What is breast cancer?

Causes and Symptoms

According to statistics published by the Centers for Disease Control and Prevention (CDC) in 2013, breast cancer is the most common malignancy in women and the second leading cause of cancer deaths in women (behind lung cancer). The National Cancer Institute (NCI) estimates that in the United States in 2014, approximately 235,000 new cases were diagnosed (2,360 in men) and approximately 40,000 deaths occurred as a consequence of the disease. A diagnosis of breast cancer may strike a profound sense of fear in a patient, but this fear can be alleviated somewhat through a better understanding of its causes and the promising treatment options and preventive strategies.

To understand breast cancer, it is first necessary to know the anatomy and structures of the breast tissue from which cancer arises. Breast tissue consists of fatty tissue and the functional tissue of the breast: the lobes and ducts that are involved in the production and secretion of milk. The arrangement of the lobes and ducts of the breast resembles the spokes of a wheel around the nipple area. Inside each lobe are multiple lobules in which the milk is produced. The milk then travels down the ducts and is released through the nipple. The growth and development of the breast tissue is controlled by hormones and begins at the time of puberty. The sex hormones progesterone and estrogen, produced by the ovaries, are largely responsible for the development of breast tissue.

The majority of breast cancers are invasive carcinomas in the ductal tissue (65 to 85 percent), and most of the rest are invasive carcinomas in the lobular tissue (about 10 percent). Many cancers are hormonally responsive, meaning that the sustained growth of the abnormal tissue is stimulated by the presence of the female sex hormones. Breast cells may undergo growth changes during the processes of tissue renewal and differentiation that ultimately may give rise to cancer.

Thus, in many ways, tumor formation in the breast may reflect aspects of the normal proliferation of newly forming ductal or lobular cells, including hormonal sensitivity. In breast cancer, however, the process goes awry, producing abnormal cells with proliferative and invasive properties that may become life-threatening. Thus, to understand how breast cancer arises, it is necessary to understand the developmental pathways of the tissue and its responses to the hormones and growth factors that regulate tissue development.

The nature of the cellular abnormalities responsible for the development of breast cancer has been the object of intense research for many years. Although the process by which malignant tumors of the breast develop remains unclear, scientists have learned a great deal about the profound cellular transformation that results in breast cancer. Tumors originate in the individual cells within the breast tissue that begin to proliferate abnormally as a direct result of genetic changes within the breast cells and/or in response to abnormal proliferative stimuli, such as hormones or other growth factors in the local environment of the breast.

Approximately 5 to 10 percent of women who develop breast cancer have inherited genetic mutations that predispose them to develop this disease. The first such mutation to be identified was in the BRCA1 gene. Carriers of this mutation have a markedly increased risk of developing breast cancer or ovarian cancer during their lifetime. Inherited mutations in a second gene, BRCA2, also produce significantly greater risks for the development of this disease. Mutations in BRCA1 and BRCA2 appear to promote the development of cancer as a result of their growth-promoting effects on breast tissue. Other genes that carry mutations associated with an increased risk of breast cancer include CDH1, STK11, and TP53.

In the vast majority of women, however, breast cancer develops in the absence of any known predisposing genetic factor. The original lesion in these cases may involve a spontaneous mutation that alters the cells’ proliferative capacity and/or sensitivity to hormonally induced signals. For patients without a family history (approximately 90 percent of women), a number of risk factors have been identified. The disease is linked to advancing age, with 66.9 percent of cases occurring in women over age fifty-five, according to the NCI's Surveillance, Epidemiology, and End Results (SEER) Program. Additional factors that may increase the risk of developing breast cancer are having one's first menstruation before age twelve, first child after age thirty-five, and menopause after age fifty-five, all of which are linked to the exposure of breast tissue to estrogen and progesterone. In fact, breast cancers can generally be divided into two groups, depending on whether or not they display sensitivity to hormonal stimulation of tumor-cell growth.

To understand further this process of malignant cell transformation, it is necessary to follow the fate of a cell along the path of malignancy. Cancer begins at the level of individual cells within a tissue that proliferates abnormally as a direct result of genetic changes and/or in response to abnormal proliferative stimuli. Abnormal cells arise in the ductal tissue of the breast in ductal carcinoma in situ (DCIS). This condition may progress to invasive infiltrating ductal carcinoma if the tumor breaks through the lining of the milk ducts and invades the fatty tissue of the breast. In the normal process of development during puberty, the ductal tissue develops in response to the hormone estrogen that is produced by the ovaries. Similarly, the growth of lobular tissue in the breast is stimulated by the hormone progesterone. Tumors that arise in this tissue are called lobular carcinoma in situ (LCIS). This type of cancer begins in the lobules that produce milk and may progress to infiltrating invasive lobular carcinoma.

During the process of development or tissue renewal, cells of the breast may undergo genetic changes that ultimately give rise to cancer. Breast cancer may take years to develop, silently progressing from a small group of abnormal cells that are no longer responsive to the “rules” governing normal cell-cycle proliferation. Over a long period, these cells may accumulate added mutations that render them even more capable of unrestricted proliferation. Target genes that frequently appear to be involved in this process include members of the epidermal growth factor receptor (EGFR) family and the estrogen receptor (ER).

By the time a tumor is palpable and can be detected as a lump by breast self-examination, the tumor may be defined as malignant based on the results of a number of diagnostic procedures. The vast majority of breast-cell abnormalities are benign, meaning that the abnormal tissue is localized in the breast and will not spread further. For example, fluid-filled cysts represent benign breast lesions, as do the cysts characteristic of fibrocystic breast disease. Mammography, a procedure involving radiography of the soft tissue of the breast, and ultrasonography, which uses sound waves to explore tissue structure, are common diagnostic tests useful for detecting the presence of small tumors in the breast and distinguishing between benign and malignant lesions. The definitive test for malignancy is the microscopic examination of affected breast tissue. This examination requires a biopsy, a procedure that involves the removal of a small amount of tissue from the breast.

The cells that make up a benign tumor generally appear very similar in morphology and appearance to normal cells of the same tissue type. In contrast, malignant cells may deviate significantly in structure, morphology, and staining properties, to the extent that the tissue of origin may not even be identifiable in tumors designated “high grade.”

At the time of diagnosis, a malignant tumor may be restricted to its site of origin, defined as a carcinoma in situ, or it may have spread within the breast or possibly to other tissues and organs of the body, such as the lungs or bones, by a process termed metastasis. Metastasis occurs when tumor cells travel first to the local lymph nodes in the area of the breast and then are disseminated to other sites within the body, where secondary tumors may develop. The diagnosis of metastatic tumor spread through lymph-node analysis is of concern because breast cancer is significantly more difficult to treat once it has spread to other sites within the body.

Treatment and Therapy

The hallmarks of malignancy—tumor size, appearance, local invasiveness, and lymph-node involvement as evidence of possible metastasis—are all critical factors in treatment recommendations and long-term prognosis. Although much research has been directed toward a more molecular diagnostic and therapeutic approach to breast cancer, few genetic lesions have been definitively linked to the occurrence of this disease.

Surgical removal of the tumor is the primary treatment for breast cancer. For small, localized tumors that show no evidence of spread within the tissue or lymph-node involvement, simple removal of the tumor and surrounding tissues by a procedure termed lumpectomy is the general treatment choice. Even for more advanced breast malignancies, radical mastectomy, a procedure that involves complete removal of the breast, associated lymph nodes, and underlying chest muscles, is seldom performed any longer, since the operation causes disfigurement and similar results can usually be obtained with less extensive surgery. For tumors that have spread within the breast, a portion of the breast may be removed without significant disfigurement. In cases where complete breast removal is required for tumor resection, simultaneous breast reconstruction often accompanies the surgical procedure in order to reduce the physical and psychological effects of mastectomy.

If any evidence exists that a cancer has spread, either locally within the breast tissue or lymph nodes or systemically to other sites within the body, then radiation and chemotherapy may be useful adjuvants to surgical removal of the tumor. Localized treatment involves the use of external-beam high-energy radiation that is directed locally to the target tissue to avoid damaging other organs and tissues in the body. The principle underlying the use of radiation to treat cancer involves the fact that high-energy ionizing radiation damages deoxyribonucleic acid (DNA) and destroys dividing cells within the body.

Similarly, conventional chemotherapy involves the use of drugs that interfere with the process of DNA duplication or replication in dividing cells by producing changes in the structure or integrity of the DNA molecule. Unlike radiation, chemotherapy is a systemic form of cancer treatment that is directed at metastatic tumors and cancer cells that may have spread to various sites within the body. Many chemotherapeutic drugs have been used in the treatment of breast cancer. Some of the more commonly used are cyclophosphamide, methotrexate, 5-fluorouracil, and cisplatin. These drugs may be administered intravenously, either individually or in combinations, over a period of weeks to months in an attempt to destroy any remaining cancer cells following surgery or radiation. Another chemotherapeutic drug that has been used successfully to treat breast cancer is paclitaxel, better known as Taxol, a drug originally obtained from the Pacific yew tree that blocks the process of cell division. Taxol targets a specific stage in the cell-division cycle involving the separation of chromosomes by threadlike fibers called microtubules in newly forming cells. Taxol binds to the microtubules, thereby arresting the cell-division process.

Both radiation and chemotherapy may produce significant side effects, such as anemia, hair loss, nausea and vomiting, fatigue, weight loss, and mouth sores. These side effects occur because radiation and chemotherapeutic drugs target not only cancer cells but also all cells within the body that are actively dividing.

In many patients, chemotherapy and radiation may block the progress of disease within the body, resulting in long-term survival. However, many women continue to die of breast cancer each year despite aggressive treatment. The reasons that some cancer treatments fail are as mysterious as the disease process itself. Tumor cells may not respond to chemotherapy and radiation even at very high doses as a result of drug resistance, which is characteristic of many cancers, especially at advanced stages. For example, very high-dose chemotherapy, which removes cells of the immune system, followed by stem-cell replacement therapy has been shown to have negligible benefits in patients with advanced metastatic disease. Though the molecular basis of drug resistance remains unclear, mutations in certain genes, such as the ABCB1 gene—previously known as the multidrug resistance gene—have been identified. Moreover, the complexities of tumor structure and behavior may overwhelm the potential cytotoxic (cell-killing) effects of drugs commonly used to treat this disease.

New treatments for breast cancer have been developed as a consequence of an increased understanding of the biology of breast cancer neoplasms. For example, a significant percentage of breast cancers have been shown to be hormonally responsive, meaning that their growth is stimulated by estrogen or progesterone. These tumors are classified as estrogen-receptor (ER) positive or progesterone-receptor (PR) positive. A class of drugs that targets the estrogen receptor in ER-positive breast cancers, called selective estrogen receptor modulators (SERMs), has shown great clinical promise in the treatment of breast cancer as well as in preventing recurrences of the disease.

The oldest and most prominent member of the SERM family is tamoxifen, which specifically targets the estrogen receptors in breast tissue and blocks the growth-promoting effects of estrogen in ER-positive breast cancers. Tamoxifen has been used therapeutically to treat metastatic breast disease and also to prevent breast cancer recurrences, with significant success. A number of clinical studies have shown that patients receiving this drug have dramatically lower recurrence and mortality rates than patients who do not receive this drug. For example, a study conducted by the NCI's National Surgical Adjuvant Breast and Bowel Project (NSABP) group revealed in 2010 that preventive use of tamoxifen reduced the risk of invasive breast cancer among high-risk women by 50 percent. Tamoxifen has also been shown to arrest the progression of DCIS and LCIS to invasive disease. Such clinical trials have shown significant benefits from tamoxifen taken over periods of up to five years to prevent the recurrence of breast cancer in high-risk patients. It is not surprising, however, that this drug is ineffective against breast cancers that are not ER positive. Tamoxifen has also been used in combined chemotherapy with conventional chemotherapeutic drugs such as cyclophosphamide, methotrexate, and 5-fluorouracil, with varying results.

Unfortunately, tamoxifen does have significant side effects, including an increased risk of developing uterine cancer, since the drug stimulates the growth of ER-positive endometrial cells in the uterus. For this reason, patients taking this drug should be monitored carefully by a physician. Tamoxifen use has also been linked to vascular disease, including blood clots and strokes, in some patients.

Another SERM called raloxifene hydrochloride, marketed under the name Evista, is an antiestrogen that has also shown significant clinical benefit, with results similar to those obtained using tamoxifen. The same NSABP study showed that raloxifene use decreases the risk of breast cancer in high-risk postmenopausal women by 38 percent—less effective than tamoxifen, but with fewer side effects. One important difference between the two drugs is that raloxifene blocks estrogen receptors in both the breast and the uterus, thereby decreasing the risk of developing uterine cancer for patients taking this drug.

A newer class of antiestrogens are the aromatase inhibitors (AI). These drugs block the formation of estrogen within the body and are especially beneficial to older, postmenopausal women. This class of drugs works by blocking the conversion, or aromatization, of androgens produced by the adrenal glands to estrogen. This reaction is carried out by enzymes called aromatases and occurs in fatty tissues throughout the body, significantly contributing to estrogen production in postmenopausal women. These aromatase inhibitors, marketed under the names Arimidex and Femara, have shown clinical promise in the treatment of postmenopausal women with advanced breast cancer. However, clinical studies on the combined use of AIs with SERMs such as tamoxifen have shown no significant clinical benefit so far over the use of these drugs individually.

As a means of reducing the potential side effects associated with tamoxifen, clinical studies published since 2002 have demonstrated the increased effectiveness of adjuvant chemotherapy in treating certain forms of breast cancer in postmenopausal women. For example, anastrozole (Arimidex), an aromatase inhibitor, when used in conjunction with tamoxifen during long-term treatment, produced fewer side effects and was as effective in reducing metastasis.

Drugs that target abnormal genes in breast cancer cells have also been used successfully to treat breast cancer and to prevent its recurrence. For example, approximately 25 percent of breast cancer patients show overexpression of the ERBB2 gene product as a consequence of genetic rearrangements that increase the number of copies of this gene by a process called gene amplification in the tumor cells. The ERBB2 gene, also commonly called HER2/neu, is a member of a family of genes that encode cell-surface receptors for epidermal growth factor, a growth-promoting protein that stimulates cell-cycle proliferation. The overexpression of ERBB2's product, the receptor tyrosine-protein kinase erbB-2, in breast cancer cells therefore renders these cells inordinately sensitive to growth-factor stimulation of cell division, which directly contributes to the growth of the malignant breast tissue. The drug trastuzumab, better known as Herceptin, is a humanized monoclonal antibody that specifically targets and binds to the erbB-2 receptor, thereby blocking its interaction with epidermal growth factor and the resulting stimulation of cell proliferation. Herceptin has shown positive clinical benefit in patients with erbB-2-positive tumors, both in the treatment phase and in long-term use for the prevention of breast cancer recurrence.

Perspective and Prospects

The ultimate goal of breast cancer research is prevention. To achieve this goal, it will be necessary to identify more clearly the risk factors that contribute to the development of this disease and to design preventive strategies for counteracting genetic changes and/or hormonal changes within the body that may ultimately give rise to malignant tumors of the breast tissue. Women with an inherited genetic predisposition to breast cancer, such as mutations in the BRCA1 and BRCA2 genes,
would receive the greatest benefit from these preventive approaches. Some women who carry BRCA1 or BRCA2 mutations undergo preventive bilateral mastectomy, as precancerous lesions that cannot be detected might exist.

Early detection methods aimed at identifying and removing precancerous breast lesions such as DCIS and LCIS represent an important preventive strategy whose benefits have not yet been fully realized. Currently, mammography and breast self-examination are the most common means of breast cancer detection. Although useful, these methods may fail to detect small tumors before they become invasive. Ultrasonography and magnetic resonance imaging (MRI), used in conjunction with other detection methods, may improve the likelihood of detecting premalignant lesions and early-stage cancers. Better methods of breast cancer detection need to be developed, a goal that may become increasingly possible given the increased understanding of the molecular basis of breast cancer. Molecular methods may also be useful in the development of diagnostic tests that identify additional genetic predispositions to developing breast cancer, so that aggressive preventive approaches can be taken in women identified as higher risk.

Clinical studies using hormone-therapy approaches have shown that under certain conditions, breast cancer can be prevented by drugs that target hormone and growth-factor-receptor signal pathways in tumor cells. These data provide further evidence in support of many epidemiological studies suggesting that the lifetime exposure of breast tissue to estrogen is associated with an increased risk of developing breast cancer. For this reason, women who take oral estrogen/progesterone in the form of oral contraceptives or hormone therapy need to be aware of potential risks associated with the use of these drugs. Many studies have shown that the use of oral contraceptives by women under age thirty-five who do not smoke does not appear to produce a significantly elevated risk of breast cancer or other complications. However, clinical data on hormone therapy in perimenopausal or postmenopausal women suggest that its use may contribute to a significantly elevated risk of aggressive breast cancers that are difficult to detect by mammography. In addition, it has been associated with side effects that may result in an increased risk of blood clots, strokes, and heart attacks. Despite these risks, there are clear benefits to using hormone therapy. Thus, it should be used under the careful supervision of a physician.

Many studies have been carried out to assess the role of diet in breast cancer prevention. For example, epidemiological studies have shown repeatedly that Japanese women have a far lower incidence of breast cancer than do American women. This has been attributed in part to dietary differences such as the amount of fat consumption and the extensive use of soy products in Japanese cooking. Soy contains an estrogen-receptor-binding substance called genistein. It is believed that the genistein in soy binds to estrogen receptors to block them from binding to the growth-promoting hormone estrogen. However, studies have shown mixed results as to whether an increase in one's soy intake will help lower one's risk of breast cancer. The role of diet in the prevention of breast cancer is unclear, as study results range from reduced risk associated with low-fat diets to no effects at all. Some of the confusion may be the result of the complexity of breast cancer. Low-fat, high-fiber (vegetarian) diets have been demonstrated to reduce the levels of estrogen and other reproductive hormones, and it may be in this manner that the risk of certain forms of cancer is reduced.

Although the goal of eliminating breast cancer still remains elusive, those who conduct breast cancer research and those whose lives have been touched by this disease may find it comforting to realize that so much progress has been made in understanding the cellular and molecular basis of this disease.

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