a humanized mouse
monoclonal antibody against the HER-2
protein
• Trastuzumab has activity as a single
agent
• Trastuzumab has synergistic activity with
chemotherapy
Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab
Hudis C. N Engl J Med 2007;357:39-51
Results of Studies of Trastuzumab as Monotherapy for Metastatic Breast Cancer
Hudis C. N Engl J Med 2007;357:39-51
Randomized Trials Comparing Chemotherapy Alone with Chemotherapy plus Trastuzumab
for Metastatic Disease
Hudis C. N Engl J Med 2007;357:39-51
HER 2 Positive Breast Cancer
Herceptin Cardiac Toxicity
• Noted during the initial trial with
chemotherapy
• Can be seen with Trastuzumab alone
• Significantly higher when given in conjunction
with anthracyclines – up to 27%
HER 2 Positive Breast Cancer
Adjuvant Therapy
Relapse-free Survival (Panel A) and Overall Survival (Panel B) According to the Type of Adjuvant Chemotherapy
in Women with HER2 Amplification on FISH (MA 5)
Node +
Premenopausal
Pritchard K et al. N Engl J Med 2006;354:2103-2111
HER 2 Positive Breast Cancer
Adjuvant Therapy with Herceptin
Multiple trials performed to examine the role of
Trastuzumab as adjuvant therapy
• NSABP B-28
• NCCTG 9831
• HERA
• BCIRG 006
• FinHER
Consistent and striking benefit seen in all
Combined Analysis – NSABP/NCCTG Trials
Kaplan-Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B)
Romond E et al. N Engl J Med 2005;353:1673-1684
NSABP/NCCTG
Summary of Efficacy End-Point Analyses
Romond E et al. N Engl J Med 2005;353:1673-1684
Consolidated Standards of Reporting Trials (CONSORT) Chart of the Herceptin Adjuvant (HERA) Trial
Piccart-Gebhart M et al. N Engl J Med 2005;353:1659-1672
Analyses of Disease-free Survival According to Subgroup
Piccart-Gebhart M et al. N Engl J Med 2005;353:1659-1672
HER 2 Positive Breast Cancer
HER 2 Positive Breast Cancer
Adjuvant Therapy
• BCIRG 006 – Results – median follow-up 65
months (estimated 5 year survival)
DFS
AC + T
75%
AC + TH
84%
TCH
81%
OS
87%
92%
91%
FINHER Trial
The Design of the Trial
12 total weeks
of trastuzumab
Joensuu H et al. N Engl J Med 2006;354:809-820
Effects of Single-Agent Docetaxel or Vinorelbine and of Trastuzumab on the Kaplan-Meier Estimates of
Recurrence-free Survival (Panels A and C) and Overall Survival (Panels B and D) among Women with Breast
Cancer
Joensuu H et al. N Engl J Med 2006;354:809-820
HER 2 Positive Breast Cancer
Adjuvant Therapy
•
•
•
•
Dana Farber Cancer Institute
Node negative less than 3 cm, N = 410
12 weeks of Paclitaxel plus Trastuzumab
followed by Trastuzumab every 3 weeks for 40
weeks
Median follow-up 3.6 years
DFS- 98.7 % overall (99.5 % for < 1 cm tumors)
Folaney et al.SABCS 2013
Cumulative incidence of cardiac events in National Surgical Adjuvant Breast and Bowel
Project B-31.
Romond E H et al. JCO 2012;30:3792-3799
©2012 by American Society of Clinical Oncology
Cardiac Tocxicity –BCIRG 006
HER 2 Positive Breast Cancer
Adjuvant Therapy: Summary
• The addition of Trastuzumab to chemotherapy
improves outcomes
• Concomitant chemotherapy plus trastuzumab
is superior to sequential chemotherapy
followed by Trastuzumab (NCCTG 9831)
HER 2 Positive Breast Cancer
Adjuvant Therapy: Summary
• The optimal chemotherapy regimen is unclear
but all include Trastuzumab plus a taxane
• Cardiac toxicity is a concern – especially
withanthracycline usage
Chemotherapy for Advanced HER 2
Positive Breast Cancer : Newer Options
Lapatinib – ( Tykerb)
Pertuzumab – (Perjeta)
TDM-1 – (Kadcycla)
Biology Directed Therapy of Breast
Cancer
EGF
IGF
Receptor
Activation
Growth
Survival
Pathway
Activation
DNA
Message
-Herceptin
-Pertuzumab
-T-DM 1
-lapatinib
-neratinib
Epidermal growth factor receptor (EGFR) family.
Alvarez R H et al. JCO 2010;28:3366-3379
©2010 by American Society of Clinical Oncology
Efficacy End Points in the Intention-to-Treat Population
Geyer C et al. N Engl J Med 2006;355:2733-2743
Efficacy End Points in the Intention-to-Treat Population
Geyer C et al. N Engl J Med 2006;355:2733-2743
(A) Kaplan-Meier estimates of overall survival (OS) in the intent-to-treat population.
Lapatinib +
Trastuzumab
both
Blackwell K L et al. JCO 2012;30:2585-2592
©2012 by American Society of Clinical Oncology
Pertuzumab Combination Therapy
Progression-free Survival, as Assessed at an Independent Review Facility.
Pertuzumab +
trastuzumab +
docetaxel
CLEOPATRA TRIAL
or
Docetaxel +
trastuzumab
PFS 18.5 vs 12.4 M
Baselga J et al. N Engl J Med 2012;366:109-119
Combination Therapy with Pertuzumab - Overall Survival.
Baselga J et al. N Engl J Med 2012;366:109-119
HER – 2: Newer Therapies – TDM – 1
Trastuzumab emtansine
Mechanism of action of T-DM1.
Krop I , and Winer E P Clin Cancer Res 2014;20:15-20
©2014 by American Association for Cancer Research
TDM-1 in Advanced HER + Breast
Cancer
Verma et al N Engl J Med 2012
TDM-1 in Advanced HER + Breast
Cancer
Verma et al N Engl J Med 2012
Her 2 Positive Breast Cancer :
Neo-Adjuvant Therapy
Neo- adjuvant Trials with Herceptin plus
chemotherapy have yielded pathologic
complete responses in 20-40 % of patients
HER 2 Positive Breast Cancer
Neo-Adjuvant Therapy
Pertuzumab
• NEOSPHERE and TRYPHENA
Trials
• All show benefit to addition of
Pertuzumab
HER 2 Positive Breast Cancer
Neo-Adjuvant Therapy:
NEOSPHERE Trial
HER 2 Positive Breast Cancer:
NEOSPHERE Trial Results
Regimen
pCR
D+P+T
45%
D+P
24%
D+T
29%
P+T
18%
P value = 0.014 for comparison of DPT and DT
HER 2 Positive Breast Cancer
Neo-Adjuvant Therapy
70
60
50
40
pCR %
30
20
10
0
HER 2 Positive Breast Cancer: Therapy
Future Directions
HER 2 Positive Breast Cancer
APHINITY Trial
• Phase 3 adjuvant trial
• 4800 patients accrued
• Herceptin plus 6-8 cycles of
chemotherapy + Pertuzumab
• Accrual completed 8/2013
•
(results 2014)
HER 2 Positive Breast Cancer
Summary
• HER 2 overexpressing breast cancer
represents a significant percentage of all
breast cancers
• Biologically these cancers behave
aggressively
• Targeted therapies have greatly improved
the outlook for this group of patients
Thank You !

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