ihc in breast ca
TRANSCRIPT
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Defining the clinical challenges – Pitfalls of Defining the clinical challenges – Pitfalls of IHC testing in Breast cancerIHC testing in Breast cancer
Dr. Ashutosh Mukherji Associate Professor,
Department of Radiotherapy, Regional Cancer Centre, JIPMER
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• Histologic subtype• Axillary lymph node status• Tumor size• Grade• Age• Comorbidities
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Molecular pathways in pathogenesis of breast cancer
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Breast Cancer Subtypes• Breast cancer is classified into clinical subtypes
based upon receptor expression• These subtypes dictate possible therapeutic
options and vary in their prognosis– Luminal: derived from the luminal cells
• TYPE A:ER+, PR+,HER-2-• TYPE B:ER+,PR+,HER-2+• Can use hormonal therapy• Less aggressive
– Basal: derived from myoepithelial cells• ER-, PR-,HER-2-,ck 5/6+ or HER -1+• No specific target for therapies• More aggressive
– HER2-enriched• More aggressive
Luminal A
Luminal B
Claudin-Low
HER2-enrichedBasal
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Luminal and Basal Characteristics
Basal• Low ER• Low HER2• High CK5/6• c-KIT higher• High EGFR• High p53 mutation• High p53 protein• High cyclin E• Very high vimentin
Luminal• High ER• Higher HER2• Low CK5/6• Low c-KIT• Low EGFR• Low p53 mutation• Low p53 protein• Low cyclin E• Low vimentin
Basement membraneMyoepithelial Cells BasalLuminal Cells Luminal
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ER Receptors
• Weak prognostic marker for clinical outcome• Strong marker for tamoxifen response• Results can be affected by method of processing (tissue
fixation/ choice of antibody / interpretation of results)• Alred scoring important• Score of more than or equal to 3 means atleast 1% cells
expressing – puts result in St Gallen uncertain group where hormone therapy may / may not help.
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HER 2 NEU
• Positive result means more than 6 copies per tumour cell or a HER2 / Chromosome 17 ratio of 1.8 – 2.2
• Positive in 15-30% cases of breast carcinoma• Associated with increase disease recurrence and poor prognosis• expression of HER2 is regulated by signaling through estrogen receptors.• Normally tamoxifen down regulate HER2
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Role of Ki67
• Prognostic indicator for high risk patients; indicates cellular proliferation
• helps decide on whether to add chemo to endocrine therapy
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• Thus Ki67 is used for adding chemo based on risk assessment:<15% means low risk16-30% means intermediate>30% is high risk
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Others……..KiS2/Ki67 (ratio)•Indicates relative fraction of proliferative cells; % of cells in the SM phase.•KiS2 improves accuracy and identifies low risk patients not requiring adjuvant therapy.
Bcl2 / p53•Indicates tumour growth / high risk•No recommendations for p53.•Bcl2 indp of group / stage / tm size improved survival
Anti angiogenetic / fibroblastic factors•For decision regarding addition of bio-molecules to therapy•Supposedly increases PFS•Not validated.
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Oxford Journals MedicineJNCI J Natl Cancer InstVolume 101, Issue 10,2009 Pp. 736-750.
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Evaluated the analytical validity, clinical validity and clinical utility of two approaches.
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Levels of Gene Expression Determine Recurrence Score
21-gene assay = 16 outcome-related genes + 5 reference genes
Higher expression levels of“favorable” genes = ↓ RS
Higher expression levels of“unfavorable” genes = ↑ RS
A risk score is calculated from 0 -100Cutoff points chosen based onResults of NSABP trial B-20
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Targeted therapy ER + ER-
Hormonal Herceptin EGFR BRCA 1 C-kit
Therapy Geftinib, erlotinib, DNA damage Imatinib
lapatinib PARP inh
Luminal A Luminal B HER 2 + Basal Like
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Predictive relevance of molecular classification
Goldhirsch et al. Ann Oncol June 2011. St Gallen 2011
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NCCN guidelines include Oncotype DX® testing in the treatment-decision pathway for node-negative and
micrometastatic disease
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•Tumor 0.6-1.0 cm, moderately or poorly differentiated, intermediate or high grade, or vascular invasion•Tumor > 1 cm with favorable or unfavorable pathologic features
Consider Oncotyp
e DX
Hormone receptor-positive, HER2-negative disease
pT1, pT2, or pT3 and pN1mi
No testRS <
18RS 18-
30RS ≥ 31
Adjuvant endocrine therapy
± adjuvant chemotherapy
Adjuvant endocrine therapy
endocrine therapy ± adjuvant chemotherapy
Adjuvant endocrine therapy
+ adjuvant chemotherapy
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THANK YOUTHANK YOU
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