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

• Histologic subtype• Axillary lymph node status• Tumor size• Grade• Age• Comorbidities

Molecular pathways in pathogenesis of breast cancer

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

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

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.

7

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

8

Role of Ki67

• Prognostic indicator for high risk patients; indicates cellular proliferation

• helps decide on whether to add chemo to endocrine therapy

9

10

• Thus Ki67 is used for adding chemo based on risk assessment:<15% means low risk16-30% means intermediate>30% is high risk

11

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.

12

Oxford Journals MedicineJNCI J Natl Cancer InstVolume 101, Issue 10,2009 Pp. 736-750.

Evaluated the analytical validity, clinical validity and clinical utility of two approaches.

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

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

Predictive relevance of molecular classification

Goldhirsch et al. Ann Oncol June 2011. St Gallen 2011

NCCN guidelines include Oncotype DX® testing in the treatment-decision pathway for node-negative and

micrometastatic disease

18

•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

THANK YOUTHANK YOU

19