Breast Cancer

Breast cancer is the common term for a set of breast tumor subtypes with distinct molecular and cellular origins and clinical behavior. Most of these are epithelial tumors of ductal or lobular origin (see the image below). Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women.

 Risk Factors for Breast Cancer

Factors that may affect breast cancer risk include the following:

• Age: The strongest risk factor for breast cancer is age. Median age at diagnosis is about 60 years.

• Family history: Having a 1st-degree relative (mother, sister, daughter) with breast cancer doubles or triples risk of developing the cancer, but breast cancer in more distant relatives increases risk only slightly. When ≥ 2 1st-degree relatives have breast cancer, risk may be 5 to 6 times higher.

• Breast cancer gene mutation: About 5 to 10% of women with breast cancer carry a mutation in one of the two known breast cancer genes, BRCA1 or BRCA2. The risk of developing breast cancer by age 80 is about 72% with a BRCA1 mutation and about 69% with a BRCA2 mutation. Women with BRCA1 mutations also have an approximate 44% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is about 17% (3, 4). Women without a family history of breast cancer in at least two 1st-degree relatives are unlikely to carry this mutation and thus do not require screening for BRCA1 and BRCA2 mutations. Men who carry a BRCA mutation have a 1 to 2% lifetime risk of developing breast cancer. The mutations are more common among Ashkenazi Jews. Women with BRCA1 or BRCA2 mutations require closer surveillance or preventive measures, such as screening with both mammography and MRI, taking tamoxifen or raloxifene, or undergoing risk-reducing mastectomy.

• Personal history: Having had in situ or invasive breast cancer increases risk. Risk of developing cancer in the contralateral breast after mastectomy is about 0.5 to 1%/year of follow-up.

• Gynecologic history: Early menarche, late menopause, or late first pregnancy increases risk. Women who have a first pregnancy after age 30 are at higher risk than those who are nulliparous.

• Breast changes: History of a lesion that required a biopsy is associated with a slightly increased risk. Women with multiple breast masses but no histologic confirmation of a high-risk histology should not be considered at high risk. Benign lesions associated with a slightly increased risk of developing invasive breast cancer include complex fibroadenoma, moderate or florid hyperplasia (without atypia), sclerosing adenosis, and papilloma. Risk is about 4 or 5 times higher than average in patients with atypical ductal or lobular hyperplasia and about 10 times higher if they have a family history of invasive breast cancer in a 1st-degree relative. Increased breast density seen on screening mammography is associated with a 1.2- to 2.1-fold increased risk of breast cancer.

• Lobular carcinoma in situ (LCIS): Having LCIS increases the risk of developing invasive carcinoma in either breast by about 7 to 12 times ; invasive carcinoma develops in about 1 to 2% of patients with LCIS annually.

• Use of oral contraceptives: Study results vary regarding the use of oral contraceptives and risk of breast cancer. Some studies have found a small increased risk in current or recent users.

• Hormone therapy: Menopausal hormone (estrogen plus a progestin) therapy appears to increase risk modestly after only 3 years of use. After 5 years of use, the increased risk is about 7 or 8 more cases per 10,000 women for each year of use (about a 24% increase in relative risk). Use of estrogen alone does not appear to increase risk of breast cancer (as reported in the Women's Health Initiative). Selective estrogen-receptor modulators (eg, raloxifene) reduce the risk of developing breast cancer.

• Radiation therapy: Exposure to radiation therapy before age 30 increases risk. Mantle-field radiation therapy for Hodgkin lymphoma about quadruples risk of breast cancer over the next 20 to 30 years.

• Diet: Diet may contribute to development or growth of breast cancers, but conclusive evidence about the effect of a particular diet (eg, one high in fats) is lacking. Obese postmenopausal women are at increased risk, but there is no evidence that dietary modification reduces risk. For obese women who are menstruating later than normal, risk may be decreased.

• Lifestyle factors: Smoking and alcohol may contribute to a higher risk of breast cancer. Women are counseled to stop smoking and to reduce alcohol consumption. In epidemiologic studies, alcohol intake is associated with a higher risk of breast cancer; however, causality is difficult to establish. The American Cancer Society recommends no more than one alcoholic drink a day for women. 

• Pathology of Breast Cancer : 

• Most breast cancers are epithelial tumors that develop from cells lining ducts or lobules; less common are nonepithelial cancers of the supporting stroma (eg, angiosarcoma, primary stromal sarcomas, phyllodes tumor).
• Cancers are divided into carcinoma in situ and invasive cancer.

Carcinoma in situ is proliferation of cancer cells within ducts or lobules and without invasion of stromal tissue. There are 2 types:

Ductal carcinoma in situ (DCIS): About 85% of carcinoma in situ are this type. DCIS is usually detected only by mammography. It may involve a small or wide area of the breast; if a wide area is involved, microscopic invasive foci may develop over time.

Lobular carcinoma in situ (LCIS): LCIS is often multifocal and bilateral. There are 2 types: classic and pleomorphic. Classic LCIS is not malignant but increases risk of developing invasive carcinoma in either breast. This nonpalpable lesion is usually detected via biopsy; it is rarely visualized with mammography. Pleomorphic LCIS behaves more like DCIS; it should be excised to negative margins.

Invasive carcinoma is primarily adenocarcinoma. About 80% is the infiltrating ductal type; most of the remaining cases are infiltrating lobular.

Rare types include medullary, mucinous, metaplastic, and tubular carcinomas. Mucinous carcinoma tends to develop in older women and be slow growing. Women with most of these rare types of breast cancer have a much better prognosis than women with other types of invasive breast cancer. However, the prognosis for women with metaplastic breast cancer is significantly worse than other types of ductal breast cancer.

Inflammatory breast cancer is a fast-growing, particularly aggressive, and often fatal cancer. Cancer cells block the lymphatic vessels in breast skin; as a result, the breast appears inflamed, and the skin appears thickened, resembling orange peel (peau d’orange). Usually, inflammatory breast cancer spreads to the lymph nodes in the armpit. The lymph nodes feel like hard lumps. However, often no mass is felt in the breast itself because this cancer is dispersed throughout the breast.

Pathophysiology of Breast Cancer:

Breast cancer invades locally and spreads through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the body—most commonly, lungs, liver, bone, brain, and skin. Most skin metastases occur near the site of breast surgery; scalp metastases are uncommon.

Hormone receptors:

Estrogen and progesterone receptors, present in some breast cancers, are nuclear hormone receptors that promote DNA replication and cell division when the appropriate hormones bind to them. Thus, drugs that block these receptors may be useful in treating tumors with the receptors. About two thirds of postmenopausal patients with cancer have an estrogen receptor–positive (ER+) tumor. Incidence of ER+ tumors is lower among premenopausal patients.

Another cellular receptor is human epidermal growth factor receptor 2 (HER2; also called HER2/neu or ErbB2); its presence correlates with a poorer prognosis at any given stage of cancer. In about 20% of patients with breast cancer, HER2 receptors are overexpressed. Drugs that block these receptors are part of standard treatment for these patients.

Breast cancer genes:

BRCA1 and BRCA2 gene mutations increase the risk of developing breast cancer to 70%. Prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% and should be offered to women with a BRCA mutation. Other genetic mutations that increase the risk of developing breast cancer include mutations in CHEK2, PALB2, ATM, RAD51C, RAD51D, BARD1, and TP53, which are usually included in panel genetic testing.

Symptoms and Signs of Breast Cancer

Many breast cancers are discovered as a mass by the patient or during routine physical examination or mammography. Infrequently, the presenting symptom is breast enlargement or a nondescript thickening of the breast. Breast pain may be present but is almost never the sole presenting symptom of breast cancer.

Some types of breast cancer manifest with notable skin changes:

Paget disease of the nipple is associated with an underlying in situ or invasive carcinoma and manifests as skin changes, including erythema, crusting, scaling, and discharge; these changes usually appear so benign that the patient ignores them, delaying diagnosis for a year or more. About 50% of patients with Paget disease of the nipple have a palpable mass at presentation.

Inflammatory breast cancer manifests as erythema and enlargement of the breast, often without a mass, and skin may be discolored or appear thickened, resembling orange peel (peau d’orange). A nipple discharge is common.

A few patients with breast cancer present with signs of metastatic disease (eg, pathologic fracture, abdominal pain, jaundice, dyspnea).

A common finding during physical examination is asymmetry or a dominant mass—a mass distinctly different from the surrounding breast tissue. Diffuse fibrotic changes in a quadrant of the breast, usually the upper outer quadrant, are more characteristic of benign disorders; a slightly firmer thickening in one breast but not the other may be a sign of cancer.

More advanced breast cancers are characterized by one or more of the following:

Fixation of the mass to the chest wall or to overlying skin

Satellite nodules or ulcers in the skin

Matted or fixed axillary lymph nodes suggest tumor spread, as does supraclavicular or infraclavicular lymphadenopathy.

Change in breast size or shape

Skin dimpling or skin changes

Recent nipple inversion or skin change, or nipple abnormalities

Single-duct discharge, particularly if blood-stained

Axillary lump

    

 

Diagnosis of breast cancer

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or health care provider.

1.Clinical examination

2.Imaging

3.Needle biopsy

4.Physical examination: The following physical findings should raise concern:

Lump or contour change

Skin tethering

Nipple inversion

Dilated veins

Ulceration

Paget disease

Edema or peau d’orange

Screening

Breast self-examination

Mammography

Ultrasonography

Magnetic resonance imaging

Treatment of Breast Cancer

Surgery

Usually radiation therapy

Systemic therapy: Endocrine therapy, chemotherapy, or both