Carcinoma of the breast

BREAST CANCER EPIDEMIOLOGY AND ETIOLOGY
Almost all breast malignancies are adenocarcinomas and based on the expression of estrogen receptor and HER2 can be divided into the three major biologic subgroups:

1. Estrogen receptor (ER)-positive and HER2-negative (50-65%)
2. HER2-positive (10-20%)
3. ER-negative and HER2-negative (10-20%)

   

   Breast cancer risk factors

 Risk factors

• Sex. Being female.
• Germline mutations
• First degree relatives with breastcancer
• Race/ethnicity
• Age. Peak at 70-80.
• Age at menarche. Menarche at ages younger than 11 years increases risk by 20% compared to menarche at ages greater than 14.
• Age at first live birth. A full-term pregnancy before the age of 20 halves the risk compared to nulliparous women or women who are older than the age 35 at the time of their first birth.
• Benign breast disease.
• Estrogen exposure e.g. hormone therapy
• Breast density. Women with very dense breasts on mammography have 4-6x higher risk compared to lower density.
• Radiation exposure.
• Carcinoma of the contralateral breast or endometrium
• Diet. Moderate/heavy alcohol consumption increases risk.
• Obesity. Obese women under the age of 40 have a decreased risk as a result of anovulatory cycles and lower progesterone levels. In contrast, postmenopausal obese women are a increased risk, which is attributed to the synthesis of estrogens in fat deposits.
• Exercise. Small protective effect.
• Breastfeeding. The longer women breastfeed the greater the reduction in risk.
• Environmental toxins.

Familial breast cancer
Approximately 12% of breast cancers occur due to inheritance of an identifiable susceptibility gene or genes. The probability of a hereditary etiology increases when there are multiple affected first-degree relatives, early onset cancers, multiple cancers, or family members with other specific cancers. The major known susceptibility genes for familial breast cancer - BRCA1, BRCA2, TP53 and CHEK2 - are all tumor suppressor genes. Mutations in BRCA1 and BRCA2 are responsible for 80-90% of "single gene" familial breast cancers and about 3% of all breast cancers. Three other tumor suppressor genes - PTEN (Cowden syndrome), STK11 (Peutz-Jeghers syndrome) and ATM (Ataxia telangiectasia) - are mutated in less than 1% of all familial breast cancers.
After a cell sustains DNA damage, it must undergo cell cycle arrest and either repair its DNA or die by apoptosis. ATM senses DNA damage and with p53 and CHEK2 induces cell cycle arrest. BRCA1, BRCA2 and CHEK2 all have important functions in repair of double stranded DNA breaks.

Sporadic breast cancer
The major risk factors for sporadic breast cancer are related to hormone exposure: gender, age at menarche and menopause, reproductive history, breastfeeding and exogenous estrogens. Estrogen clearly functions as a promoter of breast cancers, probably through several different effects on the breast.
Molecular mechanisms of carcinogenesis and tumor progression

• ER-positive, HER2-negative cancers arise via the dominant pathway of breast cancer development, constituting 50% to 65% of cases
• HER2-positive cancers arise through a pathway that is strongly associated with amplifications of the HER2 gene on chromosome 17q.  This is the most common subtype of breast cancer in patients with germline mutations in TP53 (Li-Fraumeni syndrome)
• ER-negative, HER2-negative cancers arise through a pathway that is independent of ER-mediated changeds in gene expression and HER2 gene amplification. These are the most common tumor type observed in patients with germline BRCA1 mutations.

Neoplastic epithelial cells do not develop in isolation, but are dependent on interactions with stromal cells in the local microenvironment. Cancer occur in the areas of greatest mammagraphic density, suggesting that increased amounts of fibrous stroma is both a marker of risk and biologically important for tumor genesis.

TYPES OF BREAST CARCINOMA
Almost all (>95%) of breast malignancies are adenocarcinomas that first arise in the duct/lobular system as carcinoma in situ; at time of clinical detection the majority (at least 70%) will have breached the basement membrane and invaded the stroma.

Ductal carcinoma in situ (DCIS)
DCIS is a malignant clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane. Morphologically DCIS can be divided into comedo DCIS, noncomedo DCIS.
Paget disease of the nipple is a rare manifestation of breast cancer that presents as a unilateral erythematous eruption with scale crust. Maligant cells (Paget cells) extend from DCIS within the ductual system via the lactiferous sinuses into nipple skin without crossing the basement membrane. The tumor cells disrupt the normal epithelial barrier, allowing extracellular fluid to seep out onto the nipple surface.

Paget disease of the nipple

Laobular Carcinoma in Situ
LCIS is a clonal proliferation of cells within ducts and lobules that grow in a discohesive fashion, usually due to an acquired loss of the tumor suppressive adhesion protein E-cadherin. The term lobular was used to describe this lesion because the cells expand but do not distort involved spaces, and this the underlying lobular architecture is preserved.
!LCIS is always an incidental biopsy finding, since it is not associated with calcifications or stromal reactions that produce mammographic density.

Invasive carcinoma
ER-positive, HER-negative (luminal cancer) is the most common form of invasive breast cancer. Based on proliferation rates, it is further divided into two subgroups:

• ER positive, HER2 negative, low proliferation: this group of breast cancers makes up the majority of cancers in older women and in men. They have the lowest incidence of local recurrence and are often cured by surgery.
• ER-positive, HER2-negative, high proliferation: although these tumors are ER-positive, ER levels may be low and progesterone receptor expression maybe low or absent. However unlike low-grade ER positive cancers, about 10% of these carcinomas show a complete response to chemotherapy.

HER2-positive is the second most common molecular subtype of invasive breast cancer. More than half (53%) of familial breast cancers in patients with germ line TP53 mutations (Li-fraumeni syndrome) develop carcinomas that are positive for both ER and HER2. One third or more of HER2 positive carcinomas respond completely to antibodies that bind and block HER2 activity, and such patients now have an excellent prognosis. Trastuzumab (Herceptin) is a humanized monoclonal antibody that specifically binds and inhibits HER2, however not all HER2 positive carcinomas respond and some that do become resistant to treatment.
ER-negative, HER2-negative tumors (basal-like, triple negative carcinomas) are the third major molecular subtype. Due to high proliferation and rapid growth, this type of cancer is particularly likely to present as palpable mass in the interval between mammographic screenings.

Morphology
All types of invasive carcinoma are graded using the Nottingham Histologic Score. Carcinomas are scored according to grades well differentiated-poorly differentiated.

• ER-positive, HER2-negative carcinoma: grades ranging from well to poorly differentiated. Essentially all well differentiated carcinomas are in this group.
• HER2-positive carcinoma: majority if these carcinomas are poorly differentiated
• ER- & HER2-: almost all of these tumors are poorly differentiated.

Male breast cancer
The incidence in breast cancer in men is 1% of that in women. Risk factors are similar to those in women. About 3-8% of cases are associated with Klinefelter syndrome and decreased testicular function. Because breast epithelium in men is limited to large ducts near the nipple, carcinomas usually present as a palpable subareolar mess or as nipple discharge. The carcinoma is situated close to the overlying skin and underlying thoracic wall, and even small carcinomas can invade these structures and cause ulceration. Most cancers are treated locally with mastectomy and axillary node dissection. The same systemic treatment guidelines are used for men and women, and response rated similar.

Prognostic and predictive factors
The outcome for women with breast cancer depends on the biologic features of the carcinoma (molecular or histologic type) and the extent to which the cancer has spread (stage) t the time of diagnosis. Tumors that present with distant metastasis (<10%) or with inflammatory carcinoma (<5%) have a particularly poor prognosis. Prognostic factors fall into to groups - those related to the extent of carcinoma and those related to the underlying biology of the cancer.

• Invasive carcinoma vs carcinoma in situ.  Women with in situ carcinoma understandably have an excellent prognosis..
• Distant metastases. Once distant metastases are present, cure is unlikely.
• Lymph node metastases. Axillary lymph node status is the most important prognostic factor for invasive carcinoma in the absence of distant metastases. The clinical assessment of lymph node statues is unreliable due to both false positives and false negatives. Therefore, biopsy is necessary for accurate assessment. With no nodal involvement, the 10-year disease free survival rate is close to 70%-80%; the rate falls to 35-40% with 1-3 positive nodes and to 10-15 when more than 10 nodes are positive. 
• Tumor size.
• Locally advanced disease (carcinomas invading into skin/skeletal muscle)
• Inflammatory carcinoma. Breast cancers presenting with breast erythema and skin thickening (peau d'orange) have a very poor prognosis. These clinical signs are caused by dermal lymphatic's filled with metastatic carcinoma that blocks lymphatic drainage. 3-year survival rate is 3-10%.
• Lymphovascular invasion. It is a poor prognostic factor for overall survival in women without lymph node metastases and a risk factor for local recurrence.

Other prognostic factors are related to tumor biology;

• Molecular subtype. The molecular subtype, determined by expression of ER and HER2 and proliferation, is an important prognostic factor.
• Special histologic types. The survival rate of women with some special types of invasive carcinomas (tubular, mucinous, lobular, papillary, adenoid cystic) is greater than that women with cancers of no special type.
• Histologic grade.
• Proliferate rate. Carcinomas with high proliferation rates have a poorer prognosis but may respond better to chemotherapy.
• Estrogen and progesterone receptors. ER-positive cancers are less likely to respond to chemotherapy. Conversely, cancers that fail to express either ER or PR have a less than 10% likelihood of responding to hormonal therapy but are more likely to respond to chemotherapy.
• HER2. HER2 overexpression is associated with poorer survival.

In the absence of adequate surgery, the majority of patients with breast cancer die with extensive local disease causing ulceration of the skin, Carcinoma en cuirasse is a dreaded complication that must be prevented, even in women with distant metastatic disease.