Breast Cancer Pathology,

Treatment and Genetics

 Key Issues
• Incidence of breast cancer
– Most common breast cancer of women (rare in men but does
occur.

• Environmental and inherited risk factors associated with

breast cancer.

• Pathology of breast cancer (various types).

• Treatment

• Many genetic changes associated with breast cancer

– Multifactorial
– Not all changes required for every breast cancer.
– Depends of type and nature of cancer

• Difficult to construct a genetic model.

 Incidence
• Total number cancer in women in 2000 in the UK was
136,153.

• 40, 707 of these were breast cancer.

• This represents about 30% of all cancers in women.

• Breast cancer is the most prevalent of all female

cancers.

• 1 in 8 women will develop breast cancer during their

lifetime.

• Of all male cancers (more than 150,000yr) about 250

cases are breast cancer.
 Causes of Breast Cancer -
Environmental
• Factors which can increase the lifetime risk are.
– Menarche before age 12.
– Menopause after age 55.
– First live birth after age 30yrs.
– Nulliparity.
– Previous history of breast biopsy.
– Postmenopausal obesity.
– Excessive alcohol use.
– Hormone replacement therapy.
– Excessive radiation exposure.

• These factors contribute to about a two fold

increased risk in the normal population.
 Causes of Breast Cancer -
Heritable
• Autosomal dominant syndrome

• Cowden Syndrome: associated with mutation in the

PTEN gene. 25-50% increased risk.

• Peutz-Jeghers Syndrome: Juvenile polyposis syndrome

associated with high incidence of breast cancer.
– Mutation in STK1 gene (serine-threonine kinase).

• Li-Fraumeni Syndrome: High incidence of many

different tumour types
– Autosomal dominant mutation in P53 or Chk2 gene.
• Autosomal Recessive

• Bloom Syndrome: Radiation sensitive and cancer

prone disorder. Mutation in RecQL3 gene (chr.
15q) – helicase enzyme.

• Werners syndrome: Premature ageing and cancer

prone disease. Mutation in RecQL gene (chr. 8p) –
helicase enzyme.

• Xeroderma pigmentosum: DNA repair disorder

associated with high incidence of skin cancer and
also other cancers including breast.
 Breast Cancer Types
• Carcinoma in situ:
– Confined to the ducts or lobules
• Ductal carcinoma in situ.
• Lobular carcinoma in situ.

• Infiltrating ductal carcinoma in situ (80% of all breast

cancers).

• Infiltrating lobular carcinoma in situ (10-15% of all

breast cancers).

• Medullary carcinoma: Invasive but well defined margin

between normal and cancer cells (5% of cancers)

• Colloid: Mucinous producing breast cancer

• Tubular and Adenoid cystic: Very rare breast cancers.

Histology: Normal breast
tissue
 Pathology

DCIS LCIS

Invasive CIS Medullary

Treatment of Breast Cancer
Surgery
• Breast conservation therapy: Lumpectomy removes
only the breast lump and a surrounding margin of
normal tissue.

• Partial or segmental mastectomy or quadrantectomy

removes more breast tissue than a lumpectomy (up to
one-quarter of the breast).

• Mastectomy: Simple or total mastectomy the

– removal of entire breast, but does not remove underarm
lymph nodes or muscle tissue from beneath the breast.

• All for early stage breast cancer

Treatment of Breast Cancer
Surgery
• Radical mastectomy is an extensive
operation removing:
• Entire breast
– Axillary lymph nodes
– Pectoral (chest wall) muscles under the breast.

• This surgery was once very common. But

disfigurement and side effects are extensive.

• Modified radical mastectomy

– removal of the entire breast and some of the
axillary (underarm) lymph nodes.
 Chemotherapy
• The most commonly used combinations are:

• Cyclophosphamide, methotrexate and 5-

fluorouracil (CMF)
• Cyclophosphamide, Adriamycin 5-fluorouracil (CAF)
• Adriamycin and cyclophosphamide (AC)
• Adriamycin and cyclophosphamide, Taxol or
Taxotere (AC-T).
• Adriamycin followed by CMF
• Cyclophosphamide, epirubicin and 5-fluorouracil
with or without docetaxel.

• Every 2 weeks for 4-6 months

 Anti-hormonal therapy
• Tamoxifen for 5 years or for life
depending on stage of tumour.

• Radiotherapy may also be used for

local disease.
 Principle Genes involved in
Breast Cancer

• Genes associated with breast cancer.

– BRCA1
– BRCA2
– P53
– ATM
– P65
– PTEN

– HER2 family of oncogenes

– Cyclin D1
 Tumour Suppressor Genes
• P53: Mutations of p53 are estimated to occur in up to
half of all human cancers and in approximately 20%–30%
of breast cancers.

• P27: A member of the P21 family of CDK inhibitors. P27

expression has been shown to have prognostic value in
a variety of tumours including breast cancer.

• Reduced expression of p27 is associated with shorter

overall survival and shorter time to progression.

• A stronger independent predictor of outcome than

either p53 status.
– P27lossmaybeanearlyeventinthedevelopmentofbreastcancer
 Tumour Suppressor Genes
• Linkage analysis of families with multiple breast cancers, the
locus of a gene at 17q21 was reported in 1990. BRCA-1 was
subsequently identified in 1994.

• About 0.12% of the general population carries a mutation of

BRCA-1, but this rate is much higher in certain groups
– In Ashkenazi Jews, there is a 1% rate of heterozygosity for the
mutation 185delAG and a smaller (0.1%) rate for a separate
mutation (5382insC).

• BRCA-1 mutations account for about 5% of all breast cancer

cases occurring in women under the age of 40.

• Over 90% for cases families with a history of 4+ cases of

breast cancer and more than one case of ovarian cancer
 Tumour Suppressor Genes
• Incidence of BRCA-2 heterozygotes in the general
population is similar to that for BRCA-1.
– Specific mutation 6174delT occurs at a rate of 1.5%
in the Ashkenazi Jewish population.
– The Icelandic population carries a separate
mutation, 999del5, at a rate of 0.5%.
– Present in 40% of cases of male breast cancers.

• Both Brca1 and Brca2 proteins are central to DNA

repair processes in the repair of single and
double strand DNA breaks.
– Non-homologous end joining
– Homologous recombination
 Tumour Suppressor Genes
• PTEN chromosome 10q24, encodes a phosphatase that
serves as a negative regulator to Akt signaling.

• Loss of PTEN function augments the Akt cell survival signal.

Inherited PTEN mutations, seen in Cowden syndrome.
– Increases the risk of breast and ovarian cancers
– PTEN mutations often seen in advanced breast cancer –
late genetic alteration.

• Cell cycle checkpoint kinase (CHK2- serine threonine kinase).

that is mutated in some families that have a high breast
cancer risk - Li-Fraumeni syndrome.
 Tumour Suppressor Genes
• The ATM gene senses DNA damage and activates
checkpoints and DNA repair pathways through
rapid phosphorylation of several substrates.
– p53,
– BRCA-1,
– CHK2.
– Loss of both alleles of the ATM gene causes ataxia-
telangiectasia.

• Cancer risk in heterozygotes are variable.

– Up to a twelvefold higher risk
– Suggests that the risk may be dependent on the
type of mutation.
 Oncogenes
• The HER-2 (human epithelial receptor 2: neu or erbB-2)
– Gene is located on chromosome 17q; encodes a 185-kDa
transmembrane tyrosine kinase growth factor receptor.

• Mediates signaling via:

– (MAP) kinase
– (PI3K)/Akt pathways,
– Eventuate in proliferation, angiogenesis, altered cell-cell
interactions, increased cell motility, metastases, and
resistance to apoptosis.

• The HER-2 gene is amplified and overexpressed in 30% of

invasive breast cancer and some DCIS (intermediate
change).
– Heceptin target.
 Oncogenes
• Cyclin D1: chromosome 11q13.
– overexpressed in 40%–50% of invasive breast cancers
(late stage).

• When cyclin D1 is complexed with CDK4/6, pRb is

phosphorylated, releasing the transcriptional factor
E2F and inducing proteins required for DNA
synthesis.

• High cyclin D1 expression level appears to be

positively associated an increased proliferative
index.
 Oncogenes
• The c-myc oncogene: chromosome 8q24
– Encodes a nuclear phosphoprotein that acts as a
transcriptional regulator involved in cellular
proliferation, differentiation, and apoptosis.

• It is amplified and overexpressed in about 25% of

breast cancers
– May be associated with a worse prognosis or more
aggressive clinical features.

• Myc expression alone is not sufficient for breast

carcinogenesis
 Summary
• Incidence of breast cancer
– Most common breast cancer of women (rare in men but does
occur.

• Environmental and inherited risk factors associated with

breast cancer.

• Pathology of breast cancer (various types).

• Treatment

• Many genetic changes associated with breast cancer

– Multifactorial
– Not all changes required for every breast cancer.
– Depends of type and nature of cancer

• Difficult to construct a genetic model.