Recent advances in breast cancers

Breast cancer is a hetrogenous disease due to distinct genetic alterations. Similar morphological subtypes show variation in clinical behaviour especially in response to same therapy.

Risk factors Country of origin Family History Menstrual and reproductive history Fibrocystic disease and epithelial hyperplasia Exogenous oestrogens Ionizing radiation Breast augmentation Hereditary disorders

Hereditary Breast cancer Hereditary Breast and Ovarian Ca BRCA 1 BRCA 2 Breast, Ovary, Pancreas ca. Li Fraumeni Syndrome CHEK 22q TP53 17p Breast ca sarcoma Familial linitis plastica 16q Lobular Ca, gastric Ca Cowden syndrome PTEN Breast Ca, Endometrial Ca, GIT polyps Louis Bar syndrome 11q Breast ca and Lymphoma, glioma Banyan riley Rivalcaba Syndrome PTEN Breast cancer, Meningioma, Follicular ca Throid Lynch cancer family Numerous mutation High risk of multiple primary ca

Cytological and histological investigations FNAC Trucut biopsy Lumpectomy Frozen sections HPE of Radical / Total / segmental Mastectomy Receptor studies Axillary Node studies DNA analysis

Biopsy induced artificial changes

Myoepithelial stain SMA, p63, S100, CD10

chromogranin

IHC of Lobular Carcinoma E-Cadherin Membrane glycoprotein plays role in cell to cell adhesion, Ca++ dependent, role in epithelial differentiation. Chromosome 16,22.1 deletion/ mutation Absent in lobular carcinoma, LCIS, Atypical lobular hyperplasia Lack of membranous activity

HER 2 Epidermal growth factor receptor 2 Cases selected for Herceptin Therapy: IHC positivity of 3+ OR FISH Her2 positive by 6 gene copies OR Ratio of Chromosome 17/ Her 2 positivity on dual FISH of >2.2

Factors affecting prognosis of breast cancer- I Age Size strong predictor of dissemination especially if minimal breast carcinoma is present Less than 1cm ( 75% normal after 10 years) Insitu of any size. Site Pregnancy and oral contraceptives - not proved Early Diagnosis Factors affecting prognosis of breast cancer II Histological type Favourable Tubular, Cribriform, Medullary, Mucinous, Papillary, adenoid cystic, Juvenile secretory Moderate prognosis classical Duct and Lobular Carcinoma Poor prognosis Lobular Ca, Signet ring, Metaplastic, Inflammatory Microscopic grade Nottingham modification of Bloom andrichardson system

Factors affecting prognosis of breast cancer II Presence or absence of invasiveness ( Insitu 100% cure, mixed prognosis depends on % of each ie insitu or invasive. Exception to rule Comedo Ca) Margins Tumour necrosis Stromal reaction lesser Lymphocytes lesser metastasis exception Medullary Ca Elastosis lower response to endocrine therapy Central fibrosis unfavorable sign Skin invasion Nipple invasion Lymphatic tumour emboli specially if mitosis is seen in such emboli. Blood vessel emboli Pagets disease

Factors affecting prognosis of breast cancer III Axillary node metastasis Level of node, I,II, III. No. of nodes Extracapsular infiltration Status of non involved nodes Internal Mammary node metastasis. Local recurrence Type of therapy Surgical margins Gene expressions

Factors affecting prognosis of breast cancer IV BRACA 1 /2 BRACA protein expression Reduced nuclear exp bad prognosis Cytoplasmic exp tumour recurrence Mucin production MUC1 good prognosis Reduced E cadherin reduced disease free interval Stromal CD10 associated eith Er negativity Her2 positivity opens up a new route of therapy in patients with otherwise poor prognosis. P53 COX2, BCL2, MDM2 Estrogen receptors DNA ploidy Cell proliferation

Triple negative Breast Carcinoma All 3 receptors negative - ER, PR, Her2 Only Chemotherapy treatment possible Usually prognosis Bad. Histological Findings: Grade 3 Histology, Any subtype DC, LC, NOS, Medullary Ca, Apocrine Ca, Metaplastic Ca, Adenoid cystic, Scretory, Myoepithelial Ca Large areas of necrosis, Large massive tumours, Lymphocytic infiltrates, Pushing margins

BRACA Germ line mutation of BRACA 1 and 2 Autosomal Dominant 50% chances of I heritance Result Hereditary Breast carcinoma and Ovarian carcinomas. Usually Triple-ve or Basal like Ca of breast Families at risk those to be investigated for the mutation : Age of onset < 50 years Two breast cancers One breast cancer and an ovarian cancer Mother or sister with BRACA mutation positivity. Male breast carcinoma. Testing by Targeted mutation analysis, squence analysis, Deletion analysis

Major Molecular subtypes of breast cancer Molecular subtype Histological correlation Endocrine therapy Chemotherapy prognosis Basal High grade invasive duct Ca, medullary Ca, Metaplastic Ca, scretary ca, Adenoid cystic ca. No response to endocrine therapy or Herceptin Sensitive to platinum based chemo and PAPP Poor prognosis. Her2 +/ ERve High grade invasive duct carcinoma Respond to Herceptin Respond to Anthracycline based chemo Moderate prognosis Normal breast like Classical Duct carcinoma Respond well Respond well Moderate Prognosis Luminal A Tubular Ca,Low grade Inf duct Ca, classical lobular carcinoma Respond well Response to chemotherapy variable Good prognosis Luminal B Invasive ductal Ca NOS, micropapillary Ca Respond well Response to chemo Variable but better then A Good prognosis but not as good a A

Major Molecular subtypes of breast cancer Molecular subtype Receptor Proliferation status cluster P53 mutation Cytokeratin Genomic pattern grade Basal ER-, PR-, Her2- High Ki67 very high high CK 5/6 + high Her2 +/ ERve ER-, PR-, Her2 + High Ki67 very high high CK 5/6 + high Normal breast like ER+/PR+/Her2 - Low, Ki67 < 14 low CK 5/6 - low Luminal A Er +++ PR+/++ Her2 - Low Ki67 < 14 low CK 5/6 - low Luminal B ER +/PR +/Her2 +/- High Ki67 >/= 14 Intermediate CK 5/6 - high