Breast Cancer and HER2

Structure of Normal Breast

The breast is composed of fatty tissue, milk ducts and lobes
o Layers of connective tissue sit between the fatty tissue
and ducts
Nipple and duct opening
The milk ducts are composed of a lumen surrounded by a layer of
simple columnar epithelial cells
o Epithelial cells are surrounded by layer of simple
cuboidal/myoepithelial cells
o Myoepithelial cells are surrounded by basement
membrane
The breast sits atop the ribs and intercostal muscles
How the diagnosis of breast cancer is made
A combined, clinical, imaging and pathological approach (triple approach)
Clinical = investigation of all lumps detected in breast, referral for imaging
Imaging = some types of breast cancer do not lead to palpable lump
o Tumour on x-ray = unusual opaque area
o Calcified lesions on X-ray (little white spots) = may be early sign of breast cancer
Pathological = investigation of withdrawn samples from breast
o Fine needle aspiration
Small thin needle and syringe withdraw sample of cells from lump
Extracts cytological material
o Core biopsy
Needle withdraws a core of lump tissue
Extracts histological material
o Specific diagnosis based on pathological examination
E.g. ductal carcinoma (most common)
Observed tumour cells in a biological specimen invade normal breast tissue
creating a dense fibrous stroma
E.g. Tubular carcinoma
Observed tumour cells form regular tubular structures resembling small ducts
E.g. Mucoid Carcinoma
Cells secrete mucin into the stroma
Tumour grading
o Tubule formation
>75% = 1
10-75% = 2
<10% = 3
o Nuclear pleomorphism
Small uniform cells = 1
Moderate increase in size and variation = 2
Marked variation = 3
o Mitotic count (per10 high power fields)
up to 7 = 1
8 to 14 = 2
15 or more = 3
TMN system = assessing stage of breast cancer (1= T1, N0, M0; 4 = T4, N2, M1)
o Tumour spread
T0 = breast free of tumour
T1 = Lesion <2cm in size
T2 = Lesion 2-5cm
T3 = Skin/ chest wall involved by
invasion
o Lymph Node involvement
N0= No axillary nodes involved
N1= Local nodes involved
N2= Distant nodes involved
o Metastatic spread
M0=No metastases
M1=demonstrable metastases
MX=suspected metastases
Relevance of Testing for HER2 expression
HER2 overexpressed in 25-30% of invasive breast cancers
Dimerisation of HER2 receptors + subsequent phosphorylation of signalling proteins activates
cascade of signalling pathways
HER2+ve normally ER-ve and PR-ve
o Prognosis: HER2 = significantly worse prognosis in node +ve cancer
o Treatment: favourable response to Herceptin (aka Trastuzumab) or Herceptin +
chemotherapy
Herceptin blocks receptor dimeristation between HER family
Prevents extracellular domain cleavage by sheddase enzymes (alternative mode of
activation)
Prevents activation of signalling pathways
o Prevents activation of proliferative genes/ inhibition of pro-
apoptotic genes