Breast cancer is the most prevalent malignancy in developed countries. Approximately one of nine women can expect to develop invasive breast cancer during her lifetime. About 20% of cases are diagnosed before and 80% after the age of 50. Death rates from breast cancer in the United States have been declining since 1990, particularly in women under 50, due in part to advances in treatment and in part to early detection and awareness.

1. Risk Factors

Some of the risk factors for breast cancer are listed in Table 1. It is well known that there is a familial component to the disease and this accounts for approximately 15% of cases. For example, if a first-degree relative of a woman has been diagnosed with breast cancer, her risk for developing it is increased two- to three-fold. A second relative with the diagnosis increases the risk still further. Some of this genetic risk (estimated at approximately one half) is attributable to the three genes listed in Table 1.

Table1. Some Risk Factors for Breast Cancer

BRCA1 and BRCA2 (breast cancer susceptibility gene) are genes found on chromosomes 17 and 13, respectively, that encode two different DNA repair enzymes. DNA is subject to constant damage from such sources as radiation, chemicals, and inherent instabilities in the nucleotides themselves. A mammalian cell may undergo as many as 1000 mutations due to DNA damage in a 24-hour period. The vast majority of these are repaired by one of the many DNA repair enzyme systems found in cells. If these repairs are not made, mutations accumulate. Since some of these mutations will affect genes involved in the control of cell proliferation, the outcome of their accumulation can be the uncontrolled proliferation of the cell, or cancer. The BRCA1 and BRCA2 genes, for reasons that are not fully understood, show tissue specificity in that they are linked to breast and, particularly in the case of BRCA1, ovarian cancer. The lifetime risk for breast or ovarian cancer for people (men and women) having an inactivating mutation in BRCA1 or BRCA2 is increased about five-fold over those not carrying such a mutation. This estimate may be somewhat high since many of the studies are carried out in large families in which other genetic similarities also occur. Other genes have also been associated with increased risk for breast cancer (see examples in Table 1), but these two make the largest known contribution (about half to two-thirds) of the genetic risk that can be attributed to specific genes.

Consideration of the reproductive risks listed in Table 1 suggest that the length and extent of exposure to an estrogen-rich environment is an important contributor to the risk for breast cancer. For example, greater incidence is seen in women whose reproductive cycles began early or ended late. As described below, these extensive observations have led to the hormonal therapy that has been a mainstay for a subset of breast cancer patients.

Other risk factors that have been studied in detail are obesity, particularly after menopause. Adipose cells contain aromatase and convert adrenal androgens to estro gen in the absence of ovarian activity, thus extending the length of estrogen exposure of these individuals. Alcohol use, while protective of cardiovascular tissues, appears to contribute to the risk of breast cancer, possibly by decreasing the rate of inactivation of active estrogens.

The use of oral contraceptives does not appear to be a significant factor (either positive or negative) in the risk of breast cancer. The possible role of postmenopausal hormone replacement therapy (HRT) in breast cancer risk is complex. Long-term (more than five years) use of estradiol/progestin or estradiol alone is associated with a small to moderate increased risk of breast cancer. Conjugated equine estrogens (CEE), however, especially when taken for fewer than 5 years, do not appear to increase the risk. The complex mixture of the CEE, containing sulfated estrone, 17α-estradiol, and Δ8,9 dehydroestrone, may contain compounds with both agonist and antagonist activities, offering an explanation for the difference between this estrogen source and estradiol alone.

2. Treatment

The goals of treatment of any solid tumor type of cancer are to: remove or at least control the primary tumor site; minimize the possibility or effects of metastasis; and maintain, as much as possible, the patient’s quality of life. With regard to the primary site, surgery (either mastectomy or lumpectomy) followed by radiation is the primary approach. To reduce the risk of or treat metastatic disease, chemotherapy, hormonal therapy, and, more recently, immunotherapy can be used. Whether and when to use chemotherapy depends on many factors, including the stage of the cancer, the age of the patient, and the patient’s medical history. The details of the chemicals used and the course of chemotherapy treatment are variable and beyond the scope of this chapter.

Since it is clear that an estrogenic environment con tributes to the development of breast cancer, blocking estrogen action is an obvious way to combat it. Therefore, it is not surprising that attention has been given to both estrogen antagonists and aromatase inhibitors as agents to decrease actions of estrogens on breast cancer cells. Not all breast tumors, however, contain the estrogen receptor (ERα). In fact, approximately 30% are ER negative and these patients do not, in general, receive hormone therapy.

For the cancers that are ER positive (60–70%) the main form of treatment is with tamoxifen (Figure 13-7), which acts as an estrogen antagonist in breast tissue (but is an agonist in liver, bone, and endometrium). Tamoxifin decreases the rate of growth of human breast cancer cells in vitro. Given over five years it reduces the incidence of recurrence of breast cancer. Although there are no life-threatening side effects, tamoxifen does increase the relative risk of endometrial, colon, and stomach cancers as well as blood clots. It also can lead to unpleasant perimenopausal symptoms such as hot flashes and menstrual irregularities. Another SERM, raloxifene, developed for the prevention and treatment of postmenopausal osteoporosis, was found to decrease the incidence of breast cancer in women in this age group. In a direct trial of tamoxifen and raloxifene in postmenopausal women, the latter was slightly less effective in preventing breast cancer. However, because the agonist profile of raloxifene differs from that of tamoxifen, it does not lead to the increase in uterine cancer or some of the other side effects seen with tamoxifen. Postmenopausal women who are at increased risk for breast cancer may undergo long-term treatment with either of these drugs to reduce the risk of breast cancer with the choice varying with the individual patient.

Recently it has become clear that some (about 30% of cases) breast cancer cells also contain ERβ. In fact, it appears that ERβ may, in contrast to ERα, be anti proliferative in breast cancer cells in vitro and that, in humans, the presence of ERβ is correlated with a good prognosis. If screening of breast cancer patients for ERβ becomes routine as for ERα, a clearer picture of its role in breast cancer will undoubtedly emerge.

Another approach to reducing the estrogen exposure of breast tissue is to reduce its endogenous synthesis by inhibiting aromatase. The structures of two clinically important nonsteroidal aromatase inhibitors are shown in Figure 1. Within the past decade, these compounds have become a first line of treatment for adjuvant therapy, i.e., accompanying chemotherapy or radiation following surgery. Both anastrozole and letrozole have been shown to be as effective at reducing the recurrence of disease in the same breast as well as the subsequent development of cancer in the contralateral breast. In addition, both result in fewer of the side effects of tamoxifen. The one disadvantage of the aromatase inhibitors is that they increase the number of osteoporotic fractures. Thus measures, such as bone density measurements and, if warranted, supplemental calcium, vitamin D, and bisphosphonates, are given when aroma tase inhibitors are used in breast cancer treatment.

Fig1. Aromatase inhibitors. The structures of two nonsteroidal aromatase inhibitors that are used clinically for adjuvant breast cancer treatment are shown.

In addition to inactivating mutations in tumor sup pressor genes such as BRCA1 and BRCA2, the loss of control of cell proliferation can also be attributed to the overexpression of proto-oncogenes. These are genes that are required for cell growth and division in normal cells but when overexpressed cause uncontrolled proliferation to occur. An example in the case of breast cancer (and several other solid tumors such as those found in ovary, pancreas, stomach, and bladder) is the gene for HER2, a tyrosine kinase membrane receptor which is a member (numbered 2) of the EGFR (epidermal growth fac tor) receptor family. There is no known natural ligand for HER2 but it is thought to mediate its complex actions on cell growth, survival, and differentiation through heterodimerization with other members of the EGFR family through which ligand binding and activation occurs. All cells contain two copies of the HER2 gene on chromosome 17 and express small amounts of the HER2 receptor. In some cells, the number of HER2 genes is amplified 10–100-fold, leading to greatly increased expression of the HER2 receptor and ultimately to tumorigenesis and metastasis.

The recognition of the role of HER2 in the unrestrained proliferation of breast cancer cells led to the development of a monoclonal antibody against the receptor which blocks its ability to dimerize with other receptors of the EGFR family. Breast cancer patients are screened for the presence of increased HER2 expression and if positive (about 25–30%) treatment with this anti body, trastuzumab (Herceptin), is an effective adjunct treatment with chemotherapy (before or after surgery) to slow the progression of disease. The choice to use it depends on whether the tumor is HER2 positive and what chemotherapeutic agents are being used, as the drug shows some cardiotoxic effects in the presence of certain anticancer chemicals. The molecular mechanism of action of trastuzumab is not fully understood but may include, among other actions, increased degradation of the receptor.

اخر الاخبار

اخبار العتبة العباسية المقدسة

مجموعة العميد التربوية تعقد اجتماعًا لمناقشة الاستعدادات الخاصة بالموسم التدريبي الصيفي

قسم الإعلام ينظم ورشة تدريبية حول تطبيق (إعلامي) لعدد من منتسبي قسم حفظ النظام

قسم الشؤون الخدمية ينفذ حملة لتنظيف الشوارع المحيطة بصحن مرقد أبي الفضل العباس (عليه السلام)

وفد العتبة العباسية المقدسة يزور شعبة الإعداد البدني للاطّلاع على برنامج تأهيل المنتسبين الجدد

المزيد

الآخبار الصحية

ماذا يحدث إذا تناولنا الطعام مرة واحدة فقط في اليوم

اكتشاف عوامل خطر غير متوقعة لمرض الكبد الدهني

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طبيب يحسم الجدل السجائر الإلكترونية وعلاقتها بالسرطان

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لأول مرة في الولايات المتحدة.. تشغيل مفاعل مصغر نووي يغذي الذكاء الاصطناعي بالطاقة

الكشف عن تفاصيل أول عملية ناجحة لاستعادة انتاج الحيوانات المنوية

أطلس يكشف خفايا الجسم البشري بدقة أرفع بـ50 مرة من شعر الإنسان

المتحف المصري الكبير يتحول إلى "أيقونة خضراء" بدعم ياباني

المزيد

مواضيع ذات صلة

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Factors Affecting Sensitivity to Radiation- Induced Thyroid Cancer

Thyroid Carcinoma After external Irradiation: Methodology in epidemiological Studies

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Pathological evaluation of Pituitary carcinomas

Clinical Presentation and Diagnosis of Pituitary carcinomas

Aetiopathogenesis and Pathology of Thyrotropinomas

Cancer and The Environment