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Estimated new cases and deaths from breast cancer in the United States in 2007:
New cases: 178,480 (female); 2,030 (male)
Deaths: 40,460 (female); 450 (male)
Patient EvaluationContralateral DiseaseHormone Replacement TherapyGeneticsFollow-upBreast Reconstruction
Several well-established factors have been associated with an increased risk of breast cancer. These include family history, nulliparity, early menarche, advanced age, and a personal history of breast cancer (in situ or invasive).
Clinical trials have established that screening with mammography, with or without clinical breast examination, may decrease breast cancer mortality. Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the age and menopausal status of the patient, stage of the disease, histologic and nuclear grade of the primary tumor, estrogen-receptor (ER) and progesterone-receptor (PR) status, measures of proliferative capacity, and HER2/neu gene amplification. Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on mutation carriers who have developed breast cancer are conflicting. Since criteria for menopausal status vary widely, some studies have substituted age older than 50 years as a surrogate for the postmenopausal state. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. For example, favorable histologic types include mucinous, medullary, and tubular carcinoma. This section will discuss only primary epithelial breast cancers. Rarely, the breast may be involved by other tumors such as lymphoma, sarcoma, or melanoma.
Patient management following initial suspicion of breast cancer generally includes confirmation of the diagnosis, evaluation of stage of disease, and selection of therapy. At the time the tumor tissue is surgically removed, ER and PR status should be determined.
Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. Patients who have breast cancer should have bilateral mammography at the time of diagnosis to rule out synchronous disease. The role of magnetic resonance imaging (MRI) in screening and follow-up continues to evolve. Having demonstrated an increased detection rate of mammographically occult disease, the selective use of MRI for additional screening is being suggested. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation prior to treatment action is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown. Patients should continue to have regular breast physical examinations and mammography to detect either recurrence in the ipsilateral breast in those patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast.The risk of a primary breast cancer in the contralateral breast is approximately 1% per year. Patient age younger than 55 years at the time of diagnosis or lobular tumor histology appear to increase this risk to 1.5%.The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.
Hormone Replacement Therapy
The use of hormone replacement therapy (HRT) poses a dilemma for the rising numbers of breast cancer survivors, many of whom enter menopause prematurely as a result of therapy. HRT has generally not been used for women with a history of breast cancer because estrogen is a growth factor for most breast cancer cells in the laboratory; however, empiric data on the safety of HRT after breast cancer are limited. Two randomized trials comparing HRT with no hormonal supplementation have been reported. The first trial included 345 evaluable breast cancer patients with menopausal symptoms and was terminated early because of an increased incidence of recurrences and new primaries in the HRT group (hazard ratio [HR] = 3.5; 95% confidence interval [CI], 1.5–7.4). In total, 26 women in the HRT group and 7 in the non-HRT group developed recurrences or new primaries. This study, however, was not double blinded, and it is possible that patients on HRT were monitored more closely. Because of the results of the first trial, the second trial, which was conducted under a joint steering committee with the first, closed prematurely after the enrollment of 378 patients. With a median follow-up of 4.1 years, there were 11 recurrences in the hormone replacement group and 13 recurrences in the patients assigned to no hormone replacement (HR = 0.82; 95% CI, 0.35–1.9). The trials differed in several ways; however, until further data become available, decisions concerning the use of HRT in patients with breast cancer will have to be based on the results of these studies and on inferences from the impact of HRT use on breast cancer risk in other settings. A comprehensive intervention, including education, counseling, and nonhormonal drug therapy, has been shown to reduce menopausal symptoms and to improve sexual functioning in breast cancer survivors.
Women with a family history of breast cancer may have an increased risk of disease. Age-specific risk estimates are available to help counsel and design screening strategies for these women. Of all women with breast cancer, 5% to 10% may have a germ-line mutation of the genes, BRCA1 and BRCA2.Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as great as 5% per year. Male carriers of BRCA2 mutations are also at increased risk for breast cancer.Mutations in either gene also confer an increased risk of ovarian cancer.In addition, mutation carriers may be at increased risk of other primary cancers. Genetic testing is available to detect mutations in members of high-risk families. Such individuals should first be referred for counseling.
Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared to routine physical examinations. Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected. Based on these data, some investigators recommend that acceptable follow-up be limited to physical examination and annual mammography for asymptomatic patients who complete treatment for stage I to stage III breast cancer. The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I to stage III breast cancer remain controversial.
For patients who opt for a total mastectomy, reconstructive surgery may be used at the time of the mastectomy (immediate reconstruction) or at some subsequent time (delayed reconstruction).Breast contour can be restored by the submuscular insertion of an artificial implant (saline-filled) or a rectus muscle or other flap. If a saline implant is used, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is replaced by a permanent implant. Rectus muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required. Following breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes either in the adjuvant setting or if local disease recurs. Radiation therapy following reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.
Prevention
Factors Associated with Increased Risk of Breast Cancer
Hormone Replacement TherapyIonizing radiationObesityAlcohol
Hormone replacement therapy/hormone therapy
Based on solid evidence, combination hormone replacement therapy (HRT; estrogen-progestin), also called hormone therapy (HT), is associated with an increased risk of developing breast cancer. The evidence concerning the association between estrogen-only therapy and breast cancer incidence is mixed.
Description of the Evidence for Combination Therapy
Description of the Evidence for Estrogen Only
Based on solid evidence, exposure of the breast to ionizing radiation is associated with an increased risk of developing breast cancer, starting 10 years after exposure and persisting lifelong. Risk depends on dose and age at exposure, with the highest risk occurring during puberty.
Description of the Evidence
Based on solid evidence, obesity is associated with increased breast cancer risk in postmenopausal women who have not used HRT/HT.
Based on solid evidence, exposure to alcohol is associated with increased breast cancer risk in a dose-dependent fashion.
Based on solid evidence for tamoxifen and fair evidence for raloxifene, treatment reduces the incidence of breast cancer in postmenopausal women. Tamoxifen also reduced the risk of breast cancer in high-risk premenopausal women.
Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, thrombotic vascular events (pulmonary embolism, stroke, deep venous thrombosis), and cataracts. Based on fair evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.
Based on fair evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have a history of breast cancer.
Based on fair evidence, AIs are associated with decreased bone mineral density, increased falls, and decreased cognitive function.
Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history.
Based on fair evidence, physical and psychological effects include anxiety, depression, and impaired body image.
Based on good evidence, prophylactic oophorectomies in women with BRCA gene mutations document lower breast cancer incidence. Similarly, oophorectomy or ovarian ablation are associated with decreased breast cancer incidence in normal women or in those who received thoracic irradiation.
Based on good evidence, castration may cause the abrupt onset of menopausal symptoms such as hot flashes, insomnia, anxiety, and depression. Long-term effects include decreased libido, vaginal dryness, and decreased bone mineral density.
Based on solid evidence, strenuous exercising more than 4 hours per week is associated with reduced breast cancer risk.
Musculoskeletal injury may occur.
Ductal Carcinoma in Situ
Introduction
Ductal carcinoma in situ (DCIS) is a noninvasive, precancerous condition. DCIS can progress to become invasive cancer, but estimates of the likelihood of this vary widely. Some people include DCIS in breast cancer statistics. The frequency of the diagnosis of DCIS has increased markedly in the United States since the widespread use of screening mammography. In 1998, DCIS accounted for about 18% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.
Very few cases of DCIS present as a palpable mass; 80% are diagnosed by mammography alone. DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into several subtypes based primarily on architectural pattern: micropapillary, papillary, solid, cribriform, and comedo. Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.
Treatment Option Overview
Until recently, the customary treatment of DCIS was mastectomy. The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy following wide excision alone, and a 25% to 50% incidence of breast recurrence following limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma. The combined local and distant recurrence rate following mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation are available.
In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy. Of the 818 women enrolled in the NSABP B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001). Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.
Similarly, of the 1,010 patients enrolled in the EORTC 10853 trial, mammography-detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates. In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy. In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.
Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved. The Van Nuys Prognostic Index, which combines 3 predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification), was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy. Using this prognostic index, patients with favorable lesions, who received surgical excision alone, had a low recurrence rate (i.e., 2% with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control. Patients whose excised lesions had margin widths 10 mm or larger in every direction had an extremely low probability of local recurrence with surgery alone (4% with a mean follow-up of 8 years). These reviews are retrospective, noncontrolled, and are subject to substantial selection bias. By contrast, no subset of patients was identified in the prospective NSABP trial that did not benefit from the addition of radiation therapy to lumpectomy in the management of DCIS.
To determine if tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial of 1,804 women. Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years). Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured not larger than 1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on a placebo (8.2% vs. 13.4%; P = .009). With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03). Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01). The benefit of tamoxifen extended to those patients with positive or uncertain margins
Treatment Options for Patients with DCIS
Lobular Carcinoma In Situ
The term lobular carcinoma in situ (LCIS) is misleading. This lesion is more appropriately termed lobular neoplasia. Strictly speaking, it is not known to be a premalignant lesion, but rather a marker that identifies women at an increased risk for subsequent development of invasive breast cancer. This risk remains elevated even beyond 2 decades, and most of the subsequent cancers are ductal rather than lobular. LCIS is usually multicentric and is frequently bilateral. In a large prospective series from the National Surgical Adjuvant Breast and Bowel Project with a 5-year follow-up of 182 women with LCIS managed with excisional biopsy alone, only 8 women developed ipsilateral breast tumors (4 of them were invasive).[1] In addition, three developed contralateral breast tumors (two of them were invasive).
Most women with LCIS can be managed without additional local therapy after biopsy. No evidence is available that re-excision to obtain clear margins is required. Tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women. The Breast Cancer Prevention P-1 trial of 13,388 high-risk women comparing tamoxifen to placebo demonstrated an overall 49% decrease in invasive breast cancer, with a mean follow-up of 47.7 months. Risk was reduced by 56% in the subset of 826 women with a history of LCIS, and the average annual hazard rate for invasive cancer fell from 12.99 per 1,000 women to 5.69 per 1,000 women. In women older than 50 years, this benefit was accompanied by an annual incidence of 1 to 2 per 1,000 women of endometrial cancer and thrombotic events. Bilateral prophylactic mastectomy is sometimes considered an alternative approach for women at high risk for breast cancer. Many breast surgeons, however, now consider this to be an overly aggressive approach. Axillary lymph node dissection is not necessary in the management of LCIS.
Treatment Options for Patients with LCIS
Source: National Cancer Institute