Recent advances in breastcancers

Recent advances in breastcancers

• Breast cancer is a hetrogenous diseasedue to distinct genetic alterations.

• Similar morphological subtypes showvariation in clinical behaviour especially inresponse to same therapy.

• Breast cancer is a hetrogenous diseasedue to distinct genetic alterations.

• Similar morphological subtypes showvariation in clinical behaviour especially inresponse 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

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

Hereditary Breast cancerHereditary Breast andOvarian Ca

BRCA 1BRCA 2

Breast, Ovary , Pancreasca.

Li Fraumeni Syndrome CHEK 22qTP53 17p

Breast casarcoma

Familial linitis plastica 16q Lobular Ca, gastric Ca

Cowden syndrome PTEN Breast Ca, EndometrialCa, GIT polyps

Louis Bar syndrome 11q Breast ca andLymphoma, glioma

Banyan riley RivalcabaSyndrome

PTEN Breast cancer,Meningioma, Follicularca Throid

Lynch cancer family Numerous mutation High risk of multipleprimary ca

Cytological and histological investigations

• FNAC• Trucut biopsy• Lumpectomy• Frozen sections• HPE of Radical / Total / segmental Mastectomy• Receptor studies• Axillary Node studies• DNA analysis

• FNAC• Trucut biopsy• Lumpectomy• Frozen sections• HPE of Radical / Total / segmental Mastectomy• Receptor studies• Axillary Node studies• DNA analysis

Biopsy induced artificial changes

Biopsy induced artificial changes

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 membranousactivity

• 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 membranousactivity

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

• 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 and-

Richardson 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

• 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

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

• 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, Adenoidcystic, Scretory, Myoepithelial Ca

– Large areas of necrosis, Large massive tumours,Lymphocytic infiltrates, Pushing margins

• 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, Adenoidcystic, 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 themutation :– 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, squenceanalysis, Deletion analysis

• 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 themutation :– 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, squenceanalysis, Deletion analysis

Major Molecular subtypes of breast cancerMolecularsubtype

Histological correlation Endocrinetherapy

Chemotherapy prognosis

Basal High grade invasiveduct Ca, medullary Ca,Metaplastic Ca,scretary ca, Adenoidcystic ca.

No response toendocrinetherapy orHerceptin

Sensitive toplatinum basedchemo and PAPP

Poorprognosis.

Her2 +/ ER-ve

High grade invasiveduct carcinoma

Respond toHerceptin

Respond toAnthracyclinebased chemo

Moderateprognosis

Her2 +/ ER-ve

High grade invasiveduct carcinoma

Respond toHerceptin

Respond toAnthracyclinebased chemo

Moderateprognosis

Normalbreast like

Classical Ductcarcinoma

Respond well Respond well ModeratePrognosis

Luminal A Tubular Ca,Low gradeInf duct Ca, classicallobular carcinoma

Respond well Response tochemotherapyvariable

Goodprognosis

Luminal B Invasive ductal CaNOS, micropapillaryCa

Respond well Response tochemo Variablebut better then A

Goodprognosis butnot as good aA

Major Molecular subtypes of breast cancerMolecularsubtype

Receptorstatus

Proliferationcluster

P53mutation

Cytokeratinpattern

Genomicgrade

Basal ER-,PR-,Her2-

HighKi67 – veryhigh

high CK 5/6 + high

Her2 +/ ER-ve

ER-,PR-,Her2 +

HighKi67 – veryhigh

high CK 5/6 + highER-,PR-,Her2 +

HighKi67 – veryhigh

Normalbreast like

ER+/-PR+/-Her2 -

Low,Ki67 < 14

low CK 5/6 - low

Luminal A Er +++PR+/++Her2 -

LowKi67 < 14

low CK 5/6 - low

Luminal B ER +/-PR +/-Her2 +/-

HighKi67 >/= 14

Intermediate CK 5/6 - high