Carcinoma breast is the second most common cause of cancer deaths in women
RISK FACTORS FOR BREAST CARCINOMA
Age – As the age increases, risk of developing malignancy increases with peak age at 75 to 80 years
Age at menarchy – Attaining menarche at age younger than 11 years increases risk by 20% when compared to women attaining menarche after 14 years
Age at 1st live birth – Women younger than 20 years at the 1st live birth have half the risk of nulliparous women or women over the age of age 35 years at their first birth. Early pregnancy leads to terminal differentiation of luminal cells thus removing them from the pool of cancer precursor cells.
First degree relatives with breast cancer – increases the risk of developing malignancy
Atypical hyperplasia – in the prior breast biopsy increases the risk of invasive carcinoma
Race/Ethnicity – Non-Hispanic white women have the highest incidence in US. This variation is probably due to frequency of breast cancer genes in particular ethnic group
Estrogen exposure – Post menopausal hormonal replacement therapy increases the risk of breast cancer by 1.2 to 1.7 folds. Adding progesterone increases the risk further.
Breast density –
Higher breast density in associated with increased risk
Higher breast density may be related to less complete involution of lobules at the end of each menstrual cycle which increases the number of potentially susceptible cells for neoplastic transformation.
Radiation exposure – Increases the risk of breast cancer. Risk is more in younger women exposed to radiation (cancer therapy or atomic bomb exposure)
Benign breast disease – Prior breast biopsies with atypical hyperplasia or proliferative changes increases the risk of developing invasive carcinomas
Diet – Moderate to heavy alcohol consumption increases risk
Obesity – Post menopausal obese women are at increased risk due to synthesis of estrogen in fat depots
Breast feeding – Longer the women breast feeds, the greater the reduction in risk . Lactation suppresses ovulation and may trigger terminal differentiation.
Carcinoma of contralateral breast and patients with endometrial carcinomas also have increased risk
ETIOLOGY AND PATHOGENESIS
Breast cancer is caused by clonal proliferation of ductal epithelial cells with multiple genetic aberrations caused by hormonal exposure & inherited susceptibility genes.
Familial or Hereditary breast cancer:
About 12% of breast cancers are due to inherited susceptible genes.
Major susceptibility genes for familial breast cancer are
BRCA1, BRCA2, TP53 &CHEK2.
They are tumor suppressor genes which play role in DNA repair & maintenance of genomic integrity
Mutations in BRCA1 & BRCA2 are responsible for 80% to 90% of ‘single gene’ familial breast cancer & about 3% of all breast cancers.
BRCA1 is present on chromosome 17q21 & BRCA2 on chromosome 13q12.3.
BRCA1- associated breast cancers are usually
Poorly differentiated.
Show medullary features (a syncytical growth pattern with pushing margins & lymphocytic infiltration)
Biologically similar to ER –negative /HER2-negative breast cancer, identified as “basal-like” by gene expression profiling as well as to serous ovarian carcinoma.
BRCA2- associated breast cancers are
Relatively poorly differentiated
More often ER positive.
Other genes account for less than 10% of herediatary breast carcinomas
TP53 mutations & CHEK2 mutations in 8%
PTEN, STK11 & ATM mutation in less than 1%.
All these genes have role in maintaining the genomic integrity.
ATM senses DNA damage
P53 & CHEK2 – cell cycle arrest
BRCA1, BRCA2 & CHEK2-functions is repair of double stranded DNA
Hence impaired function of any one of the gene can cause genetic damage.
Sporadic breast cancer:
Major risk factors for sporadic breast cancer are related to hormone exposure which are influenced by
Gender
Age at menarche & menopause
Reproductive history
Breast feeding
Exogenous estrogens
Other risk factors are reduction exposure and exposure to chemicals with estrogen like effect.
Estrogen causes cell proliferation especially during puberty, menstrual cycles and pregnancy. The cells with defective DNA also undergoes proliferation under the influence of hormones.
Exogenous estrogen or endogenous high levels of estrogen also has similar effect for eg as in
Hormone replacement therapy in post menopausal
Functioning ovarian tumors (granulosa cell tumor produce high estrogen levels)
Long term use of oral contraceptives.
Oestrogen given as a treatment for prostate carcinoma.
Molecular mechanism of carcinogenesis in breast cancer:
Three major genetic pathways for carcinogenesis are
Dominant pathway:
Individually inherits germline mutations in BRCA2
Constitute 50% to 60% cases
These tumors are often associated with
loss of chromosome 16q
Gain of chromosome 1q
Mutations in PIK3CA
Precursor lesions for this subtype are
Flat epithelial atypia
Atypical ductal hyperplasia
These tumors are ER positive & HER2 negative
ER positive tumors are also termed as “luminal” as they resemble normal breast luminal cells in the mRNA expression pattern.
Pathway associated with amplifications of HER2 gene on chromosome 17q
Constitute 20% of cancers
They are HER2-positive cancers which may be either ER-positive or ER negative
Most common breast cancer in patients with germline mutations in TP53 (Lifraumeni syndrome)
Precursor lesion for this sub type is Atypical apocrine adenosis
Pathway independent of ER-mediated changes in gene expression & HER2 gene amplifications
There tumors constitute 15% of breast cancers
They are ER-negative &HER2 negative
Tumors are often associated with
germline BRCA1 mutations
TP 53 mutations
Tumors have “basal like” pattern of mRNA expression which is similar to normal myoepithelial cell expression.
Neoplastic change in epithelial cells depends on the interaction with stromal cells indicating that alteration in the function of stromal cells and cross talk with epithelial cells are associated with tumors genes.
References
Vinay kumar, Abul K.Abbas, Nelson Fausto, Jon C. Aster. The Breast. In: Robbins and Cotran Pathologic basis of disease. 8th edition.
