Triple-Negative Breast Cancer And its Clinical Implication

Background

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

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

Definitions and Molecular Features Molecular genetics

Definitions and Molecular Features Triple-negative breast cancers

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

Definitions and Molecular Features Immunostaining Molecular genentics and cDNA assay

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

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

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

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

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

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

Patient Demographics

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

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.

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

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.

Clinical Implication Reason for isolating a subgroup of breast cancer ?

Clinical Implication Clinical implications ?

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

Clinical Implication Let’s utilize a clinical scenario for illustration

Clinical Implication

Clinical Implication Treatment options

Surgery BCT vs Total mastectomy ?

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

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, 2006. 24; 36; 5652-5657 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. 2009. 115(5): 946-951 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.

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

Chemotherapy Neo-adjuvant Therapy ? Adjuvant Therapy ?

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

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):2329-2334

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):2329-2334

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):2329-2334

Chemotherapy Are we giving neo-adjuvant Therapy ?

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

Chemotherapy How about adjuvant chemotherapy ?

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

Clinical Implication Prognosis Long-term surveillance

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):2329-2334

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

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);1275-1281

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% )

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