Overview of Symptoms, Diagnosis, Screening & Prevention of Breast Cancer

Learn who's at risk and how breast cancer is diagnosed and prevented

Overview of Breast Cancer

Medically reviewed by Dr.C.H. Weaver M.D. 8/2018

Breast cancer is a common cancer, with more than 232,000 individuals diagnosed in the United States each year.[1] The disease occurs most frequently in women, but can also occur in men.

The normal breast has 6 to 9 overlapping sections called lobes and within each lobe are several smaller lobules that contain the cells that produce milk. The lobes and lobules are linked by thin tubes called ducts, which lead to the nipple in the center of the breast. The spaces around the lobules and ducts are filled with fat. Lymph vessels carry colorless fluid called lymph, which contains important immune cells. The lymph vessels lead to small bean-shaped structures called lymph nodes. Clusters of lymph nodes are found in the axilla (under the arm), above the collarbone, and in the chest.

A breast cancer begins when healthy cells in the breast change and grow out of control. Most breast cancers start in the ducts or lobes and are called ductal carcinoma or lobular carcinoma. Although breast cancer most commonly spreads to nearby lymph nodes, it can also spread further through the body to areas such as the bones, lungs, liver, and brain. When breast cancer spreads to other parts of the body or when breast cancer cells move to other parts of the body through the blood vessels and/or lymph vessels. This is called metastasis.

As a result of advocacy and advances in scientific knowledge our understanding of breast cancer continues to evolve. In recent years we have witnessed a steady improvement in the early detection of breast cancer, the prevention of breast cancer in high-risk individuals through genetic testing, and improved outcomes of individuals with both early and advanced stage disease. There is indeed much to be optimistic about.[1],[2]

Symptoms & Signs of Breast Cancer

The suspicion of breast cancer often first arises when a lump is detected in the breast during breast examination or a suspicious area is identified during screening mammography. In order to diagnose the cause of the suspicious area or lump in the breast, a physician will perform a biopsy. Other signs and symptoms of breast cancer include:

  • Skin Changes with the Breast- skin can feel itchy develop redness in color. With inflammatory breast cancer, swelling and a dimpled look to the skin may occur.
  • Swelling- may occur as the cancer grows.
  • Nipple Discharge- Any type of fluid that comes from the nipple; yellow, the color of blood.
  • Pain- in the breast can be a warning.

What Causes Breast Cancer?

There are many types of breast tumors. Some breast tumors are benign (not cancerous). Benign breast tumors such as fibroadenomas or papillomas do not spread outside of the breast and are not life threatening. Other breast tumors are malignant (cancerous). The most common type of breast cancer is called ductal carcinoma and begins in the lining of the ducts. Another type of cancer is called lobular carcinoma, which arises in the lobules.

Breast cancer can be invasive or noninvasive. Invasive breast cancer is cancer that spreads into surrounding tissues. Noninvasive breast cancer does not go beyond the milk ducts or lobules in the breast.

  • Ductal carcinoma. Starts in the cells lining the milk ducts and make up the majority of breast cancers.
    • Ductal carcinoma in situ (DCIS). This is cancer that is located only in the duct.
    • Invasive or infiltrating ductal carcinoma. This is cancer that has spread outside of the duct.
  • Lobular carcinoma. Starts in the lobules.
    • Lobular carcinoma in situ (LCIS). LCIS is located only in the lobules. LCIS is not considered cancer.
  • Inflammatory breast cancer is a faster growing more aggressive cancer accounting for ~ 5% of all breast cancers.

Less common types of breast cancer include:

  • Medullary
  • Mucinous
  • Tubular
  • Metaplastic
  • Papillary breast cancer

Genetics is extremely important; women with a family history of breast cancer in a first degree relative (mother, sister, or daughter) have an increased risk of breast cancer and often have inherited genes that increase their risk of developing breast cancer.[1],[2]

Risk Factors for Developing Breast Cancer

  • Older age
  • A personal history of breast cancer or benign (non-cancer) breast disease
  • Family history of breast cancer
  • Genetic risk: BRCA1 and BRCA2 genes
  • Dense breasts
  • Exposure of breast tissue to estrogen made in the body
  • Taking hormone therapy for symptoms of menopause
  • Prior radiation therapy to the breast or chest
  • Obesity
  • Drinking alcohol

Diagnosis & Tests for Breast Cancer

If a suspicious or a precancerous lesion is found in the breast, a biopsy and additional tests will be recommended to determine whether invasive cancer exists.

A biopsy can be performed on an outpatient basis. During a biopsy, a physician removes cells for examination in the laboratory to determine whether cancer is present. If the biopsy indicates that cancer is present, additional surgery may be performed after a course of treatment is selected.

When cancer is identified in the biopsy specimen, several other tests should also be performed on the specimen in order to further classify the cancer and determine the optimal treatment strategy. Based on the stage of the cancer and the results of these tests, treatment of breast cancer is personalized for each individual. Precision treatment may involve surgery, radiation therapy, systemic treatment with precision cancer medicines or chemotherapy, and/or hormonal therapy.

Diagnostic Tests that are used to Find Breast Cancer

  • Mammogram: An x-ray is taken when the breast is pressed between two plates.
  • Ultrasound: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram.
  • Magnetic Resonance Imaging (MRI) A procedure that uses a magnet and radio waves to take a very detailed picture of both breasts. There are four types of biopsy used to check for breast cancer:

Types of Biopsies Used to Evaluate Breast Cancer

  • Excisional biopsy removes an entire lump of breast tissue.
  • Incisional biopsy removes part of a lump or a sample of breast tissue.
  • Core biopsy removes tissue using a wide needle.
  • Fine Needle Aspiration (FNA) biopsy removes tissue or fluid, using a thin needle.

Initial Staging of Breast Cancer

Stage is a measure of the extent of spread of the cancer. The first step in staging is to evaluate the cancer for “local” spread by assessing for the presence or absence of local axillary (under the arm) lymph node metastases adjacent to the breast. This may be assessed through either sentinel lymph node biopsy or axillary lymph node dissection.

Axillary lymph node dissection involves the removal of many axillary lymph nodes; the procedure can be associated with chronic side effects such as pain, limited shoulder motion, numbness, and swelling.

Sentinel lymph node biopsy involves the removal of only a small number of nodes, or even a single node. If the sentinel lymph nodes are negative (show no evidence of cancer), then no further lymph node surgery is required. Sentinel lymph node biopsy is becoming more widely adopted in the clinical setting for determining whether cancer has spread to the lymph nodes in women with localized breast cancer.

Precision Medicine & Personalized Breast Cancer Care

The purpose of precision cancer medicine is to define the genomic alterations in the cancers DNA that are driving that specific cancer. Breast cancer used to be diagnosed solely by a visual microscopic examination of tumor tissue and patients received the same chemotherapy. Precision cancer medicine utilizes molecular diagnostic & genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines are being developed for the treatment of breast cancer and patients should ask their doctor about whether testing is appropriate.

HER2 status: Twenty to thirty percent of breast cancers overexpress (make too much of) a protein known as HER2. Overexpression of this protein leads to increased growth of cancer cells. Fortunately, the development of treatments that specifically target HER2-positive cells has improved outcomes among women with HER2-positive breast cancer. For this reason, HER2 status should be accurately measured on all breast cancers.[1]

Hormone receptor status: Some breast cancer cells express an abundance of receptors for the female hormones estrogen and/or progesterone. These cancers– called hormone receptor-positive –are typically associated with a better prognosis and are treated differently from breast cancers that are hormone receptor-negative. Patients with hormone receptor-positive breast cancer often receive treatment with hormonal therapy, such as tamoxifen or an aromatase inhibitor. For more information, go to Hormonal Therapy.

Multigene Tests to Predict Recurrence: Among women with early-stage breast cancer, the expression, or activity, of certain genes has been linked with the likelihood of cancer recurrence.

  • Oncotype DX is a genomic test that predicts risk of recurrence among selected women with early-stage breast cancer, including women with ductal carcinoma in situ (DCIS).[3]
  • Mammaprint helps predict if early stage node negative breast cancer will spread to other parts of the body. If the risk that the cancer will spread is high, chemotherapy may be given to lower the risk.[4]

Use of these tests may help guide decisions about whether about additional treatment with chemotherapy or radiation therapy is necessary after surgery.

Triple Negative Breast Cancer: Approximately 12% of breast cancers are triple-negative breast cancers, meaning that they are estrogen-receptor negative (ER-), progesterone-receptor negative (PR-), and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones estrogen or progesterone, nor through an overactive HER2 pathway.

Additional tests are necessary to determine if the cancer has spread beyond the breast to other parts of the body.

  • Chest x-ray: is a picture of the bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body.
  • Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue than a CT. An MRI gives a better picture of cancer located near bone than does CT, does not use radiation, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the cancer.
  • Positron emission tomography (PET): Positron emission tomography scanning is an advanced technique for imaging body tissues and organs. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons) that create the production of gamma rays that can be detected by the PET machine to produce a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.
  • Bone Scan: A test to check if there are cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones and is detected by a scanner.

Stages of Breast Cancer

Carcinoma In Situ: Approximately 15-20% of breast cancers are very early in their development. These are sometimes referred to as carcinoma in situ and consist of two types: ductal carcinoma in situ (DCIS), which originates in the ducts and lobular carcinoma in situ (LCIS), which originates in the lobules. DCIS is the precursor to invasive cancer and LCIS is a risk factor for developing cancer.

Stage I: Cancer is confined to a single site in the breast, is less than 2 centimeters (3/4 inch) in size and has not spread outside the breast.

Stage IIA: Cancer has spread to involve underarm lymph nodes and is less than 2 centimeters (3/4 inch) in size or the primary cancer itself is 2-5 centimeters (3/4-2 inches) and has not spread to the lymph nodes

Stage IIB: Cancer has spread to involve underarm lymph nodes and/or the primary cancer is greater than 5 centimeters (2 inches) in size and does not involve any lymph nodes.

Stage IIIA: Cancer is smaller than 5 centimeters (2 inches) and has spread to the lymph nodes under the arm or the lymph nodes are attached to each other or to other structures or the primary cancer is larger than 5 centimeters (2 inches) and has spread to the lymph nodes under the arm.

Stage IIIB: Cancer directly involves the chest wall or has spread to internal lymph nodes on the same side of the chest.

Inflammatory: Inflammatory breast cancer is a special class of breast cancer that is rare. The breast looks as if it is inflamed because of its red appearance and warmth. The skin may show signs of ridges and wheals or it may have a pitted appearance. Inflammatory breast cancer tends to spread quickly.

Stage IV: Cancer has spread to distant locations in the body, which may include the liver, lungs, bones or other sites.

Recurrent/Relapsed: The breast cancer has progressed or returned (recurred/relapsed) following an initial treatment.

Screening/Prevention of Breast Cancer

Information about the prevention of cancer and the science of screening appropriate individuals at high risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best “treatment” of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable.

Breast cancer is the second leading cause of cancer death in women in the United States. Progress in the areas of screening and treatment may allow for earlier detection and higher cure rates.

The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person’s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (e.g. the correlation between smoking and lung cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer.

Heredity or Genetic Factors

Being Female: Of the close to 200,000 new diagnoses of breast cancer in the United States each year, 99 percent occur in women.[1] For both women and men, risk of breast cancer increases with age.

Family History: Women with a family history of breast cancer have an increased risk of developing breast cancer themselves. In addition, some families are at particularly high risk of cancer due to hereditary cancer syndromes. These families often have multiple family members with cancer, and are more likely to develop cancer at a young age. In the case of breast and ovarian cancers, inherited mutations in two genes – BRCA1 and BRCA2 – have been found to greatly increase the lifetime risk of developing breast and ovarian cancer. Alterations in these genes can be passed down through either the mother’s or the father’s side of the family.

Breast Density: Breast density refers to the extent of glandular and connective tissue in the breast. Breasts with more glandular and connective tissue—and less fat—are denser. Women with higher breast density are at increased risk of developing breast cancer. In addition, dense breasts make it more difficult to detect breast cancer by mammography.[2]

Personal History of Breast Cancer or Benign Breast Disease: It is important to realize the women who have been cured of a primary breast cancer are at increased risk for breast cancer in the opposite breast and that this risk persists for 20 years or more.[3] Women with certain types of benign breast disease (such as atypical hyperplasia) also have an increased risk of developing breast cancer.[4]

Environmental or Non-Genetic Factors

Reproductive Factors: Several reproductive factors have been associated with an increased incidence of breast cancer. These include an early age at first menstrual cycle, a late age at menopause, and a late age at the birth of the first child.

Exposure to Estrogen: Estrogen is a hormone that helps the body develop and maintain female sex characteristics. Being exposed to estrogen over a long time may increase the risk of breast cancer. Estrogen levels are highest during the years a woman is menstruating.[5]

A woman’s exposure to estrogen is increased in the following ways:

  • Early Onset of Menstruation: Beginning at age 11 or younger increases the number of years the breast tissue is exposed to estrogen.
  • Late Onset of Menopause: The more years a woman menstruates, the longer her breast tissue is exposed to estrogen.
  • Older age at first birth or never having given birth: Because estrogen levels are lower during pregnancy, breast tissue is exposed to more estrogen in women who become pregnant for the first time after age 35 or who never become pregnant.

Postmenopausal Hormone Use

Estrogen and progesterone can be made into a pill form and given to replace the estrogen no longer made by the ovaries in postmenopausal women or those who have had their ovaries removed. This is called hormone replacement therapy (HRT). HRT can increase the risk of developing breast cancer. Results from the Women’s Health Initiative suggest that postmenopausal HRT with a combination of estrogen and progestin increases the risk of breast cancer.[5] Furthermore, as use of postmenopausal hormones has declined, breast cancer incidence has also declined;[6] this provides additional support for a link between postmenopausal hormone use and risk of breast cancer.

Alcohol: Moderate alcohol consumption (often defined as two or more drinks per day) has consistently been linked with an increased risk of breast cancer.[7]

Obesity: In premenopausal women, obesity has been linked with a decreased risk of breast cancer, possibly as a result of disrupted menstrual cycles and altered hormone levels. In postmenopausal women, however, obesity has consistently been linked with an increased risk of breast cancer. The link between obesity and postmenopausal breast cancer appears to be strongest among women who have never used postmenopausal hormone therapy,[8],[9] and may be explained by the higher estrogen levels in obese postmenopausal women. A recent study has shown that weight gain in women during adult life increases the risk of postmenopausal breast cancer.[10]

Radiation: Women who have received radiation to the chest for the treatment of Hodgkin’s lymphoma or other cancers appear to have an increased risk of breast cancer. A study has also shown that women who have received low or high dose radiation to the chest have an increased risk of developing breast cancer.[11] Therapeutic doses of radiation have long been known to increase the risk of developing breast cancer. However, this study suggests that diagnostic procedures, such as periodic chest X-rays, can also increase the risk of developing breast cancer.

DES: Diethylstilbestrol (DES) is a synthetic estrogen that was used frequently in pregnant women between the 1940s and 1960s. The drug was used to reduce the risk of miscarriages, though later studies indicated that it most likely had no effect on miscarriage risk. In 1971 a study reported that girls born to women who had used DES (DES daughters) had a greatly increased risk of developing a certain type of vaginal cancer. More recent research suggests that DES daughters may also have an increased risk of breast cancer.[12]

Lack of Exercise: Many studies have shown that women who exercise more have a lower risk of developing breast cancer than women with little physical activity. One study involving over 100,000 women reported that long-term physical activity lowers the risk of developing breast cancer by one third.[13] A study from Europe found that physical exercise reduced the risk of postmenopausal breast cancer by 20-80%.[14]

Prevention

Although many questions remain about the causes and prevention of breast cancer, research suggests that certain behaviors are likely to reduce risk.

Limit Alcohol Consumption: Regular alcohol consumption has consistently been linked with a modest increase in risk of breast cancer;[15] by limiting alcohol intake women are likely to reduce their risk of breast cancer as well as several other types of cancer.

Achieve or Maintain a Healthy Body Weight: Excess body weight has been linked with an increased risk of breast cancer in postmenopausal women.[16] By achieving or maintaining a healthy weight, women can reduce their risk of breast cancer and other common, chronic health conditions.

Engage in Regular Physical Activity: Life-long physical activity is an important component of cancer prevention, and several studies suggest that regular physical activity may decrease the risk of developing breast cancer.[17]

Breastfeed: Long-term breastfeeding has been linked with a modest reduction in risk of breast cancer.[18]

Prevention for Women at High Risk

Women with a strong family history of breast cancer and women who carry the BRCA1 and BRCA2 genes are at an increased risk of developing breast cancer and may opt to take more aggressive preventive measures, such as the use of anti-estrogen therapy, prophylactic (preventive) bilateral mastectomy, and/or prophylactic oophorectomy.

Chemoprevention: Drugs that block the effects of estrogen have been shown to reduce the risk of breast cancer in women at high risk of the disease. Tamoxifen, Evista® (raloxifene) and anti-Aromatase drugs have been approved for breast cancer risk reduction in certain groups of women.[16]

  • Tamoxifen is approved for breast cancer risk reduction in women who are at high risk of the disease (including high-risk premenopausal women).
  • Evista – originally approved for the prevention and treatment of osteoporosis – is approved for breast cancer risk reduction in postmenopausal women with osteoporosis or postmenopausal women at high risk of breast cancer.
  • Anti Aromatase drugs Femara (letrozole), Aromasin (exmestane), and Arimidex (anastrozole) lower the risk of breast cancer recurrence and of new breast cancers in women who have a history of breast cancer. Aromatase inhibitors decrease the amount of estrogen made by the body.[16]

Bilateral Prophylactic Mastectomy (Preventive removal of both breasts): Women at high risk of breast cancer may reduce their risk of developing breast cancer by 90% by undergoing bilateral prophylactic mastectomy.[19] Prophylactic mastectomy is a drastic measure that may decrease emotional stress regarding the concern over developing breast cancer; however, it may also increase stress related with self-esteem, sexuality and femininity. Women considering this procedure need to weigh the benefits against the consequences, which include the irreversibility of the procedure, the psychological impact and potential problems with implants and reconstructive surgery. While this procedure can greatly decrease the risk of developing cancer, it is not a guarantee that cancer will not develop.

Prophylactic Oophorectomy (Preventive removal of the ovaries): The BRCA1 and BRCA2 genes increase the risk of both breast and ovarian cancer. Removal of the ovaries before cancer develops reduces the risk of ovarian cancer by about 96 percent.[20] Surgery doesn’t completely eliminate risk because some cells remain behind after surgery. Removal of the ovaries also reduces the risk of breast cancer since some breast cancers don’t grow well without the hormones produced by the ovaries. Women with a BRCA1 or BRCA2 alteration who have had their ovaries removed have about half the risk of developing breast cancer as those who have not had their ovaries removed. Adverse effects of prophylactic oophorectomy include the inability to have children and the development of menopausal symptoms such as hot flashes.

Screening and Early Detection

For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer.

Mammography: A mammogram is an x-ray image of the breast that can reveal irregularities and help to detect cancer early when it is most treatable. For women at average risk of breast cancer, the U.S. Preventive Services Tasks Force (USPSTF) recommends screening mammography every two years starting at the age of 50.[21] The American Cancer Society, in contrast, continues to recommend annual mammograms starting at the age of 40.[22] Women who have questions about the screening approach that’s right for them are advised to talk with their doctor. Women at high risk of breast cancer may need to begin screening at a younger age.

Clinical Breast Exam: Regular physical examination plays a vital role in the maintenance of health. An annual gynecological examination is an important screening procedure for several types of cancer and includes a physical examination of the breasts. During this procedure, a healthcare provider physically examines the breasts to feel for any lumps or irregularities.

Magnetic Resonance Imaging (MRI): MRI uses radio waves and a magnet to create detailed images of the inside of the body. The American Cancer Society recommends that women at high risk of breast cancer undergo yearly breast cancer screening with breast MRI in addition to mammography.[23] These recommendations were prompted by several studies of MRI screening of women at high risk of breast cancer. While these studies found that the addition of MRI to mammography increased the frequency of false-positive test results compared to mammography alone, it also produced important improvements in breast cancer detection.

Predictive Genetic Testing: The identification of the breast cancer susceptibility genes, BRCA1 and BRCA2, has led to predictive genetic testing for these genes. Since most breast cancers are not the result of known inherited mutations, not all women would benefit from genetic testing. However, women who appear to be at a high risk may benefit from undergoing a test to determine if they do carry the BRCA1 or BRCA2 gene. An accurate genetic test can reveal a genetic mutation, but cannot guarantee that cancer will or will not develop. At this point, genetic tests are used to identify individuals who are at an increased risk of developing cancer, so that these individuals may have the option of taking preventive measures. For more information about genetic testing, please refer to the section Genetic Testing.

References

[1] American Cancer Society. Cancer Facts & Figures 2012.

[2] cancer.gov/types/breast

[3] Mamounas E, Tang G, Bryant J, et al. Association between the 21-gene recurrence score assay (RS) and risk of locoregional failure in node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Proceedings from the 28th annual San Antonio Breast Cancer Symposium. December 8-11, 2005. Abstract # 29.

[4]Cardoso F, van’t Veer L, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. New England Journal of Medicine. 2016;375:717-729. DOI:10.1056/NEJMoa1602253. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1602253. Accessed August 29, 2016.

[1] American Cancer Society. Cancer Facts & Figures 2009. Available at: http://www.cancer.org/docroot/stt/stt_0.asp (Accessed July 14, 2009).

[2] Boyd N, Guo H, Martin L, et al. Mammographic density and the risk and detection of breast cancer. New England Journal of Medicine. 2007; 356:227-236.

[3] Hill-Kayser CE, Harris EER, et al. Twenty-year incidence and patterns of contralateral breast cancer after breast conservation treatment with radiation. International Journal of Radiation Oncology\ Biology* Physics*2006;66:1313-1319.

[4] Ghosh K, Pankratz VS, Reynolds CA et al. Benign breast disease and breast cancer risk in young women. Presented at the San Antonio Breast Cancer Symposium. December 13, 2008. Abstract 62.

[5] Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33.

[6] Ravdin P, Cronin K, Howlader N, et al. The Decrease in Breast-Cancer Incidence in 2003 in the United States. The New England Journal of Medicine. 2007; 356:1670-1674.

[7] Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE. Alcohol Consumption and Breast Cancer Risk in the Women’s Health Study. American Journal of Epidemiology 2007;165:667-76.

[8] Morimoto LM, White E, Chen Z et al. Obesity, Body Size, and Risk of Postmenopausal Breast Cancer: the Women’s Health Initiative (United States). Cancer Causes and Control. 2002;13:741-751.

[9] Lahmann PH, Hoffmann K, Allen N et al. Body Size and Breast Cancer Risk: Findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). International Journal of Cancer. 2004;111:762-71.

[10] Eliassen AH, Colditz GA, Rosner B, et al. Adult weight change and risk of postmenopausal breast cancer. Journal of the American Medical Association. 2006;296:193-201.

[11] John EM, Phipps AI, Knight JA et al. Medical radiation exposure and breast cancer risk: findings from the Breast Cancer Family Registry. International Journal of Cancer [early online publication]. March 19, 2007.

[12] Palmer JR, Wise LA, Hatch EE et al. Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer. Cancer Epidemiology Biomarkers and Prevention. 2006;15:1509-1514.

[13] Dallal CM, Sullivan-Halley J, Ross RK, et al. Long-term recreational physical activity and risk of invasive and in situ breast cancer. Archives of Internal Medicine 2007;408-415.

[14] Monninkhof EM, Elias, SG, Vlems FA, et al. Physical activity and breast cancer: A systematic review. Epidemiology 2007;18:137-157.

[15] Michels KB, Mohllajee AP, Roset-Bahmanuar E, Beehler EP, Boysich KB. Diet and Breast Cancer: A review of the prospective observational studies. Cancer Supplement. 2007; 109:2712-2749.

[16] cancer.gov/types/breast

[17] Scientific Program Committee. Physical activity across the cancer continuum: report of a workshop. Review of existing knowledge and innovative designs for future research. Cancer. 2002;95:1134-1143.

[18] Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breast feeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50,302 women with breast cancer and 96,973 women without the disease. Lancet. 2002; 20:187-195.

[19] Rebbeck TR, Friebel T, Lynch HT et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE study group. J Clin Oncol. 2004;22:1055-1062.

[20] Rebbeck TR, Lynch HT, Neuhausen SL et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346:1616-1622.

[21] U.S. Preventive Services Task Force. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine. 2009;151:716-726.

[22] American Cancer Society. American Cancer Society responds to changes to USPSTF mammography guidelines. Available at: http://www.cancer.org/docroot/MED/content/MED_2_1x_American_Cancer_Society_Responds_to_Changes_to_USPSTF_Mammography_Guidelines.asp?sitearea=MED Accessed November 17, 2009.

[23] Saslow D, Boetes C, Burke W et al. American Cancer Society Guidelines for Breast Screening with MRI as an Adjunct to Mammography. CA—A Cancer Journal for Clinicians. 2007;57:75-89.

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