Breast cancer

Breast cancer
Specialty	Oncology

Breast cancer is cancer of breast tissue. Worldwide, it is the most common form of cancer in females, affecting approximately one out of twelve to thirteen women who reach age ninety at some stage of their life in the Western world. It is (after lung cancer) the second most fatal cancer in women. [3] Because the breast is composed of identical tissues in males and females, breast cancer can also occur in males, but here the incidence is very low, less than 1 percent.

History of breast cancer

Breast cancer is one of the oldest known forms of cancer tumors. Our oldest description of cancer (although the term cancer was not used) was discovered in Egypt and dates back to approximately 1600 B.C. The Edwin Smith Papyrus, or writing, describes 8 cases of tumors or ulcers of the breast that were treated by cauterization, with a tool called "the fire drill." The writing says about the disease, "There is no treatment." [4] At least one of the described cases is male. This papyrus is 5 meters long and is kept in the New York Historical Society. Scholars believe that the actual document is a copy of an original document from the 30th century before Christ. In any case, for centuries, physicians described similar cases in their practises, with the same sad conclusion. It wasn't until greater understanding of the circulatory system was added to the body of medical knowledge in the 17th century that doctors made the link to the lymph glands in the armpit. The French surgeon Jean Louis Petit (1674-1750) and later the Scottish surgeon Benjamin Bell (1749-1806) were the first to remove the lymph nodes, breast tissue, and breast muscle. Their successful work was carried on by William Stewart Halsted who started performing mastectomies in 1882. He became known for his Halsted radical mastectomy, a surgical procedure that remained popular up to the 1970's and was performed on Betty Ford.

Types of breast cancer

• DCIS: Ductal Carcinoma in Situ
• LCIS: Lobal Carcinoma in Situ
• Invasive ductal carcinoma
• Invasive lobal carcinoma
• Inflamatory breast cancer
• Paget's disease

Epidemiologic risk factors and etiology

It is important to have a model of causation of a disease in order to distinguish epidemiological risk factors or associations with disease, from the biological etiology and primary cause, secondary co-factors, and simple promoters of the disease, given the underlying primary cause. The first work on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.

Today, breast cancer, like other forms of cancer, is considered to be a result of damage to DNA. How this mechanism may occur comes from several known or hypothesized factors (such as exposure to ionizing radiation). Some factors lead to an increased rate of mutation (exposure to estrogens) and decreased repair (the BRCA1, BRCA2 and p53 genes). Although many epidemiological risk factors, and biological co-factors and promoters have been identified, the majority of breast cancer incidence remains unattributable, and the primary cause is unknown.

Dietary influences have been proposed and examined, but these are small effects, and do not distinguish differences in risk within populations, as well as they do between populations.

A significant environmental effect was revealed by the large difference in breast cancer incidence between countries and continents, and a migration effect which slowly increases the risk of breast cancer even across generations after migration from a country of lower incidence to a country of higher incidence, such as moving from China or Japan to the United States.

Humans are not the only mammal prone to breast cancer. Some strains of mice, namely the house mouse (Mus domesticus) are prone to breast cancer which is caused by infection with the mouse mammary tumour virus (MMTV or "Bittner virus" for its discoverer Hans Bittner), by random insertional mutagenesis. Suspicion of MMTV or other viruses in human breast cancer is controversial, and the idea is not generally accepted for lack of direct and definitive evidence. There is much more research in diagnosis and treatment of breast cancer than in its cause.

Age

The risk of getting breast cancer increases with age. For a woman who lives to the age of 90 the chances of getting breast cancer her entire lifetime is about 14.3% or one in seven. Men can also develop breast cancer, but their risk is less than one in 1000 (see sex and illness). This risk is modified by many different factors. In a very small (~ 5%) proportion of breast cancer cases, there is a strong inherited familial risk.

The probability of breast cancer rises with age but breast cancer tends to be more aggressive when it occurs in younger women. One type of breast cancer that is especially aggressive and disproportionately occurs in younger women is inflammatory breast cancer. It is initially staged as Stage IIIb or Stage IV. It also is unique because it often does not present with a lump so that it often is not detected by mammography or ultrasound. It presents with the signs and symptoms of a breast infection like mastitis.

Genes

Two genes, BRCA1 and BRCA2, have been linked to the rare familial form of breast cancer . Women in families expressing mutations in these genes have a much higher risk of developing breast cancer than women who do not. Not all people who inherit mutations in these genes will develop breast cancer. Together with Li-Fraumeni syndrome (p53 mutations), these genetic aberrations determine around 5% of all breast cancer cases , suggesting that the remainder is sporadic. Recently it was found that newly discovered gene called BARD1 if exists in combination with BRCA2 gene may increase the risk of breast cancer to as much as 80 percent 1. Genetic counseling and genetic testing should be considered for families who may carry a hereditary form of cancer.

Alcohol

Alcohol generally appears to increase the risk of breast cancer in women. The U.K.s Review of Alcohol: Association with Breast Cancer concludes that "studies confirm previous observations that there appears to be an association between alcohol intake and increased risk of breast cancer in women. On balance, there was a weak association between the amount of alcohol consumed and the relative risk."

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) concludes that "Chronic alcohol consumption has been associated with a small (averaging 10 percent) increase in a woman's risk of breast cancer (Friedenreich et al.; Longnecker; Nasca). According to these studies, the risk appears to increase as the quantity and duration of alcohol consumption increases. Other studies, however, have found no evidence of such a link (Chu et al. ; Schatzkin et al.; Webser et al)." [5]

The Committee on Carcinogenicity of Chemicals in Food, Consumer Products Non-Technical Summary concludes, "The new research estimates that a woman drinking an average of two units of alcohol per day has a lifetime risk of developing breast cancer 8% higher than a woman who drinks an average of one unit of alcohol per day. The risk of breast cancer further increases with each additional drink consumed per day. … The research also concludes that approximately 6% (between 3.2% and 8.8%) of breast cancers reported in the U.K. each year could be prevented if drinking was reduced to a very low level (i.e. less than 1 unit/week)."

It has been reported that "Two drinks daily increase the risk of getting breast cancer by about 25 percent." (NCI) but the evidence is inconsistent. The Framingham study has carefully tracked individuals since the 1940s. Data from that research found that drinking alcohol moderately did not increase breast cancer risk (Wellness Facts). Similarly, research by the Danish National Institute for Public Health found that moderate drinking had virtually no effect on breast cancer risk (Petri et al.).

Breast cancer constitutes about 7.3% of all cancers [6]. Among women, breast cancer comprises 60% of alcohol-attributable cancers. One study suggests that women who frequently drink red wine may have an increased risk of developing breast cancer.

"Folate intake counteracts breast cancer risk associated with alcohol consumption" and "women who drink alcohol and have a high folate intake are not at increased risk of cancer" . Those who have a high (200 micrograms or more per day) level of folate (folic acid or Vitamin B9) in their diet are not at increased risk of breast cancer compared to those who abstain from alcohol . Foods rich in folate include citrus fruits, citrus juices, dark green leafy vegetables (such as spinach), dried beans, and peas. Vitamin B9 can also be taken in a multivitamin pill.

Obesity

Gaining weight after the menopause can increase a woman's risk. Putting on 9.9kg (22lbs) increased the risk of developing breast cancer by 18%.

Light levels

Researchers at the National Cancer Institute and National Institute of Environmental Health Sciences have concluded a study that suggests that artificial light can be a cause of breast cancer.

Hormones

The International Agency for Research on Cancer (IARC) in Lyon, France invited 21 scientists from eight countries in June 2005, to evaluate the risk of cancer for humans of combined estrogen-progesterone contraceptives and combined estrogen-progesterone menopausal therapy. The working group found that there is a small increase in the relative risk of breast cancer in current and recent users of combined oral contraceptives .

The risk decreases to that of those who have never used such combined therapy ten years after cessation of use. The scientists described combined oral estrogen-progesterone contraceptives as "carcinogenic to humans." They also found an increased risk of breast cancer in women under treatment with combined menopausal therapy, which is confined mostly to current or recent users, increases with duration of use and exceeds that in women taking estrogen-only therapy .

Other

Other established risk factors include not having children, delaying first childbirth, not breastfeeding, early menarche (the first menstrual period), late menopause, obesity and taking hormone replacement therapy.

Unproven

• It has been hypothesized that abortion may increase the risk of breast cancer because of hormones in early pregnancy. Recent large studies do not support this association.
• Although not well quantified there has long been a concern about risk associated with environmental estrogenic compounds, such as dioxins, or phytoestrogens such as found in soy beans.
• Aluminum salts such as those used in anti-perspirants have recently been classified as metalloestrogens. In research published in the Journal of Applied Toxicology, Dr. Philippa D. Darby of the University of Reading has shown that aluminum salts increase estrogen-related gene expression in human breast cancer cells grown in the laboratory.

Symptoms

Early signs of breast cancer.

Early breast cancer causes no symptoms and is not painful. Usually breast cancer is discovered before any symptoms are present, either on mammography or by feeling a breast lump. A lump under the arm or above the collarbone that does not go away may be present. Other possible symptoms include breast discharge, nipple inversion and changes in the skin overlying the breast.

Screening

Due to the high incidence of breast cancer among older women, screening is now recommended in many countries. Screening methods suggested include breast self-examination and mammography. Only mammography has been proved to reduce mortality from breast cancer. In some countries routine (annual) mammography of older women is encouraged as a screening method to diagnose early breast cancer.

Normal (left) versus cancerous (right) mammography image.

Mammography is still the modality of choice for screening of early breast cancer. Magnetic resonance imaging (MRI) has been shown to detect cancers that are not visible on mammograms, but it has several disadvantages. For example, although it is more sensitive, it is less specific than mammography. As a result, MRI studies will have more false positives, which may have undesirable financial and psychological costs. It is also a relatively expensive procedure, and one which requires the intravenous injection of a chemical agent to be effective. It may be valuable for younger women, whose breasts are denser with less fat and more connective tissue, making it harder to spot cancers on mammograms. Ultrasound alone is not adequate as a screening tool but it is a useful additional investigation, especially for the characterization of benign tumours.

The U.S. National Cancer Institute recommends screening mammography with a baseline mammogram at age 35, mammograms every two years beginning at age 40, and then annual mammograms beginning at age 50. In the UK, women are invited to attend for screening once every three years beginning at age 50. Women with one or more first degree relatives (mother, sister, daughter) with premenopausal breast cancer should begin screening at an earlier age. It is usually suggested to start screening at an age that is 10 years less than the age at which the relative was diagnosed with breast cancer.

Breast cancers detected by mammography are usually smaller than those detected clinically, and women who undergo mammography are more likely to be eligible for breast-conserving therapy.

Diagnosis

The diagnosis of breast cancer is established by the pathological examination of removed breast tissue. Such tissue is generally obtained at the time of surgical treatment. A number of procedures have been devised to obtain tissue or cells prior to the treatment for histological or cytological examination. Such procedures include fine-needle aspiration, nipples aspirates, ductal lavage, core needle biopsy, and local surgical biopsy. Most of these diagnostic steps, however, have some limitations as they may not yield enough tissue or miss the cancer, while the surgical biopsy already becomes an invasive procedure. Imaging tests are used to detect metastasis and include chest x-ray, bone scan, CT, MRI, and PET scanning. Ca 15.3 (carbohydrate antigen 15.3, epithelial mucin) is a tumor marker determined in blood which can be used to follow up disease activity.

Breast cancer is staged. Not only will this allow for better understanding of the disease process, but it will also facilitate interpretation of data, and determine treatment. Prognosis is closely linked to results of staging. The AJCC-TNM system is commonly used to stage breast cancer:

Summary of stages:

• Stage 0 - Carcinoma in situ
• Stage I - Tumor (T) does not exceed 2 cm, no axillary lymph nodes (N) involved.
• Stage IIA – T 2-5 cm, N negative, or T <2 cm and N positive.
• Stage IIB – T > 5 cm, N negative, or T 2-5 cm and N positive (< 4 axillary nodes).
• Stage IIIA – T > 5 cm, N positive, or T 2-5 cm with 4 or more axillary nodes
• Stage IIIB – T has penetrated chest wall or skin, and may have spread to < 10 axillary N
• Stage IIIC – T has > 10 axillary N, 1 or more supraclavicular or infraclavicular N, or internal mammary N.
• Stage IV – Distant metastasis (M)

Breast lesions are examined for certain markers, notably sex steroid hormone receptors. About two thirds of postmenopausal breast cancers are estrogen receptor positive (ER+) and progesterone receptor positive (PR+). Receptor status modifies the treatment as, for instance, ER+ lesions are more sensitive to hormonal therapy.

Treatment

The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern may be adapted as every two years a worldwide conference takes place in St. Gallen, Switzerland to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases which follow different rules for therapy. Treatment possibilities include Radiation Therapy, Chemotherapy, Hormone Therapy, and Immune Therapy.

An online resource for helping to quantify the relative risks and benefits of chemotherapy v. hormonal therapy is Adjuvant! Online (see below).

In planning treatment, doctors can also use a test called Oncotype DX that measures breast cancer recurrence risk.

The emotional impact of cancer diagnosis, symptoms, treatment, and related issues can be severe. Most larger hospitals are associated with cancer support groups which can help patients cope with the many issues that come up in a supportive environment with other people with experience with similar issues.

Online cancer support groups are also very beneficial to cancer patients, especially in dealing with uncertainty and body-image problems inherent in cancer treatment.

Surgery

Depending on the staging and type of the tumor, just a lumpectomy (removal of the lump only) may be all that is necessary or removal of larger amounts of breast tissue may be necessary. Surgical removal of the entire breast is called mastectomy.

Standard practice requires that the surgeon must establish that the tissue removed in the operation has margins clear of cancer, indicating that the cancer has been completely excised. If the tissue removed does not have clear margins, then further operations to remove more tissue may be necessary. This may sometimes require removal of part of the pectoralis major muscle which is the main muscle of the anterior chest wall.

During the operation, the lymph nodes in the axilla are also considered for removal. In the past, large axillary operations took out ten to forty nodes to establish whether cancer had spread - this had the unfortunate side effect of frequently causing lymphedema of the arm on the same side as the removal of this many lymph nodes affected lymphatic drainage. More recently the technique of sentinel lymph node dissection has become popular as it requires the removal of far fewer lymph nodes, resulting in fewer side effects.

Radiation therapy

Radiation therapy is recommended for all patients who had (lumpectomy, quadrant-resection). Radiation therapy after mastectomy is recommended only if four or more lymph nodes are involved with cancer. Radiation therapy is usually not indicated in patients with advanced (stage IV disease) except for palliation of symptoms like bone pain.

Radiation therapy consists of the use of high powered X-rays or gamma rays that precisely target the area that is being treated. These X-rays or gamma rays are very effective in destroying the cancer cells that might recur where the tumor was removed. These X-rays are delivered by a machine called a linear Accelerator or LINAC. The use of radiation therapy for breast cancer is usually given after surgery has been performed and is an essential component of breast conserving therapy. The purpose of radiation is to reduce the chance that the cancer will recur.

Radiation therapy works for breast cancer by eliminating the microscopic cancer cells that may remain near the area where the tumor was removed during surgery. Since by the nature of radiation and its effects on normal cells and cancer cells alike the dose that is given is to ensure that the cancer cells are eliminated. However, the dose cannot be given in one sitting. Radiation causes some damage to the normal tissue around where the tumor was but normal healthy tissue can repair itself. The treatments are given typically over a period of five to seven weeks, performed five days a week. Each treatment session takes about fifteen minutes per day. Breaking the treatments up over this extended period of time gives the healthy normal tissue a chance to repair itself. Cancer cells do not repair themselves as well as normal cells, which explains the efficacy of radiation therapy.

Side effects of radiation therapy

The side effects of radiation have improved considerably over the past decades. Aside from general fatigue caused by the healthy tissue repairing itself there will probably be no side effects at all. Some patients do develop a suntan like change in skin color in the exact area being treated. Like with a suntan this darkening of the skin will fade with time. Other side effects that have been experienced with radiation are:

• reddening of the skin
• muscle stiffness
• mild swelling
• tenderness in the area
• long term shrinking of the irradiated breast

Along with improved cosmetic outcome of treatment with radiation there are also other techniques for delivering radiation to the breast. One such new technology is using IMRT (intensity modulated radiation therapy) which the radiation oncologist can change the shape and intensity of the radiation beam at different points across and inside the breast. This allows for an even more focused beam of radiation directed at the tumor cells and leaving most of the healthy tissue unaffected by the radiation

Another new procedure involves a type of brachytherapy where a radioactive source is temporarily placed inside the breast in direct contact with the tumor bed (area where tumor was removed). This technique is called a Mammosite and is currently undergoing clinic trials.

Systemic therapy

Systemic therapy uses medications to treat cancer cells throughout the body. Any combination of systemic treatments may be used to treat breast cancer. Systemic treatments include chemotherapy, immune therapy, and hormonal therapy.

Chemotherapy

Chemotherapy can be given both before and after surgery. Neo-adjuvant chemotherapy is used to shrink the size of a tumor prior to surgery. Adjuvant chemotherapy is given after surgery to reduce the risk of recurrence.

There are several different chemotherapy regimens that may be used. The determination of which regimen will be used depends on many factors including the character of the tumor, lymph node status, and the age and health of the patient. Possible chemotherapy regimens include:

• CMF: cyclophosphamide, methotrexate, and 5-fluorouracil
• FAC: 5-fluorouracil, doxorubicin, cyclophosphamide
• AC: doxorubicin and cyclophosphamide
• AC with paclitaxel administered after the AC
• TAC: docetaxel , doxorubicin, and cyclophosphamide
• FEC for three cycles followed by docetaxel for three cycles
• Dose dense AC: doxorubicin and cyclophosphamide followed by paclitaxel

Since chemotherapy effects the production of white blood cells a growth factor e.g. pegfilgrastim is sometimes administered along with chemotherapy.

Chemotherapy has increasing side effects as the patient's age passes 65.

Hormonal treatment

Patients with estrogen receptor positive tumors will typically receive a hormonal treatment after chemotherapy is completed. Typical hormonal treatments include:

• Tamoxifen is typically given to premenopausal women to block estrogen the reception of estrogen by breast cancer cells
• Aromatase inhibitors are typically given to postmenopausal women to lower the amount of estrogen in their systems
• GnRH-analogues

Immune treatment

In patients whose cancer expresses an over-abundance of the HER2 protein the drug trastuzumab (Herceptin ®) is used to block the HER2 protein in breast cancer cells slowing their growth. This drug was originally used only in the treatment of patients with metastatic disease, however in the summer of 2005 two large clinical trials published results suggesting that patients with early stage disease also benefit significantly from Herceptin.

Prognosis

There are several prognostic factors associated with breast cancer. Stage is the single most important prognostic factor in breast cancer, as it will take into consideration local involvement, lymph node status and whether metastatic disease is present or not. The higher the stage at the time of diagnosis, the worse the prognosis of breast cancer is. Node negative breast cancer patients have a much better prognosis compared to node positive patients.

Presence of estrogen and progesterone receptors in the cancer cell is another important prognostic factor, and may guide treatment. Hormone receptor positive breast cancer is usually associated with much better prognosis compared to hormone negative breast cancer.

HER2/neu status has also been described as a prognostic factor. Patients whose cancer cells are positive for HER2/neu have more aggressive disease and may be treated with trastuzumab, a monoclonal antibody that targets this protein.

Ashkenazi Jewish women and black women tend to have higher rates of fatalities.

Prevention

Prevention of breast cancer in high-risk women is probably more important than treatment of breast cancer. Many women who may have inherited genetic mutations in breast cancer related genes (called BRCA1 and BRCA2) might have very high risk of developing breast cancer. In these women and other women who have very strong family history of breast cancer, the chance of developing breast cancer may be decreased by hormonal treatment . Classic drug for breast cancer prevention is tamoxifen, which is currently used extensively in high risk women. A recent clinical trial has shown that Raloxifene, which is drug commonly used for prevention of osteoporosis is as good as tamoxifen in breast cancer prevention with much less side effects . Raloxifene is not currently Food and Drug Administration (FDA) approved for breast cancer prevention.

Prophylactic oophorectomy (removal of ovaries), post-child-bearing, reduces the risk of developing breast cancer by 50%, as well as reducing the risk of developing ovarian cancer by 96%. The side effects of Oophorectomy may be alleviated by medicines other than hormonal replacement. Non-hormonal biphosphonates (such as Fosamax and Actonel) increase bone strength and are available as once-a-week pills. Low-dose Selective Serotonin Reuptake Inhibitors (e.g. Paxil, Prozac) alleviate vasomotor menopausal symptoms, i.e. "hot flashes".

Breast cancer in males

For years the medical profession assumed that male breast cancer was significantly different from female breast cancer. Today they are grouped together and receive the same treatment regimens. Since the male breast tissue is confined to the area directly behind the nipple, treatment for males has always been a mastectomy. Since the psychological effects of this surgery are just as great for males as for females, experimental surgery has been started to introduce the lumpectomy for males.

The incidence of breast cancer in males is very low, possibly due to the different endocrine milieu or the small total amount of glandular tissue. Seminal research in recognizing the incidence of male breast cancer was performed by the U.S. military at Madigan Army Medical Center. Most swelling or development of the male breast is likely to be the more benign condition of gynecomastia.

Breast cancer awareness

Pink ribbon

Pink ribbon

In the month of October, breast cancer is recognized by survivors, family and friends of survivors and/or victims of the disease. A pink ribbon is worn to recognize the struggle that men and women face when battling the cancer.

See also

• List of notable breast cancer patients according to occupation.
• List of notable breast cancer patients according to survival status.
• List of breast carcinogenic substances : cadmium.
• Mammary tumor for breast cancer in other animals.
• Breast reconstruction.
• Alcohol and cancer.

References

• Chu, S.Y.; Lee, N.C.; Wingo, P.A.; and Webster, L.A. Alcohol consumption and the risk of breast cancer. American Journal of Epidemiology 130(5):867-877, 1989.
• Friedenreich, C.M.; Howe, G.R.; Miller, A.B.; and Jain, M.G. A cohort study of alcohol consumption and risk of breast cancer. American Journal of Edidemiology 137(5):512-520, 1993.
• Longnecker, M.P.; Berlin, J.A.; Orza, M.J.; and Chalmers, T.C. A meta-analysis of alcohol consumption in relation to risk of breast cancer. Journal of the American Medical Association 260(5):652-656, 1988.
• Longnecker, M.P. Alcohol consumption in relation to risk of cancers of the breast and large bowel. Alcohol Health & Research World 16(3)':223-229, 1992.
• Nasca, P.C.; Baptiste, M.S.; Field, N.A.; Metzger, B.B.; Black, M.; Kwon, C.S.; and Jacobson, H. An epidemiological case-control study of breast cancer and alcohol consumption. International Journal of Epidemiology 19(3):532-538, 1990.
• Petri, A.L., et al. Alcohol intake, type of beverage, and risk of cancer in pre- and postmenopausal women. Alcoholism: Clinical & Experimental Research, 2004, 28(7), 1084-1090).
• Schatzkin, A.; Piantadosi, S.; Miccozzi, M.; and Bartee, D. Alcohol consumption and breast cancer: A cross-national correlation study. International Journal of Epidemiology 18(1):28-31, 1989.
• Webster, L.A.; Layde, P.M.; Wingo, P.A.; and Ory, H.W. Alcohol consumption and risk of breast cancer. Lancet 2(8352):724-726, 1983.

External links

• International Agency for Research on Cancer home page
• Australia: Cancer Control Bulletin Alcohol and cancer risk (PDF format)
• Johns Hopkins Avon Foundation Breast Center
• Breast cancer incidence by country
• National Cancer Institute - Breast Cancer Home Page
• Mayo Clinic: How the grading system for cancerous tumors was developed.
• Cornell University Alcohol and the Risk of Breast Cancer