Breast cancer

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Breast cancer
ICD-10 C50
ICD-9 174-175
OMIM 114480
DiseasesDB 1598
MedlinePlus 000913
MeSH D001943

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-In-Chief: Jack Khouri

Overview

Classification

Major Scheme | Staging | Pathologic Types | Histologic Types

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.[1]

Signs and 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.

Epidemiology and etiology

Main article: Epidemiology and etiology of Breast cancer

Epidemiological risk factors for a disease can provide important clues as to the etiology of a disease. The first work on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.

Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors.

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

The primary risk factors that have been identified are sex,[4] age,[5] childbearing, hormones,[6] a high-fat diet,[7] alcohol intake,[8] obesity,[9] and environmental factors such as tobacco use and radiation.[10]

Prevention

Phytoestrogens and soy

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

  1. Plant estrogen intake, such as from soy products, in early adolescence may protect against breast cancer later in life.[11]
  2. Plant estrogen intake later in life is not likely to influence breast cancer incidence either positively or negatively.[12]

It seems reasonable to conclude that soybean-based phytoestrogens are not a major contributor to the incidence of breast cancer.

Folic acid (folate)

Main article: Folic acid

Studies have found that "folate intake counteracts breast cancer risk associated with alcohol consumption"[13] and "women who drink alcohol and have a high folate intake are not at increased risk of cancer."[14][15][16] A prospective study of over 17,000 women found that those who consume 40 grams of alcohol (about 3-4 drinks) per day have a higher risk of breast cancer. However, in women who take 200 micrograms of folate (folic acid or Vitamin B9) every day, the risk of breast cancer drops below that of alcohol abstainers.[17]

Folate is involved in the synthesis, repair, and functioning of DNA, the body’s genetic map, and a deficiency of folate may result in damage to DNA that may lead to cancer.[18] In addition to breast cancer, studies have also associated diets low in folate with increased risk of pancreatic, and colon cancer.[19][20]

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.

Oophorectomy and mastectomy

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%.[21]

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 US Preventive Services Task Force (USPSTF) recommended that "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.[22][23][24]

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%.[25] 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).[26][27] The Italian trial showed benefit from tamoxifen.[28]

Additional randomized controlled trials have been published since the guidelines. The IBIS trial found benefit from tamoxifen.[29] 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.[30] 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".[31] On September 14, 2007, Steven Galson, director, US Food and Drug Administration's Center for Drug Evaluation and Research announced approval of the sale of raloxifene to prevent invasive breast cancer in postmenopausal women.[32]

Screening

X Ray Mammography | Breast MRI | Breast Ultrasound | Self Exam | Genetic Testing

Diagnosis

Breast cancer is diagnosed by the 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 excision. 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, Cat scan, 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 American Joint Committee on Cancer (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+).[33] 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.[34]

Treatment

Main article: Breast cancer 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.[35]

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.

Psychological aspects of 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.

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.

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.The writing says about the disease, "There is no treatment."[36] 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.

Cultural references

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.

The patron saint of breast cancer is Saint Agatha of Sicily.

Related Chapters

References

  1. ↑ Giordano SH, Hortobagyi GN (2003). "Inflammatory breast cancer: clinical progress and the main problems that must be addressed". Breast Cancer Res. 5 (6): 284–8. doi:10.1186/bcr608. PMID 14580242. Free Full Text.
  2. ↑ Cavalieri E, Chakravarti D, Guttenplan J; et al. (2006). "Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention". Biochim. Biophys. Acta. 1766 (1): 63–78. doi:10.1016/j.bbcan.2006.03.001. PMID 16675129.
  3. ↑ Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN (1995). "Proportion of breast cancer cases in the United States explained by well-established risk factors". J. Natl. Cancer Inst. 87 (22): 1681–5. PMID 7473816. |access-date= requires |url= (help)
  4. ↑ Giordano, Sharon H (May 2004). "Breast carcinoma in men". Cancer. American Cancer Society. 101 (1): 51–57. Unknown parameter |coauthors= ignored (help)
  5. ↑ "Individual Risk Factors". BreastCancer.org. Retrieved 2007-03-11.
  6. ↑ Yager JD (2006). "Estrogen carcinogenesis in breast cancer". New Engl J Med. 354 (3): 270–82. PMID 16421368. Unknown parameter |coauthors= ignored (help)
  7. ↑ Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A, Hoy MK; et al. "Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women's Intervention Nutrition Study (WINS)". J Natl Cancer Inst. 98 (24): 1767–1776. PMID 17179478.
  8. ↑ Boffetta, Paolo (2006-03-23). "The burden of cancer attributable to alcohol drinking". International Journal of Cancer. Wiley-Liss, Inc. 119 (4): 884–887. doi:10.1002/ijc.21903. PMID 16557583. Retrieved 2006-10-09. Unknown parameter |coauthors= ignored (help)
  9. ↑ BBC report Weight link to breast cancer risk
  10. ↑ ACS (2005). "Breast Cancer Facts & Figures 2005-2006" (PDF). Retrieved 2007-04-26.
  11. ↑ Rice S, Whitehead SA (2006). "Phytoestrogens and breast cancer--promoters or protectors?". Endocr. Relat. Cancer. 13 (4): 995–1015. doi:10.1677/erc.1.01159. PMID 17158751.
  12. ↑ Gikas PD, Mokbel K. (2005Phytoestrogens and the risk of breast cancer: a review of the literature. Int J Fertil Women's Med.
  13. ↑ Mayo Clinic news release June 26 2001 "Folate Intake Counteracts Breast Cancer Risk Associated with Alcohol Consumption"
  14. ↑ Boston University,Folate, Alcohol, and Cancer Risk
  15. ↑ Bailey, L.B. Folate, methyl-related nutrients, alcohol and the MTHFR 677C -> T polymorphous affect cancer risk: intake recommendations. Journal of Nutrition, 2003, 133, 37485-37535
  16. ↑ Zhang S, Hunter D, Hankinson S, Giovannucci E, Rosner B, Colditz G, Speizer F, Willett W (1999). "A prospective study of folate intake and the risk of breast cancer". JAMA. 281 (17): 1632–7. PMID 10235158.
  17. ↑ Baglietto, Laura, et al. Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study. British Medical Journal, August 8, 2005
  18. ↑ Jennings E. (1995). "Folic acid as a cancer preventing agent". Medical Hypotheses. 45 (3): 297–303. PMID 8569555.
  19. ↑ Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC. (1998). "Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study". Annals of Internal Medicine. 129 (7): 517–524. PMID 9758570.
  20. ↑ name="Oldref_42">Freudenheim JL, Grahm S, Marshall JR, Haughey BP, Cholewinski S, Wilkinson G (1991). "Folate intake and carcinogenesis of the colon and rectum". International Journal of Epidemiology. 20 (2): 368–374. PMID 1917236.
  21. ↑ 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 (2002). "Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation". N Engl J Med. 346 (21): 1609–15. PMID 12023992.
  22. ↑ "Guide to Clinical Preventive Services, Third Edition: Periodic Updates, 2000-2003". Agency for Healthcare Research and Quality. US Preventive Services Task Force. Retrieved 2007-10-07.
  23. ↑ "Chemoprevention of breast cancer: recommendations and rationale". Ann. Intern. Med. 137 (1): 56–8. 2002. PMID 12093249.
  24. ↑ Kinsinger LS, Harris R, Woolf SH, Sox HC, Lohr KN (2002). "Chemoprevention of breast cancer: a summary of the evidence for the U.S. Preventive Services Task Force". Ann. Intern. Med. 137 (1): 59–69. PMID 12093250.
  25. ↑ Cummings SR, Eckert S, Krueger KA; et al. (1999). "The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation". JAMA. 281 (23): 2189–97. PMID 10376571.
  26. ↑ Fisher B, Costantino JP, Wickerham DL; et al. (2005). "Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study". J. Natl. Cancer Inst. 97 (22): 1652–62. doi:10.1093/jnci/dji372. PMID 16288118.
  27. ↑ Fisher B, Costantino JP, Wickerham DL; et al. (1998). "Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study". J. Natl. Cancer Inst. 90 (18): 1371–88. PMID 9747868.
  28. ↑ Veronesi U, Maisonneuve P, Rotmensz N; et al. (2007). "Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy". J. Natl. Cancer Inst. 99 (9): 727–37. doi:10.1093/jnci/djk154. PMID 17470740.
  29. ↑ Cuzick J, Forbes JF, Sestak I; et al. (2007). "Long-term results of tamoxifen prophylaxis for breast cancer--96-month follow-up of the randomized IBIS-I trial". J. Natl. Cancer Inst. 99 (4): 272–82. doi:10.1093/jnci/djk049. PMID 17312304.
  30. ↑ Vogel VG, Costantino JP, Wickerham DL; et al. (2006). "Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial". JAMA. 295 (23): 2727–41. doi:10.1001/jama.295.23.joc60074. PMID 16754727.
  31. ↑ Barrett-Connor E, Mosca L, Collins P, et al Raloxifene Use for The Heart (RUTH) Trial Investigators. (2006). "Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women". N. Engl. J. Med. 355 (2): 125–37. doi:10.1056/NEJMoa062462. PMID 16837676.
  32. ↑ AFP.google.com, US approves Lilly's Evista for breast cancer prevention
  33. ↑ Rusiecki JA, Holford TR, Zahm SH, Zheng T. Breast cancer risk factors according to joint estrogen receptor and progesterone receptor status. Cancer Detect Prev 2005;29:419-26
  34. ↑ accessed 1/30/07 cancer.gov
  35. ↑ "FDA Approves New Breast Cancer Test". Associated Press, February 6, 2007.
  36. ↑ "The History of Cancer". American Cancer Society. 2002-03-25. Retrieved 2006-10-09.

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