3 Definitions and Molecular Features Invasive breast cancer was previously identified as a homogeneous group of disease
4 Definitions and Molecular Features Different subgroups existPatient demographicsClinical behaviorPrognosisBreast CancerBasal-like SubtypesLuminal 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 cancersLack the clinical manifestations of ER, PR, Her-2 receptorsOccupy 10-17% of the breast cancer populationImmunostaining for ER
8 Definitions and Molecular Features ImmunostainingMolecular genentics and cDNA assay
9 Definitions and Molecular Features Basal-like breast cancersBasal-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 cytokeratinsCK5CK14EGFRMore “progenitor” like in germline
12 Definitions and Molecular Features Triple-Negative Breast CancersOverlapNeg for ER, PR, HER2Possess cytokeratins e.g. EGFR, CK15, CK40BRCA1 mutationBasal-like Breast Cancers
13 Definitions and Molecular Features Triple-negative breast cancersClinicalNegativity for ER, PR, HER2Basal-like breast cancersBased on cDNA assays for identification of cytokeratinsCK5, CK14, CK17, epidermal growth factor receptors, etc
14 Definitions and Molecular Features The 2 entities are almost used anonymously in clinical settings
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 positivity1. 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 behavior1. 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; 5367–53742. 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 ImplicationReason for isolating a subgroup of breast cancer ?
27 Surgery More aggressive clinical behaviour Larger tumour size Higher rate of axillary LN positivityHigher histological grade
28 Clinical ImplicationNo difference in locoregional recurrence between mastectomy group and BCT with radiation group when multivariate regression was applied1. 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 ImplicationTNBC is not a sole indicator for / against mastectomyFactors which determine BCT / mastectomy :E.g. multicentricity, tumour size
31 Clinical Implication Lack of ER, PR No role of hormonal therapy Lack Her-2 receptorNo 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 ImplicationIn patients achieving CR, survival similar to patients in non-TNBC groupResidual disease1. 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 Implication1. 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 ChemotherapyAre we giving neo-adjuvant Therapy ?
36 Clinical Implication Aim To achieve resectability of the tumour DownstageDownsizeTo achieve resectability of the tumour
40 Clinical Implication Poorer prognosis Higher mortality Reduced overall survival and disease-free survival1. 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 spreadLungsBrainMuch less spread to lymphatics and bones1. 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 relapseShorter post-recurrence survival1. 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 cancers12 cases of triple negative breast cancers ( 6.9% )
44 Summary Triple negative breast cancer Special breast cancer subgroup Different patient demographics and different clinical behaviourTreatment optionsSubgroups of TNBC ?New therapeutic agents targeted at the surface molecular markers under developmentDirection for the future development of modern medicine in breast cancer