Breast cancer

Breast cancer
ICD-10	ICD10 F84.0-F84.1
ICD-9	174 -175
OMIM	114480
MedlinePlus	000913

Breast cancer is a cancer of the glandular breast tissue. Worldwide, it is the fifth most common cause of cancer death (after lung cancer, stomach cancer, liver cancer, and colon cancer). In 2005, breast cancer caused 502,000 deaths (7% of cancer deaths; almost 1% of all deaths) worldwide. Among women worldwide, breast cancer is the most common cancer.

In the U.S.A., breast cancer is the most prevalent cancer in women, and the second most common cause of cancer death in women (after lung cancer). In 2007, breast cancer is expected to cause 40,910 deaths (7% of cancer deaths; almost 2% of all deaths) in the U.S.A. Women in the U.S.A. have a 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death.

The number of cases has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world. Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males, though it is less common.

History

Breast cancer may be one of the oldest known forms of cancer tumors in humans. The oldest description of cancer (although the term cancer was not used) was discovered in Egypt and dates back to approximately 1600 BC. The Edwin Smith Papyrus 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." For centuries, physicians described similar cases in their practises, with the same sad conclusion. It wasn't until doctors achieved greater understanding of the circulatory system in the 17th century that they could establish a link between breast cancer and the lymph nodes 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 underlying chest 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 1970s.

In 1971, the situation changed when a major study revealed no survival improvement of radical mastectomy over lumpectomy with adjuvant radiation. Radical mastectomy, however, reduced quality of life.

Classification

These are the pathological and clinical categories of breast cancer. There can overlap; for example, a ductal carcinoma can also be an inflammatory breast cancer.

• Ductal carcinoma 65-90%
• Lobular carcinoma 10%
• Inflammatory breast cancer
• Medullary carcinoma 5%
• Colloid carcinoma 2%
• Papillary carcinoma 1%
• Metaplastic carcinoma

Symptoms

Early breast cancer sometimes presents as breast pain (mastodynia) or a painful lump. Since the advent of breast mammography, breast cancer is most often discovered as an asymptomatic nodule on a mammogram, before any symptoms are present. A lump under the arm or above the collarbone that does not go away may be present. Other possible symptoms or medical signs include nipple discharge, bleeding from the nipple, new nipple inversion, and changes in the skin overlying the breast, often resembling an orange peel, known as peau d'orange.

When breast cancer associates with skin inflammation, this is known as inflammatory breast cancer. In inflammatory breast cancer, the breast tumor itself causes an inflammatory reaction of the skin, and this can cause pain, swelling, warmth, and redness throughout the entire breast. Changes in the appearance or shape of the breast can raise suspicions of breast cancer.Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes at the nipple, and is a late manifestation of an underlying breast cancer.

Most breast symptoms do not turn out to reflect underlying breast cancer. Benign breast diseases such as fibrocystic mastopathy, mastitis, functional mastodynia, and fibroadenoma of the breast are more common causes of breast symptoms. The appearance of a new breast symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.

Breast cancer metastasis

Most people understand breast cancer as something that happens in the breast. However it can metastasise (spread) via lymphatics to nearby lymph nodes usually those under the arm. That is why surgery for breast cancer always involves some type of surgery for the glands under the arm- either axillary clearance, sampling or sentinel node biopsy. Cancer localized to the breast is rarely fatal.

In metastatic breast cancer, the neoplasm in the breast spreads to other parts of the body. So it can spread to the lungs, pleura (the lining of the lungs), the liver, the brain and most commonly to the bones. In fatal outcomes, the tumor has almost always metastasized. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. Pleural effusions are not uncommon with metastatic breast cancer. These symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.

Seventy percent of the time that breast cancer spreads to other locations, it spreads to bone, especially the vertebrae and the long bones of the arms, legs and ribs. Breast cancer cells "set up house" in the bones and form tumors. When breast cancer is found in bones, it has usually spread to more than one site. At this stage, it is treatable, often for many years, but it is not curable. Specialized pain management is available for primary or metastatic bone canceer.

Usually when breast cancer spreads to bone, it eats away healthy bone causing weak spots. The bones break easily at these weak spots. That is why breast cancer patients are often seen wearing braces or using a wheel chair, and why they complain about aching bones. If a patient has had breast cancer in the past and notices pain in the bones, the patient should see a doctor.

Psychological aspects of breast cancer diagnosis and treatment

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.

Epidemiologic risk factors and etiology

Epidemiological risk factors for a disease can provide important clues as to the etiology of a disease. 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 the final outcome of multiple environmental and hereditary factors.

1. Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer. Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
2. Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
3. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells, for example in the angiogenesis necessary to promote new blood vessel growth near new cancers
4. Inherited defects in DNA repair genes, such as BRCA1 gene, BRCA2 gene and p53 gene.

Although many epidemiological risk factors have been identified, the cause of any individual breast cancer is often unknowable. In other words, epidemiological research informs the patterns of breast cancer incidence across certain populations, but not in a given individual. Approximately 5% of new breast cancers are attributable to hereditary syndromes, while no etiology is known for the other 95% of cases.

Age

The risk of getting breast cancer increases with age. A woman who lives to age 90 has a lifetime risk of about 14.3%, or one in seven. The probability of breast cancer rises with age, but breast cancer tends to be more aggressive when it occurs in younger people. One type of breast cancer that is especially aggressive and that occurs disproportionately in younger people 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 it is often undetected by mammography or ultrasound. It presents with the signs and symptoms of a breast infection like mastitis, and the treatment is usually a combination of surgery, radiation, and chemotherapy.

Gender

Men have a lower risk of developing breast cancer (approximately 1.08 per 100,000 men per year), but this risk appears to be rising.

Heredity

In 5% of breast cancer cases, there is a strong inherited familial risk. Two autosomal dominant genes, BRCA1 gene and BRCA2 gene, account for most of the cases of familial breast cancer. Family members who harbor mutations in these genes have a 60% to 80% risk of developing breast cancer in their lifetimes. Other associated malignancies include ovarian cancer and pancreatic cancer. If a mother or a sister was diagnosed breast cancer, the risk of a hereditary ‘’’BRCA1 gene’’’ or ‘’’BRCA2 gene’’’ mutation is about 2-fold higher than those women without a familial history. In addition to the BRCA genes associated with breast cancer, the presence of NBR2, near breast cancer gene 1, has been discovered, and research into its contribution to breast cancer pathogenesis is ongoing. Commercial testing for ‘’’BRCA1 gene’’’ and ‘’’BRCA2 gene’’’ gene mutations has been available since at least 2004. Genetic testing for BRCA gene mutations is conducted exclusively by Myriad Genetics, located in Salt Lake City.

Diet

Recent research suggests that low-fat diets may significantly decrease the risk of breast cancer as well as the recurrence of breast cancer. Another study showed no contribution of dietary fat intake on the incidence of breast cancer in over 300,000 women. A randomized controlled study of the consequences of a low-fat diet, the Women's Health Initiative, failed to demonstrate any reduction in breast cancer incidence with reduction in fat intake. Another randomized trial, the Nurses' Health Study II, found increased breast cancer incidence in premenopausal women only, with higher intake of animal fat, but not vegetable fat. Taken as a whole, these results point to a possible association between dietary fat intake and breast cancer incidence, though these interactions are hard to measure in large groups of women.

An environmental effect is probably responsible for the different rates of breast cancer incidence between countries with different dietary customs. Researchers have long measured that breast cancer rates in an immigrant population soon come to resemble the rates of the host country after a few generations. The reason is speculated to be immigrant uptake of the host country diet. The prototypical example of this phenomenon is the changing rate of breast cancer after the arrival of Japanese immigrants to America.

Alcohol

Alcohol appears to increase the risk of breast cancer, though meaningful increases are limited to higher alcohol intake levels. Among women, breast cancer comprises 60% of alcohol-attributable cancers. The UK'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." 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.

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 UK each year could be prevented if drinking was reduced to a very low level (i.e. less than 1 unit/week)." Breast cancer incidence seems to increase with increasing alcohol consumption. 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, and 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.

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.

Obesity

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

Radiation

Radiotherapy for childhood cancers may increase the risk of breast cancer.

Late pregnancy

Giving birth before the age of 24 was shown to be associated with a decreased lifetime risk of contracting breast cancer. Subsequent successful deliveries further increase the protective effect.

Hormones

Persistently increased blood levels of estrogen are associated with an increased risk of breast cancer, as are increased levels of the androgens androstenedione and testosterone (which can be directly converted by aromatase to the estrogens estrone and estradiol, respectively). Increased blood levels of progesterone are associated with a decreased risk of breast cancer in premenopausal women. A number of circumstances which increase exposure to endogenous estrogens including not having children, delaying first childbirth, not breastfeeding, early menarche (the first menstrual period) and late menopause are suspected of increasing lifetime risk for developing breast cancer.

Hormonal contraceptives may produce a slight increase in the risk of breast cancer diagnosis among current and recent users, but this appears to be a short-term effect. In 1996 the largest collaborative reanalysis of individual data on over 150,000 women in 54 studies of breast cancer found a relative risk (RR) of 1.24 of breast cancer diagnosis among current combined oral contraceptive pill users; 10 or more years after stopping, no difference was seen. Further, the cancers diagnosed in women who had ever used hormonal contraceptives were less advanced than those in nonusers, raising the possibility that the small excess among users was due to increased detection. The relative risk of breast cancer diagnosis associated with current and recent use of hormonal contraceptives did not appear to vary with family history of breast cancer.

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. The largest meta-analysis (1997) of data from 51 observational studies, indicated a relative risk of breast cancer of 1.35 for women who had used HRT for 5 or more years after menopause. The estrogen-plus-progestin arm of the Women's Health Initiative (WHI), a randomized controlled trial, which randomized more than 16,000 postmenopausal women to receive combined hormone therapy or placebo, was halted early (2002) because health risks exceeded benefits. One of the adverse outcomes prompting closure was a significant increase in both total and invasive breast cancers (RR = 1.24) in women randomized to receive estrogen and progestin for an average of 5 years. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.

Environmental causes

Tobacco

Most studies have not found an increased risk of breast cancer from active tobacco smoking, although a number of studies suggest an increased risk of breast cancer in both active smokers and those exposed to secondhand smoke compared to women who reported no exposure to secondhand smoke.

Radiation

Women who have received high-dose ionizing radiation to the chest (for example, as treatments for other cancers) have a relative risk of breast cancer between 2.1 to 4.0.

Impact of environmental estrogenic mimics

Although environmental exposures are not generally cited as risk factors for the disease (except for diet, pharmaceuticals and radiation), a substantial and growing body of evidence indicates that exposures to certain toxic chemicals and hormone-mimicking compounds including chemicals used in pesticides, cosmetics and cleaning products contribute to the development of breast cancer. A recent Canadian study concluded that female farm workers are three times more likely to have breast cancer. The increasing prevalence of these substances in the environment may explain the increasing incidence of breast cancer, though direct evidence is sparse.

Viral breast cancer pathogenesis research

Humans are not the only mammals 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. This finding is taken to mean that a viral etiology of human breast cancer is at least possible, though there is no definitive evidence to support the claim that MMTV causes human breast cancer. For example, there may be critical differences between cancer pathogenesis in mice and people. The understanding of the role of MMTV or other viruses in human breast cancer is preliminary as of May 2007.

Factors with minimal impact on breast cancer risk

Abortion

Studies in rats led to speculation that abortion may increase the risk of breast cancer because of hormones initiating breast tissue growth in early pregnancy. Some early interview based case-control studies indicated a possible correlation, but more recent large record based studies and meta-analysis studies do not support this association.

Deodorants

Much has been made of the possible contribution of aluminum-containing underarm antiperspirants to the incidence of breast cancer, since the most common location of a breast cancer is the upper outer quadrant of the breast. Aluminum salts, such as those used in anti-perspirants, have recently been classified as metalloestrogens. Fortunately, this in-vitro association between aluminum salts and estrogen activity does not translate into an increased risk of breast cancer in humans. The lack of association between underarm deodorants and breast cancer has been the subject of a number of research articles.

Fertility treatments

There is no persuasive connection between fertility medications and breast cancer.

Phytoestrogens and soy

Phytoestrogens such as found in soybeans have been extensively studied in animal and human in-vitro and epidemiological studies. The literature support the following conclusions:

1. Plant estrogen intake, such as from soy products, in early adolescence may protect against breast cancer later in life.
2. Plant estrogen intake later in life is not likely to influence breast cancer incidence either positively or negatively. It seems reasonable to conclude that soybean-based phytoestrogens are not a major contributor to the incidence of breast cancer.

Prevention in high-risk individuals

Prophylactic oophorectomy

Prophylactic oophorectomy (removal of ovaries), in high-risk individuals, when child-bearing is complete, reduces the risk of developing breast cancer by 60%, as well as reducing the risk of developing ovarian cancer by 96%.

Managing side effects of prophylactic oophorectomy

Hormonal treatments

Short-term hormone replacement with estrogen, in high-risk BRCA mutation carriers, was not shown to increase the risk of breast cancer in women who are post-oophorectomy. The results were published in JCO in 2004, and the conclusions based on a computerized simulation using models of risk and benefit, a lower level of data than a randomized trial per se. PMID: 14981106. This result can probably be generalized to other women at high risk, in whom short term (i.e., one or two year) treatment with estrogen for hot flashes, may be acceptable.

Prophylactic mastectomy

Bilateral prophylactic mastectomies have been shown to prevent breast cancer in high-risk individuals, such as patients with BRCA1 gene or BRCA2 gene mutations.

Medications

Hormonal therapy has been used for chemoprevention in individuals at high risk for breast cancer. The current U.S. Preventive Services Task Force (USPSTF) was published in 2009. Previously, in 2002, a clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF) recommended "clinicians discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention" with a grade B recommendation.

Selective estrogen receptor modulators (SERMs)

The guidelines were based on studies of SERMs from the MORE, BCPT P-1, and Italian trials. In the MORE trial, the relative risk reduction for raloxifene was 76%. The P-1 preventative study demonstrated that tamoxifen can prevent breast cancer in high-risk individuals. The relative risk reduction was up to 50% of new breast cancers, though the cancers prevented were more likely estrogen-receptor positive (this is analogous to the effect of finasteride on the prevention of prostate cancer, in which only low-grade prostate cancers were prevented). The Italian trial showed benefit from tamoxifen.

Additional randomized controlled trials have been published since the guidelines. The IBIS trial found benefit from tamoxifen. In 2006, the NSABP STAR trial demonstrated that raloxifene had equal efficacy in preventing breast cancer compared with tamoxifen, but that there were fewer side effects with raloxifene. The RUTH Trial concluded that "benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke".

Raloxifene is only FDA-approved for osteoporosis as of May 2007.

Screening

Breast self-examination

Breast self-exam was widely discussed in the 1990s as a useful modality for detecting breast cancer at an earlier stage of presentation. A large clinical trial in China reduced enthusiasm for breast self-exam. In the trial, 132,979 female Chinese factory workers were taught breast self-exam monthly by nurses at their factories, while 133,085 other workers were not taught self-exam. The women taught self-exam tended to detect more breast nodules, but breast cancer mortality was no different from the control women. In other words, women taught breast self-exam were mostly likely to detect benign breast disease, but were just as likely to die of breast cancer. An editorial in the Journal of the National Cancer Institute reported in 2002, "Routinely Teaching Breast Self-Examination is Dead. What Does This Mean?"

Clinical breast examination

The Clinical breast examination (a breast examination performed by a trained health care provider), if carefully done over 8 to 10 minutes increases both detection and false positives.

X-ray mammography

Due to the high incidence of breast cancer among older women, screening is now recommended in many countries. Mammography has been estimated to reduce breast cancer-related mortality by 20-30%. Routine (annual) mammography of women older than forty or fifty years of age is recommended by numerous organizations as a screening method to diagnose early breast cancer, and has demonstrated a protective effect in multiple clinical trials. The evidence in favor of mammographic screening comes from eight randomized clinical trials from the 1960s through 1980s. Many of these trials have been criticised for methodological errors, and the results were summarized in a review article published in 1993.

Several scientific groups however have expressed concern on the perceived benefits of breast screening by the public. In 2000 and 2001, a controversial meta-analysis by members of the Cochrane Collaboration claimed that there is no reliable evidence that screening for breast cancer reduces mortality. The final meta-analysis by the Cochrane Collaboration concluded that the number needed to screen is 2000.

Reasons for differences of opinion between the Cochrane Collaboration and the US Preventive Services Task Force have been reviewed.

In 2009, the US Preventive Services Task Force reversed its position on screening mammography for women aged 40-50. This change generated much controversy.

Screening women aged 40 to 50

The US Preventive Services Task Force most recent clinical practice guidelines were published in 2009:

• "The USPSTF recommends biennial screening mammography for women between the ages of 50 and 74 years. (Grade B recommendation)"
• "The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. (I statement)"
• "The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination beyond screening mammography in women 40 years or older. (I statement)"
• "The USPSTF recommends against clinicians teaching women how to perform breast self-examination. (Grade D recommendation)"
• "The USPSTF concludes that the current evidence is insufficient to assess additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer. (I statement)"

The US Preventive Services Task Force states in their clinical practice guidelines published in 2002:

• "recommends screening mammography, with or without clinical breast examination (CBE), every 1 to 2 years for women aged 40 and older"
• Regarding women at all ages, the number needed to screen is 1224
• Regarding women less than 50 years old, the number needed to screen is 1792

The American College of Physicians states:

1. "In women 40 to 49 years of age, clinicians should periodically perform individualized assessment of risk for breast cancer to help guide decisions about screening mammography."
2. "Clinicians should inform women 40 to 49 years of age about the potential benefits and harms of screening mammography"
3. "For women 40 to 49 years of age, clinicians should base screening mammography decisions on benefits and harms of screening, as well as on a woman's preferences and breast cancer risk profile."

The U.S. National Cancer Institute concludes that the benefit from screening mammography is:

• "Absolute mortality benefit for women screened annually starting at age 40 is 4 per 10,000 at 10.7 years." The number needed to screen is 2500.
• "The comparable number for women screened annually starting at age 50 is approximately 5 per 1000." The number needed to screen is 2000.

The Institute makes no recommendation about whether screening should be done.

The American Cancer Society states:

• "Women at average risk should begin annual mammography at age 40."

False positives

False positives are a major problem of mammographic breast cancer screening. Data reported in the UK Million Woman Study indicates that if 134 mammograms are performed, 20 women will be called back for suspicious findings, four biopsies will be necessary, to diagnose one cancer. Recall rates are higher in the USA than in the UK. The contribution of mammography to the early diagnosis of cancer cannot be overstated, but it comes at a huge financial and psychological cost to the women found to have a nodule.

Overdiagnosis

Mammography may lead to overdiagnosis - detection of true breast cancer that is clinically not relevant. This may be due to ductal carcinoma in situ (DCIS).

Breast MRI

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 27-36% more sensitive, it is less specific than mammography. As a result, MRI studies will have more false positives (up to 5%), 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. Proposed Indications for using MRI for screening include:

• Strong family history of breast cancer
• Patients with BRCA1 gene or BRCA2 gene mutations
• Evaluation of women with breast implants
• History of previous lumpectomy or breast biopsy surgeries
• Axillary metastasis with an unknown primary tumor
• Very dense or scarred breast tissue

Breast ultrasound

Ultrasound alone is not usually employed as a screening tool but it is a useful additional tool for the characterization of palpable tumours and directing image-guided biopsies. U-Systems is a US-based company that is selling a breast-cancer detection system using ultrasound that is fully-automated. Using an ultrasound allows a look at dense breast tissue which is not possible with digital mammmography. It is closely correlated with the digital mammography. The other significant advantage over digital mammography is that it is a pain-free procedure.

Genetic testing

Currently, testing for the BRCA1 gene and BRCA2 gene is not recommended according to clinical practice guidelines by the US Preventive Services Task Force.

Diagnosis

The diagnosis of breast cancer is established by the pathological (microscopic)examination of surgically removed breast tissue. A number of procedures can obtain tissue or cells prior to definitive treatment for histological or cytological examination. Such procedures include fine-needle aspiration, nipple aspirates, ductal lavage, core needle biopsy, and local surgical excisional biopsy. These diagnostic steps, when coupled with radiographic imaging, are usually accurate in diagnosing a breast lesion as cancer. Occasionally, pre-surgical procedures such as fine needle aspirate may not yield enough tissue to make a diagnosis, or may miss the cancer entirely. Imaging tests are sometimes used to detect metastasis and include chest x-ray, bone scan, CT, MRI, and PET scanning. While imaging studies are useful in determining the presence of metastatic disease, they are not in and of themselves diagnostic of cancer. Only microscopic evaluation of a biopsy specimen can yield a cancer diagnosis. Ca 15.3 (carbohydrate antigen 15.3, epithelial mucin) is a tumor marker determined in blood which can be used to follow disease activity over time after definitive treatment. Blood tumor marker testing is not routinely performed for the screening of breast cancer, and has poor performance characteristics for this purpose.

Prognosis

5-Year Relative Survival Rates By Year Dx By Cancer Site All Ages, All Races, Female 1975-2000.

There are several prognostic factors associated with breast cancer.

Staging

Breast cancer staging information from the National Cancer Institute's Physician Data Query

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.

Breast cancer is staged according to the TNM system, updated in the American Joint Committee on Cancer Staging Manual. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.

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)

Cell receptor proteins

Breast lesions are examined for certain markers including cytoplasmic receptors for sex steroid hormones and cell surface receptors for epidermal growth factor receptor.

Estrogen receptors

About two thirds of postmenopausal breast cancers are estrogen receptor positive (ER+) and progesterone receptor positive (PR+). Hormone receptor positive breast cancer is usually associated with much better prognosis compared to hormone negative breast cancer. Receptor status modifies the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are sensitive to hormonal therapy.

Epidermal growth factor receptor

The breast cancer is also usually tested for the presence of ErbB-2 receptor, also called human epidermal growth factor receptor 2, HER2, neu or erbB2. HER2 is a cell-surface protein involved in cell development. In normal cells, HER2 controls aspects of cell growth and division. About 20-30% of breast cancers overexpress HER2. Patients whose cancer cells are positive for HER2/neu have more aggressive disease as when activated in cancer cells, HER2 accelerates tumor formation. Those patients may be candidates for the drug trastuzumab (Herceptin), a monoclonal antibody that targets this protein. Trastuzumab may be used both in the postsurgical setting (so-called "adjuvant" therapy), and in the metastatic setting.

Gene expression profiling

Recently, the acceleration of gene expression profiling research has made available additional markers to predict disease recurrence. Beyond conventional TNM staging, doctors can now order a gene expression profile on tumors to predict whether a breast cancer patient will have a high chance of developing breast cancer again. The test, Oncotype-DX, is not used in every clinical setting; for example, in a patient with positive lymph nodes who is a candidate for chemotherapy, the test would not change therapy decisions. The most useful setting for Oncotype-DX testing is where there are negative lymph nodes, and the benefit of chemotherapy is felt to be small. In up to 10% of patients, there will be disease recurrences, but treating every patient with chemotherapy is overkill. In this setting, a high-risk score on the Oncotype-DX can help doctors decide whether to recommend chemotherapy.

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 is subject to change 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 and hormonal therapy is Adjuvant! Online (see below).

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2006, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether women with early stage breast cancer will relapse in five or 10 years, this could help influence how aggressively they fight the initial tumor.

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.

While there has been an increasing utilization of lumpectomy techniques for breast-conservation cancer surgery, mastectomy may be the preferred treatment in certain instances:

• Two or more tumors exist in different areas of the breast (a "multifocal" cancer).
• The breast has previously received radiation (XRT) treatment.
• The tumor is large relative to the size of the breast.
• The patient has had scleroderma or another disease of the connective tissue, which can complicate XRT treatment.
• The patient lives in an area where XRT is inaccessible.
• The patient is apprehensive about their risk of local recurrence after lumpectomy.

Standard practice requires the surgeon to 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 (SLN) dissection has become popular, as it requires the removal of far fewer lymph nodes, resulting in fewer side effects. The sentinel lymph node is the first node that drains the tumor, and subsequent SLN mapping can save 65-70% of patients with breast cancer from having a complete lymph node dissection for what could turn out to be a negative nodal basin. Advances in Sentinel Lymph Node mapping over the past decade have increased the accuracy of detecting Sentinel Lymph Node from 80% using blue dye alone to between 92% and 98% using combined modalities. SLN biopsy is indicated for patients with T1 and T2 lesions (<5cm) and carries a number of recommendations for use on patient subgroups.

Radiation therapy

Radiation therapy consists of the use of high powered X-rays or gamma rays (XRT) 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. Alternatively, the use of implanted radioactive catheters (brachytherapy), similar to those used in prostate cancer treatment, is being evaluated. 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.

Although radiation therapy can reduce the chance that breast cancer will recur in the breast, it is much less effective in prolonging patient survival. The National Cancer Institute reviews this information. in a paragraph that begins:“Breast-conserving surgery alone without radiation therapy . . .” The NCI includes six studies; none of them found a survival benefit for radiation therapy. Abstracts from all six studies are available for review. Patients who are unable to have radiation therapy after lumpectomy should consult with a surgeon who understands this research and who believes that lumpectomy (or partial mastectomy) alone is a reasonable treatment option.

Indications for radiation

Indications for radiation treatment are constantly evolving. Patients treated in Europe have been more likely in the past to be recommended adjuvant radiation after breast cancer surgery. Radiation therapy is usually recommended for all patients who had (lumpectomy, quadrant-resection). Radiation therapy is usually not indicated in patients with advanced (stage IV disease) except for palliation of symptoms like bone pain.

In general recommendations would include:

• As part of breast conserving therapy of breast cancer when the whole breast is not removed (lumpectomy or wide local excision)
• After mastectomy: Patients with higher chances of cancer recurring such as : large primary tumor and involvement of 4 or more lymph nodes.

Other factors which may influence adding adjuvant radiation therapy:

• Tumor close to or involving the margins on pathology specimen
• Multiple areas of tumor (multicentric disease)
• Microscopic invasion of lymphatic or vascular tissues
• Microcopic invasion of the skin, nipple/areola, or underlying pectoralis major muscle
• Patients with <4 LN involved, but extension out of the substance of a LN
• Inadequate numbers of axillary LN sampled

Types of radiotherapy

Radiotherapy can be delivered in many ways. Most commonly this is done using radiation from linear accelerators. Since this is delivered from outside, one needs to restrict the amount of dose that can be given at one time so that normal tissues are not harmed. So the course usually lasts for several days, typically every day for 5 to 6 weeks.

New technology has allowed more precise delivery of radiotherapy in a portable fashion - for example in the operating theatre. Targeted intraoperative radiotherapy (TARGIT). is a method of delivering therapeutic radiation from within the breast using a portable x-ray generator called Intrabeam. It is undergoing clinical trials in several countries at present to test whether it can replace the whole course of radiotherapy in selected patients. It may also be able provide a much better boost dose to the tumour bed and appears to provide superior control. This will be tested in a Targit-B trial.

Side effects of radiation therapy

The side effects of radiation have decreased 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 develop a suntan-like change in skin color in the exact area being treated. As with a suntan, this darkening of the skin will fade with time. Other side effects experienced with radiation include the fact that radiation therapy can and often does cause permanent changes in the color and texture of skin, in addition to:

• 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 have been improvements in the techniques that deliver radiation to the breast. One such new technology is using IMRT (intensity modulated radiation therapy), in 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 a more focused beam of radiation directed at the tumor cells and leaves 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.

The use of adjuvant radiation has significant potential effects if the patient has to later undergo breast reconstruction surgery. Fibrosis of chest wall skin from radiation negatively affects skin elasticity and makes tissue expansion techniques difficult. Traditionally most patients are advised to defer immediate breast reconstruction when adjuvant radiation is planned and are most often recommended surgery involving autologous tissue reconstruction rather then breast implants.

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 (drug treatment for cancer) may used before surgery, after surgery, or instead of surgery in those patients who are unsuitable for surgery.

Nonhormonal

While monoclonal antibodies and other biologicall engineered drugs, simpler molecules continue to have a role in adjuvant treatment and the treatment of metastatic disease. They divide roughly into nonhormonal and hormonal agents.

To avoid tumor cell resistance, increase coverage, and decrease side effects, the use of multiple drugs is standard. Greenspan and colleagues first used multiple agents in 1963. By the late sixties, three- to five-drug combinations were common, such as Cooper's regimen of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone. A 1976 review reinforced the importance of using combined, rather than sequential, drugs.

The Cooper regimen was high-dose and toxic, although did produce remissions in metastatic disease. In the mid-seventies, low-dose regimens, initially CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) were introduced for adjuvant postoperative chemotherapy, with minimal side effects and improved survival). Modifications were also made to the salvage combined therapies, with the anthracycline agent, doxorubricin (Adriamycin) prominent in many. Doxorubricin, however, had a maximum lifetime dose before cardiac toxicity was likely.

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 inhibit the estrogen receptors
• Aromatase inhibitors are typically given to postmenopausal women to lower the amount of estrogen in their systems
• GnRH-analogues
• ovarian ablation or suppression is used in premenopausal women

In 2007, researchers from Canada's McGill University reported that they have developed a potential drug target for treating up to 40 percent of breast cancers by blocking an enzyme called PTPB1, which has been implicated in the onset of breast cancer in mouse models of the disease. Elevated levels of PTPB1 have also been found in diabetes and obesity. A drug to block the activity of PTPB1 is under development by Merck, and was found to delay the development of breast tumors and prevent lung cancer up to two months from the administration of the drug. The researchers hope to continue further research in mouse models which are also HER-2 positive (responsive to Herceptin) so that the drug could benefit a significant population of women.

Biologic therapies

Targeted therapy

In patients whose cancer expresses an over-abundance of the erbB-2 receptor (HER2, HER2/neu), a monoclonal antibody known as trastuzumab (Herceptin ®) is used to block the activity of 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 trastuzumab. The drug was approved by the FDA in 1998 for the treatment of metastatic breast cancer, though oncologists have also been using it since 2005 for postoperative patients with localized, Her-2/neu positive disease.

Antiangiogenic therapy

An commercially-available angiogenesis inhibitor, a monoclonal antibody that blocks the activation of the VEGF receptor, bevacizumab, underwent testing in a randomized clinical trial in patients with metastatic breast cancer. There has been no formal publication of the data in the peer-reviewed literature as of May, 2007. The data indicate that bevacizumab delays disease progression for up to five months over conventional chemotherapy, but survival was no better. Genentech, manufacturer of bevacizumab, has filed a supplemental biological application with the FDA for approval of bevacizumab in the setting of metastatic breast cancer, on the strength of the improvement in progression-free survival.

It had received accelerated approval based on the surrogate marker that it decreased tumor size. On 16 July 2010, the FDA announced "FDA reviewers said two follow-up studies recently submitted by Roche failed to show that Avastin significantly extended lives compared to chemotherapy alone Additionally, the FDA said that in follow-up studies the drug did not slow tumor growth to the same degree as in earlier studies. Patients taking Avastin showed significantly more side effects, including high blood pressure, fatigue and abnormal white blood cell levels."

Breast cancer in males

Less than 1% of breast cancers occur in men, and incidence is about 1 in 100,000. Men with gynaecomastia do not have a higher risk of developing breast cancer. There may be an increased incidence of breast cancer in men with prostate cancer. The prognosis, even in stage I cases, is worse in men than in women. The treatment of men with breast cancer is similar to that in older women. Since the male breast tissue is confined to the area directly behind the nipple, treatment for males has usually been a mastectomy with axillary surgery. This may be followed by adjuvant radiotherapy, hormone therapy (such as tamoxifen), or chemotherapy.