CHAPTER 58 BREAST CANCER: CURRENT TRENDS IN SCREENING, PATIENT EVALUATION, AND TREATMENT
GRANT W. CARLSON
Cancer of the breast is the most common cancer in women with the exception of skin cancer. It is the second leading cause of cancer death after lung cancer. Approximately 200,000 new cases of breast cancer are diagnosed each year in the United States. They account for over 40,000 deaths a year. The incidence of breast cancer has decreased over the last decade largely due to a discontinuation of hormone replacement therapy among postmenopausal women.
The treatment of breast cancer has evolved because of the results of large, prospective, randomized clinical trials organized by the National Surgical Adjunctive Breast and Bowel Project (NSABP) in the United States and the National Cancer Institute in Milan, Italy. The majority of women with breast cancer are eligible for breast conservation therapy and receive some form of systemic adjuvant therapy.
One in nine women in the United States who reaches the age of 85 will develop breast cancer. The etiology is unknown but is clearly multifactorial, with many exogenous and endogenous risk factors being identified (Table 58.1).
Aside from gender, age is the single most important factor in determining breast cancer risk. The probability that breast cancer will develop increases throughout a woman’s life, with half of all cases occurring in women older than age 65. Family history is also important since 20% of breast cancer patients will have a relative with the disease. The magnitude of breast cancer risk is influenced by several factors pertaining to family history: number and proximity of affected relatives, their menstrual status, age at diagnosis, and the presence of bilateral cancer.
Hereditary breast cancer accounts for 5% to 10% of breast cancer cases and is caused largely by the presence of BRCA gene mutations. The genes are more common in women of Ashkenazi ancestry, patients with bilateral breast cancer, cancer diagnosed before age 50, and patients with ovarian cancer. The presence of a BRCA gene confers a 60% to 85% risk of developing breast cancer and a 10% to 40% risk of developing ovarian cancer.
Many epidemiological studies have linked early menarche, late menopause, and late age at first full-term pregnancy to breast cancer. The total duration of menstrual cycles and the number of menstrual cycles before full-term pregnancy appear to be proportional to breast cancer risk. Premalignant histology on breast biopsy may increase breast cancer risk, as discussed in the following section. A woman with unilateral breast cancer is at increased risk for developing cancer in the opposite breast. Studies have not shown that the development of contralateral breast cancer impacts adversely on survival.
Screening mammography, by detecting early breast cancers, has increased our understanding of the malignant transformation process. Most cancers arise from the ductal elements of the breast after passing, presumably, through a sequence of premalignant stages as depicted below.
Normal breast → hyperplasia → atypical hyperplasia → ductal carcinoma in situ → invasive cancer
This process can occur over a 10- to 20-year period, and orderly progression through the various stages is not obligatory. Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is cancer confined by the basement membrane of the ducts. DCIS most commonly presents as mammographic microcalcifications and currently comprises 30% of newly diagnosed cancers in populations following screening mammography guidelines. DCIS occurs in several histological patterns with varying propensities to progress to invasive cancer. Comedo DCIS is characterized by pleomorphic cells, high-grade nuclei, and central areas of necrosis. Noncomedo DCIS occurs in several subtypes that are generally not as cytologically malignant as comedo DCIS. It may be difficult to distinguish noncomedo DCIS from atypical hyperplasia.
Invasive ductal carcinoma accounts for the majority of breast cancer cases. Grossly, it appears as a gray-white, irregular, speculated mass that is hard and gritty on cut section. It has no specific microscopic features but can be recognized histologically as an invasive adenocarcinoma involving the ductal elements.
A number of histological variants arise from ductal epithelium. Medullary carcinoma is grossly soft and fleshy and accounts for 6% of invasive cancers. It tends to grow to a large size and is well circumscribed. Histologically, it is characterized by poorly differentiated nuclei and infiltration by lymphocytes. Medullary carcinoma has a favorable prognosis even in the presence of nodal metastases.Tubular carcinoma is a rare histological variant in its pure form and accounts for 2% of breast cancer. It is characteristically small and is usually found on mammography. It tends to be highly differentiated and has an excellent prognosis. Mucinous or colloid carcinoma is another well-differentiated variant, which tends to form a well-circumscribed soft, gelatinous mass. Histologically, nests of tumor cells are surrounded by a mucinous matrix.
Although most cancers arise from the ductal elements, malignancies may also arise from the epithelium of the breast lobules. Lobular carcinoma in situ (LCIS) has no radiological or physical manifestations and has traditionally not been regarded as a malignancy. LCIS is usually an incidental finding after a biopsy of a mass or mammographic abnormality. Current evidence suggests that the histological diagnosis of LCIS confers a 20% risk of developing cancer in either breast at 20-year follow-up.
About 5% to 15% of infiltrating cancers arise from the breast lobules. Once it has become invasive, lobular carcinoma has a prognosis similar to the ductal type. It tends to be extensively infiltrative without a distinct tumor mass. Histologically, the cells demonstrate a characteristic single file pattern. The tumor does not form microcalcifications, and mammographic detection may be difficult.
The American Cancer Society recommends that women at average risk should begin annual mammography at the age of 40 years.1 This has been shown to reduce the risk of dying of breast cancer. Early detection can also result in less aggressive surgery and adjuvant therapy to treat the cancer. The sensitivity of mammography is related to patient age, breast density, and breast cancer histology. False-positive exams may result in additional breast biopsies, especially in young patients. There is no specific age to discontinue screening mammography.
Breast magnetic resonance imaging (MRI) is increasingly used for breast cancer screening. It has the greatest sensitivity of all imaging modalities for detecting breast cancer of a few millimeters in diameter. MRI suffers from a low specificity, which can result in unnecessary biopsies as well as a high cost. The American Cancer Society recommends breast MRI in the management of women at high risk for developing breast cancer beginning at age 30.2 This includes women with known or suspected BRCA gene mutations and women who have undergone mantle radiation to the chest for the treatment of Hodgkin’s disease. Women felt to have a 20% to 25% or greater lifetime risk of breast cancer based on risk estimation models are also included in this high-risk category
The American Joint Committee on Cancer TNM staging system is based on clinical as well as pathological information. The classification by primary tumor (T), status of axillary lymph nodes (N), and presence of distant metastases (M) places patients in different prognostic groups (Tables 58.2 and 58.3). Stages I and II are considered early breast cancer for which surgery plays a primary role in treatment. Stage III disease is also known as locally advanced breast cancer (LABC). Despite the absence of metastatic disease, this stage has a poor prognosis and is best treated with a combination of chemotherapy, surgery, and radiation therapy. This stage includes inflammatory breast cancer, a clinical entity characterized by breast warmth, erythema, and edema. The orange peel appearance of the skin, peau d’orange, results from dermal lymphatic invasion.
Most patients with breast cancer are diagnosed with image-guided core biopsy. Ultrasound of the axilla is routinely performed to screen for potential nodal spread. Mammography/ultrasound and histological information are used to guide patient management. Breast MRI is used in patients with dense breasts and in those presenting with lobular carcinoma to define the extent of disease. The modality is also useful in the detection of contralateral disease and the assessment of tumor response after neoadjuvant chemotherapy. There are concerns that breast MRI may overestimate the extent of disease, resulting in more patients being treated by total mastectomy.
The goals of locoregional treatment are to provide optimal local control, adequate disease staging, long-term survival, and preservation or restoration of body form. Total mastectomy and axillary dissection were the standard treatment for over 50 years, based on the Halsted mechanistic theory of cancer dissemination. Halsted believed that cancer was predominantly a local disease that spreads by permeation of lymphatic pathways. He proposed the radical mastectomy to remove the cancer and prevent systemic spread. Numerous prospective randomized trials have refuted this theory of tumor biology. The bloodstream is an important pathway in early tumor dissemination, and more conservative locoregional treatment combined with systemic therapy has proved to provide local disease control with prolonged survival.
Breast conservation is the treatment of choice for the majority of stage I and II breast cancers. Six prospective randomized trials of over 4,300 women have found breast-conserving treatment to result in survival rates similar to those achieved by total mastectomy. Removal of the cancer with pathologically negative margins is termed as lumpectomy or partial mastectomy. The remaining breast is usually treated with 50 Gy of external breast radiation to improve local control. The NSABP B-06 trial compared total mastectomy, lumpectomy, and lumpectomy and radiation in 1,843 women.3 The survival was the same for all three groups but the addition of breast irradiation to lumpectomy reduced the local recurrence from 40% to 8%. Young patients and those with extensive intraductal cancer surrounding the invasive component are at increased risk for local recurrence. Because of the propensity for ductal carcinoma to spread upward toward the nipple along the duct, a quadrantectomy has been proposed to reduce local recurrence. Larger excisions result in slightly improved local control rates at the expense of the cosmetic result but have no impact on ultimate survival.Local recurrences are generally treated by total mastectomy.
There are few absolute contraindications to breast conservation (Table 58.4). The cosmetic outcome of lumpectomy is dependent on both treatment-related factors and patient selection and is judged to be excellent to good by 60% to 90% of patients.
Accelerated Partial Breast Irradiation
Whole breast irradiation after lumpectomy or partial mastectomy is the standard of care to prevent local recurrences. Studies have shown that most recurrences after breast conservation occur near the original disease site. Recurrence rates away from the tumor bed are similar after lumpectomy whether adjuvant whole breast irradiation is administered or not.4 This is the rationale for accelerated partial breast irradiation (APBI). It concentrates radiation to a partial volume of the breast over a 1- to 2-week period compared with a 6- to 7-week period for conventional whole breast irradiation. Potential advantages of APBI include convenience and less toxicity with the potential for better cosmetic results.
The most common method of delivering APBI is through implantation of multiple interstitial catheters or a single balloon catheter. This allows radiation to be delivered locally to the tissue at highest risk of recurrence. Randomized trials comparing APBI with standard external beam radiation have yet to mature but the early results appear promising.
Oncoplastic surgery combines the oncological principles of tumor extirpation with plastic surgical techniques such as breast parenchymal rearrangement and flap reconstruction. It has the potential to increase surgical resection margins and improve cosmetic results after breast conservation. It is useful in patients with moderate- to large-sized breasts whenever a partial mastectomy would result in noticeable breast deformity. This includes patients with medial and inferior pole cancers and patients requiring removal of greater than 15% of the breast volume. Patients with small breasts and large tumor volume removal are best treated by total mastectomy. Breast reshaping is generally performed by replacing missing tissue with various glandular flaps based on reduction mammoplasty techniques. The opposite breast is generally reduced to achieve symmetry. If the defect is too large or in a medium-sized breast and cannot be corrected using local tissue, distant flaps can be used.
Removal of the entire breast, nipple–areola, and skin overlying superficial tumors is still the most common local treatment of breast cancer despite the proven results of breast conservation. In continuity removal of the axillary lymph nodes is termed as modified radical mastectomy. The pectoralis major and minor muscles are usually preserved. A skin-sparing mastectomy preserves the inframammary fold and as much native skin as possible. It is used when immediate breast reconstruction is planned. Its oncological safety has been proven by numerous studies.
Nipple-sparing mastectomy which preserves the entire breast skin envelope is being evaluated to further improve the aesthetic results of breast reconstruction. It is being used in women with small to moderate breast size and minimal breast ptosis. Many centers are evaluating its use both in the prophylactic setting and in the treatment of early breast cancer.
Management of the Axilla
The removal of axillary lymph nodes provides pathologic staging as well as regional disease control. Lymph node involvement is an important prognostic factor in breast cancer. The clinical examination of the axilla is inaccurate, with up to a quarter of clinically normal axillae harboring micrometastatic disease. Sentinel lymph node dissection (SLND) has supplanted axillary lymph node dissection (ALND) as the standard of care for staging the axilla in early breast cancer. It has equivalent sensitivity and reduced morbidity in terms of arm stiffness, pain, paresthesia, and risk of lymphedema. Blue dye and radioactive tracers are injected into the breast and are taken up by breast lymphatic system. This allows identification and removal of the lymph node(s) most likely to contain metastases. Veronesi et al.5 performed a prospective randomized trial of 516 breast cancer patients randomized to SLND and ALND or SLND alone. A completion lymph node dissection was performed if sentinel node metastasis were found. They reported better arm mobility and less pain in the SLND-alone group. At a median follow-up of 102 months, the regional failure rate in the SLND-alone group was 0.77%. There was no significant difference in the disease-free survival between the groups.
ALND is the standard of care in patients found to have sentinel lymph node metastasis. Studies are emerging that show that completion ALND can be omitted in patients with early breast cancer treated by excision and whole breast irradiation.6
Treatment of DCIS
The malignant potential of DCIS depends on the size, tumor grade, and the presence of comedo necrosis. If left untreated, some but not all will progress to invasive cancer. Local recurrence after surgical excision alone occurs in up to 30% of cases depending on tumor size and histology. One-half of recurrences will be invasive carcinomas. Radiation therapy has been shown to reduce local recurrences. The NSABP B-17 trial studied 818 women with DCIS randomly assigned to either lumpectomy alone or lumpectomy followed by breast irradiation.7 With a median follow-up of 43 months, local recurrences developed in 16% treated by lumpectomy alone and 7% treated by lumpectomy plus irradiation. The role of tamoxifen in the management of DCIS was addressed in the NSABP B-24 trial, which studied 1,804 women treated with breast conservation therapy.8 After a median follow-up of 74 months, tamoxifen was found to reduce the risk of ipsilateral breast tumors in women under age 50 by 38% and in those age 50 and older by 22%. There was also a 52% reduction in contralateral breast cancer events. This translates into an absolute reduction in breast cancer events from 13.4% to 8.2%.
To correlate the risk of recurrence with pathological features and treatment, Silverstein et al.9 devised an index dependent on major risk factors for local recurrence: nuclear grade, size, comedo histology, and surgical margins based on retrospective data analysis. The Van Nuys Prognostic Index is based on tumor size, tumor grade, and the presence of comedo necrosis. Small, low-grade tumors without comedo necrosis have a low incidence of recurrence and may be treated with excision alone in select patients.
Postmastectomy radiation therapy (PMRT) is increasingly being administered in patients with early breast cancer. Studies have shown that it reduces the risk of locoregional recurrence (LRR) of breast cancer by approximately 67% but a survival benefit has been largely offset by an increase in cardiac deaths secondary to radiation. Indications of PMRT include patients at high risk for LRR: large tumors, four or more metastatic lymph nodes, close or involved surgical margins, and LABC. Two randomized trials have shown a survival benefit for postmastectomy radiotherapy in patients with one to three metastatic lymph nodes.10,11 These studies have been criticized for having a high regional failure rate in the control nonirradiated groups. A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group has provided strong evidence supporting the use of postmastectomy radiotherapy.12 The group studied the results of 8,500 women treated by total mastectomy and axillary clearance. They found a 20% absolute reduction in LRR in node-positive patients treated with PMRT. This resulted in a 5% improvement in breast cancer survival at 15 years follow-up.
The use of PMRT is based on the absolute risk of LRR. Extrapolating the data from the meta-analysis of PMRT, every 5% reduction in LRR could result in a 1% improvement in breast cancer survival. The benefits in low-risk patients must be balanced against the potential cardiovascular morbidity of chest wall irradiation.
Adjuvant chemotherapy, hormonal therapy, and biologic therapy are used to eliminate occult metastases responsible for later recurrences. Clinical trials have shown that adjuvant therapy can reduce the odds of cancer recurrence up to 30%. The effect on disease-free interval is generally larger than the effect on overall survival. Obviously, those at higher risk for recurrence and death will obtain a greater benefit. Prognostic factors, including tumor size and grade, nodal involvement, hormone receptor status, and HER2 overexpression, are used to predict the risk of distant metastases. Gene expression assays of individual breast cancers are used to provide tumor-specific treatment based on the risk of recurrence. Commonly used chemotherapy regimens include anthracyclines, cyclophosphamide, and taxanes. In premenopausal women with hormone responsive tumors, tamoxifen, a selective estrogen receptor modulator, is used. Aromatase inhibitors (anastrozole and letrozole) block the peripheral conversion of adrenal steroids to estrogen and have been shown to be more effective than tamoxifen in postmenopausal women.13 Anti-HER2 targeted therapy is used in cancers that have HER2 oncogene overexpression.
The Early Breast Cancer Trialists’ Collaborative Group performed an overview of 69 randomized trials of adjuvant combination chemotherapy.14 For recurrence, combination chemotherapy produced significant proportional reductions among women younger than 50 years of age (35% reduction) and those 50 to 69 years of age (20% reduction). For mortality, the reductions for women younger than 50 years of age (27% reduction) and those 50 to 69 years of age (11%) were significant. Adjuvant tamoxifen administered for 5 years reduces the risk of recurrence at 10 years by 47% and the mortality at 10 years by 26% in estrogen receptor-positive tumors.
Preoperative chemotherapy is indicated in patients with LABC. It may be considered in patients with operable invasive cancers who would be candidates for adjuvant chemotherapy. The goal would be tumor shrinkage to permit breast conservation. Randomized trials of neoadjuvant chemotherapy in operable breast cancer have shown significant tumor downstaging with a pathological complete response rate of 12% to 50% depending on tumor characteristics.15
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