discussion on role of Ki67 and clinical situations for such testing in breast cancers

1. Defining the clinical challenges – Pitfalls ofDefining 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

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

3. Molecular pathways in pathogenesis of breast cancer

5. 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-enriched
Basal

6. 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
membrane
Myoepithelial Cells 
Basal
Luminal Cells 
Luminal

7. 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

8. 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

9. Role of Ki67
• Prognostic indicator for high risk patients; indicates cellular
proliferation
• helps decide on whether to add chemo to endocrine therapy
9

10. 10

11. • Thus Ki67 is used
for adding chemo
based on risk
assessment:
<15% means low
risk
16-30% means
intermediate
>30% is high risk
11

12. Others……..
KiS2/Ki67 (ratio)
•Indicates relative fraction of proliferative cells; % of cells in the SM 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

13. Oxford Journals Medicine
JNCI J Natl Cancer Inst
Volume 101, Issue 10,2009
Pp. 736-750.

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

15. 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 -100
Cutoff points chosen based on
Results of NSABP trial B-20

16. 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

17. Predictive relevance of molecular
classification
Goldhirsch et al. Ann Oncol June 2011. St Gallen 2011

18. 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 test
RS <
18
RS 18-
30
RS ≥
31
Adjuvant endocrine
therapy
± adjuvant chemotherapy
Adjuvant endocrine
therapy
endocrine therapy
± adjuvant chemotherapy
Adjuvant endocrine
therapy
+ adjuvant chemotherapy

19. THANK YOUTHANK YOU
19