Triple Negative Breast Cancer

Transcription

1 Triple Negative Breast Cancer Prof. Dr. Pornchai O-charoenrat Division of Head-Neck & Breast Surgery Department of Surgery Faculty of Medicine Siriraj Hospital

2 Breast Cancer Classification Traditional morphology-based system to molecular-based system Molecular portraits of human breast tumors Nature 2000;406: Basal-like breast cancers (and HER2+ group) were associated with the shortest survival times PNAS 2001;98:

3 Breast Cancer Classification Specific gene expression signatures predicted poor prognosis Nature 2002;415:530 6 Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome Am J Pathol 2002;161: Molecular breast tumor subtypes represent distinct biologic entities in independent gene expression data sets PNAS 2003;100:

4 Molecular Classification 2 main types with 6 subtypes Hormone receptor expression (positive or negative) Epithelial cellular origin (luminal or basal) BMC Genomics 2006, 7:96

5 Breast Tumor Intrinsic Subtype Classification BMC Genomics 2006, 7:96

6 Survival Curves Classified by Intrinsic Subtype BMC Genomics 2006, 7:96

7 Basal-like Breast Cancer 15% of all invasive ductal carcinoma of no special type (NST) High prevalence in premenopausal African- American women BRCA1-related breast cancers Distinct pattern of genetic alterations, including frequent TP53 mutations, proliferation genes

8 Definition of Basal-like Cancer Basal/myoepithelial profile - cdna microarray (gold standard) - immunohistochemical signatures Morphologic characteristics

9 Normal Breast Duct Luminal (glandular) cells: CK8, 18 Basal/myoepithelial cells: CK5/6, 14, 17, smooth muscle actin, S-100, CD10 Stem cells (CD24/CD44+)

10 Mammary Gland Stem Cell and Respective Cellular Phenotypes

11 Immuno-phenotype of Basal-like Breast Cancer ER-, PR-, HER2- (90%) High expression of basal cytokeratins (CK5/6, 14, 15 and 17) EGFR+ (>60%) Specificity of 100% and sensitivity of 76% Modern Pathology (2006) 19,

12 Immuno-phenotype of Basal-like Breast Cancer CK5/6 EGFR Modern Pathology (2006) 19,

13 Immuno-phenotype of Basal-like Ductal Carcinoma in Situ DCIS high grade CK17 CK14 EGFR CK5/6 P63 Modern Pathology (2006) 19,

14 Triple Negative Breast Cancer (TNBC) 10-15% of all invasive breast cancers, up to 25% in high grade tumors Predominance in younger women (<50 yr) Pre-menopausal African or Hispanic ancestry BRCA1-related tumors Cancer 2007;109:25 32

15 Triple Negative Breast Cancer (TNBC) Much lower proportion of breast cancers first detected by mammography/ultrasound Often present as interval cancers Most common histologic types are ductal carcinoma of NST (80%), metaplastic carcinoma and medullary carcinoma Lower incidence of associated DCIS Cancer 2007;109:25 32

16 Triple Negative Breast Cancer (TNBC) Rapidly growing tumors and advanced stages Weak relationship between tumor size and node status Predominance towards visceral metastases with specific pattern (spinal cord and meninges, brain, liver, and lung) Lancet Oncol 2007; 8:

17 Mammographic Features of Triple Negative Breast Cancer Circumscribed masses with no associated microcalcifications Round, oval, or lobular in shape, with indistinct margins Less frequently irregular in shape or to have spiculated margins Less frequently associated with calcifications Breast Cancer Res Treat Nov 17

18 Triple Negative Breast Cancer (TNBC) Rapid rise in risk of recurrence following diagnosis Peak risk of recurrence between 1 st -3 rd years Distal recurrence rarely preceded by local recurrence Local recurrence not predictive of distal recurrence Clin Cancer Res 2007;13)

19 Triple Negative Breast Cancer (TNBC) Difficult to treat owing to lack of effective therapeutic targets Increased mortality rate first 5 y Majority of deaths occur in first 5 y Rapid progression from distant recurrence to death Histopathology 2008, 52,

20 Triple-negative and Basal-like Breast Cancers: Synonyms? NO

21 Interrelationship of TNBCs, BP and BRCA1-related Tumors

22 Potential roles of BRCA1 in the formation of TNBCs and BP tumors Adv Anat Pathol 2007;14:419 30

23 Molecular Pathogenesis of TNBCs and BP tumors TRENDS in Mol Med 2006;12:537-44

24 Morphologic Characteristics of TNBC and BP Breast Cancer Pushing border of invasion Geographic tumor necrosis Central scar or sclerosis Lymphocytic response Spindled tumor cells Squamous metaplasia High nuclear grade High mitotic count High nuclear cytoplasmic ratio Metaplastic features Adv Anat Pathol 2007;14:419 30

25

26 Comparison of Triple Negative vs Non-triple Negative Tumors Cancer 2007;109:25 32

27 Rates of Distant Recurrences following Surgery Clin Cancer Res 2007;13)

28 Locoregional Relapse is NOT increased in Conservatively Managed Early-Stage TNBC J Clin Oncol 2006; 24:5652-7

29 TNBCs are Associated with Poorer Outcome Disease Free Interval Overall Survival Cancer 2007;109:25 32

30 TNBCs are Associated with Poorer Outcome Cancer 2008;112:737-47

31 TNBCs with Central Fibrosis and without Lymph. Infiltrate have poorer prognosis Breast Cancer Res 2007; 17: 405

32 TNBCs expressing CK5/6 and/or EGFR have poorer prognosis BMC Cancer 2007, 7:134

33 Poor Prognostic Markers of TNBC Large tumor size Presence of nodal metastasis Presence of distant metastasis Presence of central necrosis Absence of lymphocytic infiltration Absence of androgen receptor Basal phenotype (basal cytokeratins) EGFR

34 Gene Expression Profiles of TNBC Breast Cancer Res 2007; 17: 405

35 Current Practices for Evaluation of TNBCs and BP Tumors Hormone receptors and HER2 No or low expression (<10%) Morphologic features of BP tumors Basal cytokeratin testing, vimentin, P63 Androgen receptor, EGFR, c-kit, BRCA1, others?

36 Take Home Messages TNBC encompasses a heterogeneous group of tumors that show distinctive pathological and clinical features triple negativity should not be used as a surrogate marker for basal-like cancers Survival is poor and management requires a more aggressive alternative intervention

37 In Memory of Nancy Block- Zenna Home Get Involved Mission Home About Triple Negative Breast Cancer 2007 TNBC Symposium Clinical Trials Spotlight Stories TNBC in the News Our mission is to raise awareness of triple negative breast cancer and to support scientists and researchers in their effort to determine the definitive causes of triple negative breast cancer, so that effective detection, diagnosis, prevention and treatment can be pursued and achieved. "Her fight against breast cancer inspired charity" TNBC Discussion Forums What is Triple Negative Breast Cancer? Peace, Love and a Cure 2007 It is only in the last few years that professionals studying breast cancer have concluded Get Involved that breast cancer is not one disease, but many different forms of cancer all originating in Our People the breast. Depending on its stage of diagnosis, triple negative breast cancer can be extremely aggressive and more likely to recur and metastasize than other subtypes of breast cancer. It typically is responsive to chemotherapy, although it can be more difficult to treat because it is unresponsive to the most effective receptor targeted treatments. Triple negative breast cancer accounts for approximately 15% of all breast cancer cases. It occurs most often in African American and younger women. Because it is a recently recognized form of breast cancer, there is very little known about its pathology. Thus, there is an urgent need for targeted research and better treatment options for this disease. Who We Are TNBC Foundation was started by a group of young women who have been personally affected by triple negative breast cancer. The foundation's staff is comprised entirely of volunteers. Our Goals are: to ignite interest in the study of triple negative breast cancer among researchers, physicians, educators and scientists to support professionals seeking to identify the cause(s) of triple negative breast cancer and to discover new and effective treatment options