Breast Cancer

Breast cancers usually arise in the inner lining of the small tubes (ducts) that carry milk to the nipple (ductal carcinomas) or in the lobules where milk is made (lobular carcinoma). These tubes and lobules are lined by two types of epithelial cells: luminal (secretory) cells and myoepithelial cells.

Breast cancer is by far the most common cancer in women, with 1.38 million new cases worldwide in 2008, 23% of all cancers. It is over 100 times more common in women than in men (yes men can get it) and it causes nearly 14% of all female cancer deaths. Over the last 30 years mortality has declined, due to contributions from new drugs and more widespread screening mammography, and over 80% of women now live more than five years after diagnosis.  In the UK this X-ray method for the detection of abnormalities is recommended every three years for women between 50 and 70 years of age: from 2012 the age range is to be extended to women between 47 and 73 years.  In the USA the recommendation is that women between 40 and 50 are screened every two years with annual examinations after the age of 50.

Treatment is almost always initially by surgery, either the removal of the tumour and a small amount of adjacent tissue (‘lumpectomy’) or the removal of all the breast tissue (‘mastectomy’).  If the cancer has spread to the lymph nodes in the armpit (axilla), axillary lymph node dissection (removal) can be carried out at the same time.  Prophylactic mastectomy is an option for women at high risk, for example, if they have a family history of the disease and they are carrying a mutation in a pre-disposing gene (e.g., BRCA1).  Adjuvant therapy usually involves radiotherapy and chemotherapy.

New cases/year

World 2008: 1,384,155; USA 2011 (est): 230,620 [male: 2,140, female: 230,480];

UK 2008: 48,034 [male: 341, female: 47,693]

Deaths/year 

World 2008: 458,503; USA 2011 (est): 39,970 [male: 450, female: 39,520];

UK 2008: 12,116 [male: 69, female: 12,047]

Risk factors Sex (99% female, 1% male; UK: 300 cases/year, 90 deaths).Age: increases with age until menopause when it plateaus.  Four in every five cases aged 50 or over.Race: most common in Caucasians, then African-Americans, Hispanic, Asian Americans.

Family History: about 10% of breast cancers are caused by inherited mutations.

Hormonal status: early menarche and late first full-term pregnancy (longer exposure to estrogen and higher risk).

High breast tissue density (visualised in mammograms).

Obesity: linked to estrogen-dependent breast cancer via increased aromatase expression. The AMP-activated protein kinase (AMPK: a master regulator of energy homeostasis that plays an important role in balancing energy expenditure and the requirement for food intake) regulates aromatase expression and reduced AMPK activity occurs in breast cancer.

Alcohol also increases the risk and physical activity may decrease it.

Symptoms

Most commonly the first symptom is a lump or thickening in an area of the breast.  However, 90% of such abnormalities are benign.  Other symptoms may include change in breast size, lumps in the armpit, bleeding or discharge from the nipple, peau d’orange (orange peel skin) on the breast and weight loss.

Staging TNM tumour staging system is used. For breast cancer the designation Tis (sometimes called ‘stage zero breast cancer’) means carcinoma in situ, which includes ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS: not a true cancer but does carry an increased risk that breast cancer will develop) and Paget’s disease of the nipple. The term in situmeans that cancer cells have not spread from their place of origin. Invasive cancers have spread beyond the lining of the duct or lobule. A sub-set of women with untreated DCIS progress to develop invasive (or infiltrating) ductal carcinoma (IDC).Example: T2, N0, M0 describes a tumour between 2 and 5 cm in diameter that has not spread to lymph nodes or metastasized to distant sites.
Classification

There are four main molecular classes, based on hormonal status (estrogen receptor (ER) and progesterone receptor (PR)) and ERBB2 expression, listed in order of increasingly poor prognosis:

Luminal-A: Mostly ER+ and/or PR+, ERBB2. Histologically low grade, less aggressive, most common subtype, associated with increasing age.

Luminal-B: Mostly ER+ and/or PR+, ERBB2+. High grade, poorer outcome than Luminal A.

Basal-like: Mostly ER, PR, ERBB2 (triple negative): cytokeratin 5/6+ and/or EGFR+. 15% of all diagnoses, risk at younger age (<40).

ERBB2+: Amplification and high ERBB2 amplicon expression. Highly aggressive, less common, risk at younger age (over 40) greater than luminal subtypes.

Luminal-type cancers are the most common sub-type and tend to have the most favorable long-term survival, whereas the basal-like and ERBB2-positive tumours are most sensitive to chemotherapy but have the worst prognosis overall.

Metastasis to the bone occurs in ~30% of invasive breast cancers.  This condition is essentially untreatable (average survival from diagnosis 2-3 years).

Major gene mutations

EGFR and ERBB2 are abnormal in about 25% of invasive breast tumours. Other frequently abnormal genes include FGFR1 and MYC.

Mutations in BRCA1 or BRCA2 contribute to ~5% of all breast cancers and to about two thirds of familial breast cancers. Inheritance of a BRCA1 mutation carries a 60% risk of breast cancer for that individual by age 50 and a 90% lifetime risk.  Inherited mutations in P53 also strongly promote breast cancer.

Treatment

Surgery.  Radiotherapy.  Chemotherapy. For cancers that are either ER+, PR+ or both three different classes of hormonal therapy agents may be used: (1) aromatase inhibitors (anastrozole, exemestane or letrozole), (2) selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene or toremifene) and (3) estrogen receptor downregulators (fulvestrant).  In addition goserelin, which blocks the production of estrogen and/or progesterone by the pituitary gland, is also used in the treatment of breast cancer.

Trastuzumab (better known as Herceptin) for tumours over-expressing ERBB2: only one third of newly diagnosed tumours show regression with Herceptin monotherapy and the majority that do have an initial response become resistant to Herceptin within one year. Herceptin resistance may be promoted by phosphorylation of EPHA2 and activation of PI3K and MAPK signalling.

For the treatment of metastatic bone disease bisphosphonates, inhibitors of bone resorption (the breakdown of bone), are used and the SRC inhibitor dasatinib is undergoing clinical trials.

Side effects

Herceptin: 1-4% develop congestive heart failure, 10% significant decrease in cardiac function. Aromatase inhibitors: bone loss, arthralgia, cardiovascular effects and possibly cognitive defects. General suppression of the immune system and increased infection risk.

Prognosis

5-year survival rates: USA: Over 98% for tumours than have not spread from the primary, over 83% for tumours that have spread to lymph nodes. For tumours that have metastasized to distant sites the rate is 23%. Metastasis to the bone occurs in ~30% of invasive breast cancers.  This condition is essentially untreatable (average survival from diagnosis 2-3 years).

UK: Overall 5-year survival rate: 82%.