1. Triple-Negative Breast Cancer
And its Clinical Implication

2. Background

3. Definitions and Molecular Features
Invasive breast cancer was previously identified as a homogeneous group of disease

4. Definitions and Molecular Features
Different subgroups exist
Patient demographics
Clinical behavior
Prognosis
Breast Cancer
Basal-like Subtypes
Luminal Subtypes

5. Definitions and Molecular Features
Molecular genetics

6. Definitions and Molecular Features
Triple-negative breast cancers

7. Definitions and Molecular Features
Triple-negative breast cancers
Lack the clinical manifestations of ER, PR, Her-2 receptors
Occupy 10-17% of the breast cancer population
Immunostaining for ER

8. Definitions and Molecular Features
Immunostaining
Molecular genentics and cDNA assay

9. Definitions and Molecular Features
Basal-like breast cancers
Basal-like breast cancer cells demonstrating EGFR immunostaining

10. Definitions and Molecular Features
Resemble myoepithelial cells in basal layer of ductal system

11. Definitions and Molecular Features
Possess cytokeratins
CK5
CK14
EGFR
More “progenitor” like in germline

12. Definitions and Molecular Features
Triple-Negative Breast Cancers
Overlap
Neg for ER, PR, HER2
Possess cytokeratins e.g. EGFR, CK15, CK40
BRCA1 mutation
Basal-like Breast Cancers

13. Definitions and Molecular Features
Triple-negative breast cancers
Clinical
Negativity for ER, PR, HER2
Basal-like breast cancers
Based on cDNA assays for identification of cytokeratins
CK5, CK14, CK17, epidermal growth factor receptors, etc

14. Definitions and Molecular Features
The 2 entities are almost used anonymously in clinical settings

15. Patient Demographics

16. Patient Demographics Patient demographics
Younger age of onset ( <50 years old )

17. Patient Demographics Patient demographics Larger mean tumour size
Higher rate of node positivity
1. Abd El-Rehim DM, Pinder SE, Paish CE et al. Expression of luminal and basal cytokeratins in human breast carcinoma.
J. Pathol. 2004; 203; 661–671.
2. Fan C, Oh DS, Wessels L et al. Concordance among geneexpression-
based predictors for breast cancer. N. Engl. J. Med.
2006; 355; 560–569.

18. Patient Demographics Patient demographics Higher histological grade
1. Fulford LG, Easton DF, Reis-Filho JS et al. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 2006; 49;
22–34.
2. Lakhani SR, Reis-Filho JS, Fulford L et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin. Cancer Res. 2005; 11; 5175–5180.
3. Livasy CA, Karaca G, Nanda R et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod. Pathol. 2006; 19; 264–271.
4. Tsuda H, Takarabe T, Hasegawa F, Fukutomi T, Hirohashi S. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. Am. J. Surg. Pathol. 2000; 24; 197–202.
5. Tsuda H, Takarabe T, Hasegawa T, Murata T, Hirohashi S. Myoepithelial differentiation in high-grade invasive ductal carcinomas with large central acellular zones. Hum. Pathol. 1999; 30; 1134–1139

19. Patient Demographics Patient demographics
More aggressive clinical behavior
1. Nielsen TO, Hsu FD, Jensen K et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin. Cancer Res. 2004; 10; 5367–5374
2. Abd El-Rehim DM, Pinder SE, Paish CE et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J. Pathol. 2004; 203; 661–671.
3. Fan C, Oh DS, Wessels L et al. Concordance among geneexpression-based predictors for breast cancer. N. Engl. J. Med. 2006; 355; 560–569.

20. Clinical Implication
Reason for isolating a subgroup of breast cancer ?

21. Clinical Implication
Clinical implications ?

22. Clinical Implication
Does it affect our way of treating our patients ?

23. Clinical Implication
Let’s utilize a clinical scenario for illustration

24. Clinical Implication

25. Clinical Implication
Treatment options

26. Surgery
BCT vs Total mastectomy ?

27. Surgery More aggressive clinical behaviour Larger tumour size
Higher rate of axillary LN positivity
Higher histological grade

28. Clinical Implication
No difference in locoregional recurrence between mastectomy group and BCT with radiation group when multivariate regression was applied
1. Bruce G. Haffty, Qifeng Yang, Michael Reiss, et al. Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer. J Clin Onc, ; 36;
2. Gary M. Freeman, Penny R. Anderson, Tianyu Li, Nicos Nicolaou. Local-Regional Recurrence of Triple Negative Breast Cancer after Breast-Conserving Surgery and Radiation. Cancer (5):
3. Parker C.C., Smith M.H., Henderson B.D. Li, Ampil F., Chu Q.D. Breast Conservation Therapy Is a Viable Option for Patients with Triple-Receptor Negative Breast Cancer.

29. Clinical Implication
TNBC is not a sole indicator for / against mastectomy
Factors which determine BCT / mastectomy :
E.g. multicentricity, tumour size

30. Chemotherapy
Neo-adjuvant Therapy ?
Adjuvant Therapy ?

31. Clinical Implication Lack of ER, PR No role of hormonal therapy
Lack Her-2 receptor
No role for current targeted therapy towards Her-2 receptor

32. Clinical Implication High chemosensitivity
Higher rate of achieving complete pathological remission CR ( 36% )
1. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumour chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):

33. Clinical Implication
In patients achieving CR, survival similar to patients in non-TNBC group
Residual disease
1. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumour chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):

34. Clinical Implication
1. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumour chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):

35. Chemotherapy
Are we giving neo-adjuvant Therapy ?

36. Clinical Implication Aim To achieve resectability of the tumour
Downstage
Downsize
To achieve resectability of the tumour

37. Chemotherapy
How about adjuvant chemotherapy ?

38. Clinical Implication St. Gallen consensus recommendations
Tumor size >2 cm
ER and PR negativity
Tumor histologic grade 2 or 3
Age <35 years
Nodal involvement

39. Clinical Implication
Prognosis
Long-term surveillance

40. Clinical Implication Poorer prognosis Higher mortality
Reduced overall survival and disease-free survival
1. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumour chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):

41. Clinical Implication Patient demographics
More frequent haemaogeneous spread
Lungs
Brain
Much less spread to lymphatics and bones
1. Fulford LG, Reis-Filho JS, Ryder K et al. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res. 2007; 9; R4.
2. Hicks DG, Short SM, Prescott NL et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5 ⁄ 6, and overexpress HER2 or EGFR. Am. J. Surg. Pathol. 2006; 30; 1097–1104.
3. Rodriguez-Pinilla SM, Sarrio D, Honrado E et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin. Cancer Res. 2006; 12; 1533–1539.
4. Tsuda H, Takarabe T, Hasegawa F et al. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. Am. J. Surg. Pathol. 2000; 24; 197–202

42. Clinical Implication Increased rate of loco-regional recurrence
Earlier relapse
Shorter post-recurrence survival
1. Liedte C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8);

43. Figures in NTWC During the period from 1 Jan 2010 to 31 Dec 2010
Total no. of 176 breast cancers
12 cases of triple negative breast cancers ( 6.9% )

44. Summary Triple negative breast cancer Special breast cancer subgroup
Different patient demographics and different clinical behaviour
Treatment options
Subgroups of TNBC ?
New therapeutic agents targeted at the surface molecular markers under development
Direction for the future development of modern medicine in breast cancer