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'Breast cancer' is a cancer of the glandular breast tissue.
Worldwide, breast cancer 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 and the most common cause of cancer death.[1]
In the United States, breast cancer is the third most common cause of cancer death (after lung cancer and colon 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.[2]
Among women in the U.S., breast cancer is the most common cancer and the second most common cause of cancer death (after lung cancer). Women in the U.S. have a 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death.[3]
The number of cases has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world. Breast cancer cases rise 80% since Seventies Jeremy Laurance [4]
Excised breast tissue showing a stellate, pale area of cancer measuring 2cm across. The tumor could be felt as a hard, mobile lump before the surgical excision.
__TOC__
Time line of breast cancer suggesting probable heterogeneity. Primary breast cancers begin as single (or more) cells which have lost normal regulation of differentiation and proliferation but remain confined within the basement membrane of the duct or lobule. As these cells go through several doublings, at some point they invade through the basement membrane of the duct or lobule and ultimately metastasize to distant organs.[5]
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."[6] 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.
Classification
There are numerous ways breast cancer is classified. Like most cancers, breast cancer can be divided into groups based on the tissue of origin, e.g. epithelial (carcinoma) versus stromal (sarcoma). The vast majority of breast cancers arise from epithelial tissue, i.e. they are carcinomas, which can divided further into subclassifications (e.g. DCIS versus LCIS versus papillary carcinoma).
Other pathologically based classifications:
★ Location of the tumour origin - breast duct (i.e. ductal) versus breast lobule (i.e. lobular).
★ Histology - see ''Histologic types'' section.
★ Grade of tumour - ''well-differentiated'' (looks almost like normal tissue) versus ''poorly differentiated'' (does not look like any normal tissue/mass of proliferating cells) versus ''moderately differentiated'' (somewhere between ''poorly differentiated'' and ''well-differentiated'').
★ Stage of the tumour.
★ Immunohistochemical marker status - (ER positive versus ER negative versus HER2/neu positive versus HER2/neu negative), e.g. ''triple negative breast cancer'' which is ER negative, PR negative and HER2/neu negative.
★ TNM classification -
★
★ Tumour size/invasiveness - presence of invasion (poorer prognosis) versus ''in situ'' (better prognosis).
★
★ Nodal status.
★
★ Presence/absence of metastases.
Histologic types
Carcinomas
in situ
★ Ductal carcinoma (DCIS) 80%
★ Lobular carcinoma (LCIS) 20%
Invasive
★ Carcinoma NOS (not otherwise specified)
★ Lobular carcinoma
★ Tubular/cribriform carcinoma
★ Mucinous (colloid) carcinoma
★ Medullary carcinoma
★ Papillary carcinoma
★ Metaplastic carcinoma
Sarcomas
★ Phyllodes tumour
Clinical categorizations
Breast cancer is occasionally classified clinically (on physical exam findings, (medical) history). Inflammatory breast cancer (IBC) is an example of a clinically classified breast cancer and can be any histologic type.[7]
Symptoms
Early breast cancer can in some cases present as breast pain (mastodynia) or a painful lump. Since the advent of breast mammography, breast cancer is most frequently 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. When breast cancer associates with skin inflammation, this is known as inflammatory breast cancer. In inflammatory breast cancer, the breast tumor itself is causing an inflammatory reaction of the skin, and this can cause pain, swelling, warmth, and redness throughout the 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 represent 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.
Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. More common sites of metastasis include bone, liver, lung, and brain. 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. Obviously, these symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.
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.
# Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer.[8] Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
# Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
# 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.
# Inherited defects in DNA repair genes, such as ''BRCA1'', ''BRCA2'' and ''p53''.
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. Proportion of breast cancer cases in the United States explained by well-established risk factors, Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN, , , J. Natl. Cancer Inst., 1995
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.[9] 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.
Sex
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.[10]
Heredity
In 5% of breast cancer cases, there is a strong inherited familial risk.[11]
Two autosomal dominant genes, ''BRCA1'' and ''BRCA2'', 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’’’ 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. Specific binding of the methyl binding domain protein 2 at the ''BRCA1-NBR2'' locus, Emilie Auriol, Lise-Marie Billard, Frederique Magdinier, Robert Dante, , , Nucleic Acids Research, 2005
Commercial testing for ‘’’BRCA1’’’ and ‘’’BRCA2’’’ 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
Dietary influences have been proposed and examined, and recent research suggests that low-fat diets may significantly decrease the risk of breast cancer as well as the recurrence of breast cancer.[12]
Another study showed no contribution of dietary fat intake on the incidence of breast cancer in over 300,000 women.[13] A randomized controlled study of the consequences of a low-fat diet, the Women's Health Initiative, failed to show a statistically significant reduction in breast cancer incidence in the group assigned to a low-fat diet, although the authors did find evidence of a benefit in the subgoup of women who followed the low-fat diet in a strict manner.[14] 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.
In a study published in the ''Journal of the American Medical Association'', biomedical investigators found that Brassica vegetable intake (broccoli, cauliflower, cabbage, kale and Brussels sprouts) was inversely related to breast cancer development. The relative risk among women in the highest decile of Brassica vegetable consumption (median, 1.5 servings per day) compared to the lowest decile (virtually no consumption) was 58%. That is, women who consumed the most Brassica vegetables were 58% less likely to develop breast cancer.[15]
A significant environmental effect is likely 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 for this 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.[16]
Alcohol
Alcohol appears to increase the risk of breast cancer, though meaningful increases are limited to higher alcohol intake levels. Breast cancer constitutes about 7.3% of all cancers. Statistics for 2007 Among women, breast cancer comprises 60% of alcohol-attributable cancers. The burden of cancer attributable to alcohol drinking, , Paolo, Boffetta, International Journal of Cancer, 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." Review of Alcohol: Association with Breast Cancer
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." A cohort study of alcohol consumption and risk of breast cancer, Friedenreich C, Howe G, Miller A, Jain M, , , Am J Epidemiol, 1993 A meta-analysis of alcohol consumption in relation to risk of breast cancer, Longnecker M, Berlin J, Orza M, Chalmers T, , , JAMA, 1988 Alcohol consumption in relation to risk of cancers of the breast and large bowel, Longnecker MP, , , Alcohol Health & Research World, 1992 An epidemiological case-control study of breast cancer and alcohol consumption, Nasca P, Baptiste M, Field N, Metzger B, Black M, Kwon C, Jacobson H, , , Int J Epidemiol, 1990 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. Alcohol consumption and the risk of breast cancer, Chu S, Lee N, Wingo P, Webster L, , , Am J Epidemiol, 1989 Alcohol consumption and breast cancer: a cross-national correlation study, Schatzkin A, Piantadosi S, Miccozzi M, Bartee D, , , Int J Epidemiol, 1989 Alcohol consumption and risk of breast cancer, Webster L, Layde P, Wingo P, Ory H, , , Lancet, 1983
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. CONSUMPTION OF ALCOHOLIC BEVERAGES AND RISK OF BREAST CANCER IN WOMEN 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)." A review article from JAMA also found that breast cancer incidence seems to increase with increasing alcohol consumption.[17] 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. Alcohol intake, type of beverage, and risk of breast cancer in pre- and postmenopausal women, Petri A, Tjønneland A, Gamborg M, Johansen D, Høidrup S, Sørensen T, Grønbaek M, , , Alcohol Clin Exp Res, 2004
One study suggests that women who frequently drink red wine may have an increased risk of developing breast cancer. The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor alpha in human breast cancer cells, Maggiolini M, Recchia A, Bonofiglio D, Catalano S, Vivacqua A, Carpino A, Rago V, Rossi R, Andò S, , , J Mol Endocrinol, 2005
"Folate intake counteracts breast cancer risk associated with alcohol consumption"[18] and "women who drink alcohol and have a high folate intake are not at increased risk of cancer."[19] 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. A prospective study of folate intake and the risk of breast cancer, Zhang S, Hunter D, Hankinson S, Giovannucci E, Rosner B, Colditz G, Speizer F, Willett W, , , JAMA, 1999 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 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%.[20]
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.[21] 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.[22]
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.[23][24] 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. Hormone Therapy National Cancer Institute
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. Hormone Therapy National Cancer Institute
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.[25]
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.[26]
The increasing prevalence of these substances in the environment may explain the increasing incidence of breast cancer, though direct evidence is sparse.
Dioxins
Although not well-quantified, there has long been a concern about risk associated with environmental estrogenic compounds, such as dioxins.
Light levels
Researchers at the National Cancer Institute and National Institute of Environmental Health Sciences have concluded a study that suggests that artificial light during the night can be a factor for breast cancer.[27]
Viral breast cancer pathogenesis research
Humans are not the only mammals susceptible 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 or no impact on breast cancer risk
Abortion
Main articles: Abortion-breast cancer hypothesis
Studies in rats[28] 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[29] and record[30] based case-control studies indicated a possible correlation, but more recent record based studies[31][32][33] and a large meta-analysis[34] study do not support this association. The subject was examined by a National Cancer Institute (NCI) workshop in 2003, in response to the Bush Administration's alteration of the NCI's website to emphasize studies indicating a potential link.[35] The NCI expert panel concluded, with the strongest level of evidence, that induced abortion is not associated with an increased breast cancer risk.[36]
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. In research published in the ''Journal of Applied Toxicology'', Dr. Philippa D. Darbre of the University of Reading has shown that aluminum salts increase estrogen-related gene expression in human breast cancer cells grown in the laboratory.[37][38][39]
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.[40][41]
Fertility treatments
There is no persuasive connection between fertility medications and breast cancer.[42]
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:
# Plant estrogen intake, such as from soy products, in early adolescence may protect against breast cancer later in life.[43]
# Plant estrogen intake later in life is not likely to influence breast cancer incidence either positively or negatively.[44]
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%. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation, Kauff N, Satagopan J, Robson M, Scheuer L, Hensley M, Hudis C, Ellis N, Boyd J, Borgen P, Barakat R, Norton L, Castiel M, Nafa K, Offit K, , , N Engl J Med, 2002
Prophylactic mastectomy
Bilateral prophylactic mastectomies have been shown to prevent breast cancer in high-risk individuals, such as patients with BRCA1 or BRCA2 gene mutations.
Medications
Hormonal therapy has been used for chemoprevention in individuals at high risk for breast cancer. 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.[45][46]
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%.[47] 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).[48][49] The Italian trial showed benefit from tamoxifen.[50]
Additional randomized controlled trials have been published since the guidelines. The IBIS trial found benefit from tamoxifen. [51]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.[52] 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".[53]
Raloxifene is only FDA-approved for osteoporosis as of May 2007.
Screening
X-ray mammography
Due to the high incidence of breast cancer among older women, screening is now recommended in many countries. Recommended screening methods include breast self-examination and mammography. Mammography has been estimated to reduce breast cancer-related mortality by 20-30%.[54] Routine (annual) mammography of women older than age 40 or 50 is recommended by numerous organizations as a screening method to diagnose early breast cancer and has demonstrated a protective effect in multiple clinical trials.[55] 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. Report of the International Workshop on Screening for Breast Cancer, Fletcher SW, Black W, Harris R, Rimer BK, Shapiro S, , , J. Natl. Cancer Inst., 1993
CAD Systems (Computer Aided Diagnosis) may help radiologists to evaluate X-ray images to detect breast cancer in an early stage. CAD is especially established in US and the Netherlands. It is used in addition to the human evaluation of the diagnostician.
Improvements in mortality due to screening are hard to measure; similar difficulty exists in measuring the impact of Pap smear testing on cervical cancer, though worldwide, the impact of that test is likely enormous. Nationwide mortality due to cancer before and after the institution of a screening test is a surrogate indicator about the effectiveness of screening, and results of mammography are favorable.
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 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.
Part of the difficulty in interpreting mammograms in younger women stems from the problem of breast density. Radiographically, a dense breast has a preponderance of glandular tissue, and younger age or estrogen hormone replacement therapy contribute to mammographic breast density. After menopause, the breast glandular tissue gradually is replaced by fatty tissue, making mammographic interpretation much more accurate. Some authors speculate that part of the contribution of estrogen hormone replacement therapy to breast cancer mortality arises from the issue of increased mammographic breast density. Breast density is an independent adverse prognostic factor on breast cancer prognosis.
Several scientific groups however have expressed concern about the public's perceptions of the benefits of breast screening.[56] In 2001, a controversial review published in The Lancet claimed that ''there is no reliable evidence that screening for breast cancer reduces mortality''.[57] The results of this study were widely reported in the popular press.[58]
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, and four biopsies will be necessary, to diagnose one cancer. Recall rates are higher in the U.S. than in the UK.[59] 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.
In general, digital mammography and computer-aided mammography have increased the sensitivity of mammograms, but at the cost of more numerous false positive results.
Mammography is still the modality of choice for screening of early breast cancer, since it is relatively fast, reasonably accurate, and widely available in developed countries. Breast cancers detected by mammography are usually much smaller (earlier stage) than those detected by patients or doctors as a breast lump.
Breast MRI
Magnetic resonance imaging (MRI) has been shown to detect cancers not visible on mammograms, but has long been regarded to have disadvantages. For example, although it is 27-36% more sensitive, it is less specific than mammography.[60] 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:[61]
★ Strong family history of breast cancer
★ Patients with BRCA-1 or BRCA-2 oncogene 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
However, two studies published in 2007 demonstrated the strengths of MRI-based screening:
★ In March 2007, an article published in the ''New England Journal of Medicine'' demonstrated that in 3.1% of patients with breast cancer, whose contralateral breast was clinically and mammographically tumor-free, MRI could detect breast cancer. Sensitivity for detection of breast cancer in this study was 91%, specificity 88%.[62]
★ In August 2007, an article published in ''The Lancet'' compared MRI breast cancer screening to conventional mammographic screening in 7,319 women. MRI screening was highly more sensitive (97% in the MRI group vs. 56% in the mammography group) in recognizing early high-grade Ductal Carcinoma in situ (DCIS), the most important precursor of invasive carcinoma. Despite the high sensitivity, MRI screening had a positive predictive value of 52%, which is totally accepted for cancer screening tests.[63] The author of a comment published in the same issue of ''The Lancet'' concludes that "MRI outperforms mammography in tumour detection and diagnosis."[64]
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.
Breast self-exam
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, reported in the ''Journal of the National Cancer Institute'' first in 1997 and updated in 2002, 132,979 female Chinese factory workers were taught by nurses at their factories to perform monthly breast self-exam, while 133,085 other workers were not taught self-exam. The women taught self-exam tended to detect more breast nodules, but their breast cancer mortality rate was no different from that of women in the control group. 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.[65] An editorial in the Journal of the National Cancer Institute reported in 2002, "Routinely Teaching Breast Self-Examination is Dead. What Does This Mean?"[66]
Diagnosis
Breast cancer is diagnosed 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.
Staging
Breast cancer is staged according to the TNM system, updated in the AJCC Staging Manual, now on its sixth edition. 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 involve axillary lymph nodes (N).
★ ''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+).[67] Receptor status modifies the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are sensitive to hormonal therapy.
The breast cancer is also usually tested for the presence of human epidermal growth factor receptor 2, a protein also known as 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. When activated in cancer cells, HER2 accelerates tumor formation. About 20-30% of breast cancers overexpress HER2. Those patients may be candidates for the drug trastuzumab, both in the postsurgical setting (so-called "adjuvant" therapy), and in the metastatic setting.[68]
Treatment personalization with 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. There are currently 2 commercial tests on the market, MammaPrint and Oncotype DX. 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, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.
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 2007, 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 5 or 10 years, this could help influence how aggressively the initial tumor is treated.[69]
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.
Lumpectomy techniques are increasingly utilized for breast-conservation cancer surgery. However, 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 the 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 removed tissue does not have clear margins, 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 10 to 40 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. Sentinel Lymph Node Biopsy for Breast Cancer and Melanoma, , , , Oncology Issues, 2006
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 involves using high-powered X-rays or gamma rays (XRT) that precisely target the area being treated. These X-rays or gamma rays are very effective in destroying the cancer cells that might recur where the tumor was removed. The 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. Radiation therapy for breast cancer is usually performed after surgery 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 eliminates the microscopic cancer cells that may remain near the area where the tumor was surgically removed. The dose of radiation must be strong enough to ensure the elimination of cancer cells. However, radiation affects normal cells and cancer cells alike, causing some damage to the normal tissue around where the tumor was. Healthy tissue can repair itself, while cancer cells do not repair themselves as well as normal cells. For this reason, radiation treatments are given over an extended period, enabling the healthy tissue to heal. Treatments are typically given over a period of five to seven weeks, performed five days a week. Each treatment takes about 15 minutes.
Although radiation therapy can reduce the chance of breast cancer recurrence, it is much less effective in prolonging patient survival. According to a review of six studies by the National Cancer Institute, none of them found a survival benefit for radiation therapy.[70] 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' when the whole breast is not removed (lumpectomy or wide local excision)
★ 'After mastectomy': Patients with higher chances of cancer recurring because of conditions such as a large primary tumor or involvement of four 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. The most common delivery method is linear accelerators.
There have been many 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.
New technology has also allowed more precise delivery of radiotherapy in a portable fashion — for example in the operating theatre. Targeted intraoperative radiotherapy (TARGIT)[71] 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 to test whether it can replace the whole course of radiotherapy in selected patients. Protocol 99PRT/47 Targeted Intraoperative radiotherapy (Targit) for breast cancer Vaidya J, Tobias J, Baum M, Houghton J It may also be able provide a much better boost dose to the tumor bed and appears to provide superior control. Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost, Vaidya J, Baum M, Tobias J, Massarut S, Wenz F, Murphy O, Hilaris B, Houghton J, Saunders C, Corica T, Roncadin M, Kraus-Tiefenbacher U, Melchaert F, Keshtgar M, Sainsbury R, Douek M, Harrison E, Thompson A, Joseph D, , , Int J Radiat Oncol Biol Phys, 2006 This will be tested in a TARGIT-B trial.[72]
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
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.
''See breast cancer chemotherapy.''
Hormonal treatment
Patients with estrogen receptor positive tumors will typically receive hormonal therapy 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
Targeted therapy
In patients whose cancer expresses an over-abundance of the HER2 protein, a monoclonal antibody known as trastuzumab (Herceptin ®) is used to block the activity of the HER2 protein in breast cancer cells, slowing their growth.
In the advanced cancer setting, trastuzumab use in combination with chemotherapy can both delay cancer growth as well as improve the recipient's survival.[73]
More recently, several clinical trials have also confirmed that in the adjuvant setting i.e. postoperative following breast cancer surgery, the use of trastuzumab for up to one year also delays the recurrence of breast cancer and improves survival.[74][75][76]
Antiangiogenic therapy
A commercially available monoclonal antibody that blocks the activation of the VEGF receptor, bevacizumab, underwent testing in a randomized clinical trial whose preliminary results were announced by the National Cancer Institute in 2005.[77] The preliminary data indicated 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.
Preclinical
Protein tyrosine phosphatase 1B (PTP1B)
In the March 2007, edition of the scientific journal, ''Nature Genetics'', 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 protein tyrosine phosphatase 1B (PTP1B), which has been implicated in the onset of breast cancer in mouse models of the disease.[78] Elevated levels of PTP1B have also been found in diabetes and obesity. A drug to block the activity of PTP1B 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.[79]
Flax seeds
Preliminary research into flax seeds indicate that flax can significantly change breast cancer growth and metastasis, and enhance the inhibitory effect of tamoxifen on estrogen-dependent tumors.[80][81][82][83]
Traditional Chinese medicine
The use of traditional Chinese medicine to treat breast cancer has been claimed, but no successful clinical trials have yet been reported.
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.
Prognosis
There are several prognostic factors associated with breast cancer. Stage is the most important, as it takes into consideration local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the worse the prognosis. Breast cancer patients whose lymph nodes are cancer-free have a much better prognosis than those whose lymph nodes are positive for cancer.
The presence of estrogen and progesterone receptors in the cancer cell is another important prognostic factor which 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.
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.[84] 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. Carcinoma of the Male Breast - General Considerations Armando E. Giuliano, MD 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.
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.
Breast cancer can also spread to other parts of the body via blood vessels. So it can spread to the lungs, pleura (the lining of the lungs), liver, brain, and most commonly to the bones. 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. Usually when breast cancer spreads to bone, it eats away healthy bone, causing weak spots, where the bones can break easily. That is why breast cancer patients are often seen wearing braces or using a wheelchair, and why they complain about aching bones.
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. Like normal breast cells, these tumors in the bone often thrive on female hormones, especially estrogen. Therefore, the doctor often treats the patient with medicines that lower her estrogen levels.
Breast cancer awareness
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 sufferers face when battling the cancer.
Pink for October is an initiative started by Matthew Oliphant, which asks that any sites willing to help make people aware of breast cancer, change their template or layout to include the color pink, so that when visitors view the site, they see that the majority of the site is pink. Then after reading a short amount of information about breast cancer, or being redirected to another site, they are aware of the disease itself.
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
★ Mammary tumor for breast cancer in other animals
★ Breast reconstruction
★ Alcohol and cancer
★ Mammography Quality Standards Act
★ National Breast Cancer Coalition
★ National Comprehensive Cancer Network
★ Breast Cancer Action
★ Breakthrough Breast Cancer
★ Barron Lerner (Physician)
★ William Stewart Halsted (Radical Masectomy)
★ International Agency for Research on Cancer
★ The Hormone Foundation
★ Susan G. Komen for the Cure
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External links
★
General
★ John's Hopkins Breast Cancer Center
★ American Cancer Society - Learn About Breast Cancer Page
★ History of breast cancer treatment
★ The Breast: Neoplasms of the Breast
★ Breast Cancer Care (UK charity)
★ Abortion and Breast Cancer
★ National Cancer Institute: Breast Cancer
★ Breast Cancer Campaign (UK research charity)
★ Imaginis -Award winning Breast Cancer site
Research and statistics
★ Breast cancer incidence by country
★ eMaxHealth Breast Cancer Publishes Research News on Breast Cancer from Research Institutions and Universities
Clinical
★ RadiologyInfo - The radiology information resource for patients: Breast Cancer
★ Surgery Choices for Women with Early-Stage Breast Cancer, National Cancer Institute
★ Mastectomy vs.n Lumpectomy: Who Decides?, National Research Center for Women & Families
★ Australia: ''Cancer Control Bulletin'' Alcohol and cancer risk
★ Cornell University Alcohol and the Risk of Breast Cancer
Videos
★ Health Video: Breast Cancer - Overview, Prevention and Treatment
★ Early-onset Breast Cancer among Black Women
Other
★ Mayo Clinic: How the grading system for cancerous tumors was developed.
★ Interviews with Breast Cancer Experts
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