Update on HER2 testing

UPDATE ON HER-2 TESTING
Pathmanathan
Adjunct Professor
MonashMedical School
ManipalMedical School
Senior Consultant Pathologist, SDMC

Introduction
For many years, breast cancer has been considered as a unique disease and treated as a unique disease based on clinical and pathological parameters
During the last 20 years, extended knowledge of breast cancer biology, has put some light in our understanding of breast cancer

High throughput technologies such as expression profiling recently introduce new classifications of IBC
Some cellular targets, such as HER2, have been identified and drugs have been designed to specifically fight them

HER2 + breast cancer represents a heterogeneous disease targeted by specific drugs and is a hallmark of strategic treatment

HER receptors
HER2
HER1
HER3
HER4
Cell membrane
5

ErbB-2
HER2/neu
Does not need ligands
activation occurs through heterodimerization with another ErbB family member or homidimerization when HER2 is overexpressed.
ErbB-2 is the preferred dimerization partner of the other 3 ErbB family members.
Heterodimers including ErbB-2 exhibit increased stability and prolonged activation
HER2 is a poor prognosis factor in breast cancer

Trastuzumab: targeting HER2
Attacks HER2-positive tumours via 5 distinct mechanisms of action
Activation of antibody-dependent cellular cytotoxicity (ADCC)
Prevention of the formation of p95HER2, a truncated and very active form of HER2
Degradation of HER2 dimers
Inhibition of cell proliferation by preventing HER2-activated intracellular signalling
Inhibition of HER2-regulated angiogenesis
3

Herceptinis an effective drug
For HER2 + positive patients (importance of the quality of testing
In the metastatic setting in combination with taxanes, other CT agents + / -antiaromatase (ER+)
Herceptin action
Potentialization of cytotoxic drugs and hormonal treatment
HER2 targeting

HER-2 Positive state shortens survival
Median survival from first diagnosis:
HER2 positive  3 years
HER2 normal  6 - 7 years
Slamon DJ et al. Science 1987;235: 177-182

HER2+ is a heterogeneous disease
Up to 50% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers are also oestrogen receptor (ER) positive
Evidence of crosstalk between HER2 and ER signalling pathways
Simultaneous targeting of both pathways may improve outcomes over monotherapy
Vogel et al 2001;Penault-Llorca et al 2002; Piccart-Gebhart et al 2005

Herceptin® is indicated for HER2-positive breast cancer
HER2 positivity is the criterion to select patients for Herceptin® therapy
strong overexpression of the HER2 protein on the cell surface
HER2 gene amplification

HER2
TESTING
HER2 PROTEIN OVEREXPRESSION
IHC
FISH OR CISH
HER2 GENE AMPLIFICATION

0 ou 1+
FISH or CISH
IHC
+
2+
3+
–
FISH or CISH
+
–
Aneuploidy or ambiguous case
Tester by
IHC
Anti her2 treatment
Anti her2 treatment
2+ or -
3+
Breast tumor
Anti her2 treatment
Anti her2 treatment
ASCO, CAP Guidelines 2006

Importance of accurate testing
Accurate testing is essential to identify those patients who will benefit from Herceptin®
false-negative assessment:denies patients life-extending treatment
false-positive assessment: patients will not benefit from Herceptin®
Important requirements for the pathology laboratory
standardisation and regular validation of testing
quality control measures and quality assurance
minimum number of cases (>150 per year)
detailed documentation

Normal
Normal
Abnormal low
Abnormal high
amplification
amplification
Abnormal 2+
Abnormal 3+
Normal 0
Normal 1+
ErbB-2/HER2 in Breast Cancer

Published in 2007
Problem of tumour heterogeneity apparent at that time
Group consensus meeting in 2008 to discuss this problem
Vetted through CAP / American College of Medical Cytogenetics Resource Committee
ASCO / CAP guidelines

Well documented
Represents subclonal diversity
Incidence varies from 5 – 30 %
Increases subjectivity of HER-2 interpretation by pathologist
Intratumoral heterogeneity

Definition
> 5 % but < 50 % of infiltrating tumour cells have ratio higher than 2.2
HER-2 genetic heterogeneity (GH)

If 20 cells are counted and at least one cell is identified with a HER2/ CEP17 ratio of > 2.2, the specimen has GH
If 60 cells are counted, > 3 cells show a ratio of 2.2 , GH exists
These definitions based on published works, agreed by consensus

Polyploidy 17
In about 19.5 % of cases tested with FISH which show an equivocal result by absolute copy number
About 1.3 % of patients showing equivocal result by HER2/ CEP17 ratio
Polysomy 17 in Breast Cancer

Polysomy, PathVysion™ kit
The >2 green signals (CEP17) and 2 orange signals (HER2 genes) per nucleus indicate polysomy

Polysomy 17 on its own
Not associated with HER2 overexpression
Not associated with increased levels of HER2 mRNA on RT-PCR
Not associated with high grade tumours
Not associated with ER negativity
Not associated with reduced disease free survival
May not benefit from Herceptin therapy
MORE STUDIES NEEDED
Bempt et.al (2008) J ClinOncol 26: 30, pp 4869- 4874

Tubbs RR, Hicks DG, Cook J, et al. Diagn Mol Pathol. 2007;16:207– 210.
Lewis JT, Ketterling RP, Halling KC, et al. Am J Clin Pathol. 2005;124:273–281.
Fujii H, Marsh C, Cairns P, Sidransky D, Gabrielson E. Cancer Res. 1996;56:1493–1497.
Miller DV, Jenkins RB, Lingle WL, et al. 2004 ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22(14S):568.
Glockner S, Buurman H, Kleeberger W, Lehmann U, Kreipe H. Lab Invest. 2002;82:1419–1426
References

Update on HER2 testing

by Dr. Pathmanathan on Sep 01, 2009

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