In the United States, breast cancer is the most common cancer in women and the second most frequent cause of cancer-related mortality (second to lung) (Siegel, 2014). Although the incidence of breast cancer increased steadily in this country through the 1980s and 1990s, it has leveled at approximately 125 cases per year per 100,000 postmenopausal women and is declining for some ethnicities. Concurrently, survival rates steadily improve (Fig. 12-14) (Howlader, 2013).
Trends in breast cancer incidence and survival in the United States. Curve of decreasing breast cancer rates in U.S. ⦁ = incidence of invasive breast cancer; ▴ = incidence in situ; ■ = 5-year survival. (Data from Howlader N, Noone AM, Krapcho M, et al: SEER Cancer Statistics Review, 1975–2010, National Cancer Institute. 2013. Available at: http://seer.cancer.gov/archive/csr/1975_2010/. Accessed August 7, 2014.)
Primary cancers of the breast comprise 97 percent of malignancies affecting the breast, whereas 3 percent represent metastases from other sites. The most common of these, in descending order, are the contralateral breast, sarcoma, melanoma, serous epithelial ovarian cancer, and lung cancer (DeLair, 2013). Cancers of mammary epithelial structures account for most of primary breast cancer. Infiltrating ductal carcinoma is the most common form of invasive breast cancer (∼80 percent), and infiltrating lobular carcinoma is the second most frequent (∼15 percent). Other malignancies such as phyllodes tumors, sarcoma, and lymphoma form the remainder.
Apart from stage, the primary tumor characteristics that most influence prognosis and treatment decisions are hormone receptor status, nuclear grade, and Her-2/neu expression (Harris, 2007). Approximately two thirds of breast cancers are estrogen- and progesterone-receptor positive. This feature is generally associated with a better prognosis and more treatment options.
Her-2/neu is a membrane tyrosine kinase that cooperates with other Her-family receptors to generate proliferation and survival signals in breast cancer cells. Approximately 25 percent of breast cancers have increased expression of Her-2/neu (Masood, 2005). The list of medications that specifically target HER2 overexpressing breast cancer is growing and includes trastuzumab (Herceptin), trastuzumab emtansine (Kadcyla), pertuzumab (Perjeta), neratinib, and lapatinib (Tykerb)(Tolaney, 2014).
Gene expression profiling has identified several “intrinsic subtypes” of breast cancer with prognostic significance (Cadoo, 2013). Multigene assays are now available in the clinic for individualized prediction of prognosis and treatment response, especially for estrogen-receptor positive tumors (Rouzier, 2013).
Careful breast cancer staging is essential for predicting outcome, planning treatment, and comparing treatment effects in clinical trials. Each patient is assigned both a clinical and a pathologic stage. The clinical stage is based on examination and radiographic findings, whereas the pathologic stage is based on actual tumor measurements and histologic assessments of lymph nodes after primary surgery. Surgical staging of breast cancer is based on the TNM system, which includes primary tumor size (T), regional lymph node involvement (N), and presence of distant metastases (M) (Table 12-5). For patients with a clinically negative axilla, sentinel lymph node biopsy has replaced complete axillary dissection for nodal staging (Lyman, 2014).
TABLE 12-5Breast Cancer Surgical Staging ||Download (.pdf) TABLE 12-5 Breast Cancer Surgical Staging
| T Stage || Stage Grouping |
|Tis ||In situ ||0 ||Tis ||N0 ||M0 |
|T1mi ||≤1mm ||IA ||T1 ||N0 ||M0 |
|T1 ||≤2 cm ||IB ||T1 ||N1mi ||M0 |
|T2 ||>2 cm but ≤5 cm ||IIA ||T0 ||N1 ||M0 |
|T3 ||>5 cm || ||T1 ||N1 ||M0 |
|T4 ||Involvement of skin or chest wall or inflammatory cancer || ||T2 ||N0 ||M0 |
|IIB ||T2 ||N1 ||M0 |
| ||T3 ||N0 ||M0 |
|N Stage ||IIIA ||T0 ||N2 ||M0 |
|N0 ||No lymph node involvement || ||T1 ||N2 ||M0 |
|N0i+ ||≤ 0.2 mm metastasis || ||T2 ||N2 ||M0 |
|N1mi ||> 0.2 mm and/or > 200 cells but < 2mm || ||T3 ||N1 ||M0 |
|N1 ||1–3 nodes || ||T3 ||N2 ||M0 |
|N2 ||4–9 nodes ||IIIB ||T4 ||N0 ||M0 |
|N3 ||≥ 10 nodes or any infraclavicular nodes || ||T4 ||N1 ||M0 |
| || || ||T4 ||N2 ||M0 |
| M Stage ||IIIC ||Any T ||N3 ||M0 |
| || ||IV ||Any T ||Any N ||M1 |
|M0 ||No distant metastases || || || || |
|M1 ||Distant metastases || || || || |
The most common distant metastatic site in breast cancer is bone, followed by lung, liver, and brain. Thus, for newly diagnosed breast cancer patients, a complete blood count and liver function tests including alkaline phosphatase are recommended. Whole body screening with CT of the chest, CT or MR imaging of the abdomen and pelvis, and bone scan or whole body PET/CT are only recommended for clinical suspicion of metastases or for patients with clinical stage III disease (National Comprehensive Cancer Network, 2014).
Breast cancer is best managed by a multidisciplinary team of breast surgeons, medical oncologists, and radiation oncologists. Goals of surgery and radiation therapy are elimination of all local or regional tumor in a way that maximizes cosmesis and minimizes the risk of local or regional recurrence. There is some evidence that these local modalities reduce the risk of subsequent metastases and therefore increase survival rates (Darby, 2011). However, a significant proportion of patients with apparently localized disease have tumor cells detectable in their blood or bone marrow at diagnosis (Braun, 2005; Giuliano, 2011a). For these women, systemic treatment with chemotherapy, hormone manipulation, or targeted therapies is the primary approach for reducing metastasis risk and death (Dowsett, 2010; Peto, 2012).
Halstead (1894) revolutionized the treatment of breast cancer by demonstrating improved outcome for patients treated with radical mastectomy. However, results from recent randomized clinical trials have appropriately fostered a trend toward less aggressive surgery. Specifically, lumpectomy with postoperative radiation therapy results in the same breast cancer-specific survival rate as total mastectomy (Fisher, 2002).
Axillary dissection, that is, near-complete axillary lymphadenectomy, was also once a standard part of breast cancer staging and treatment, but its role is diminishing (Rao, 2013). The procedure is still indicated for patients with clinically node positive disease at diagnosis. However, it is frequently omitted in selected patients with clinically negative nodes but positive sentinel nodes, because radiation therapy and systemic adjuvant therapies achieve the same low axillary recurrence rate and the same survival rate (Galimberti, 2013; Giuliano, 2010, 2011b). When required, axillary dissection results in lymphedema in 15 to 50 percent of women, depending on how it is measured (Morrell, 2005). Dissection is also associated with persistent shoulder or arm symptoms in up to 70 percent (Kuehn, 2000).
After breast-conserving surgery, whole breast radiation reduces local recurrence from approximately 5 percent per year to 1 percent per year, although it may be omitted in elderly patients with favorable tumors (Fisher, 2002; Hughes, 2013). Shorter courses of partial breast irradiation may be appropriate in selected patients (Smith, 2009). Postmastectomy chest wall radiation improves survival in women with high-risk lymph node positive breast cancer (Overgaard, 1999; Ragaz, 2005). Recent clinical trial data are driving a marked increase use of extended-field radiation therapy (Early Breast Cancer Trialists’ Collaborative Group, 2014).
In the past, adjuvant chemotherapy was reserved for patients with nodal metastases and was always given after definitive surgery. However, randomized prospective trials have shown that adjuvant chemotherapy also improves survival rates for high-risk node-negative patients (Fisher, 2004a). Increasingly, however, the decision for chemotherapy is influenced by specific measures of tumor biology including results from multigene assays (Rouzier, 2013; Sparano, 2008).
If used, adjuvant chemotherapy is usually administered after primary surgery but before radiation therapy. Neoadjuvant chemotherapy is given prior to definitive surgery and is gaining popularity. Neoadjuvant chemotherapy permits assessment of a given tumor’s sensitivity to the selected agents, and tumor shrinkage permits less aggressive surgery (von Minckwitz, 2013).
Modern breast cancer chemotherapy often includes an anthracycline such as doxorubicin (Adriamycin), in conjunction with cyclophosphamide (Cytoxan) (Trudeau, 2005). The addition of a taxane has been shown to improve outcome (A’Hern, 2013). Platins such as cisplatin (Platinol) or carboplatin (Paraplatin) are increasingly used to replace doxorubicin when other cardiotoxic drugs such as trastuzumab are required and to treat certain tumor subtypes that have defects in homologous recombination. Chemotherapeutic agents are described more fully in Chapter 27.
Hormonal Therapy and Targeted Therapies
Adjuvant hormonal therapy is used for estrogen-receptor positive tumors. In pre- or postmenopausal women, one option is the selective estrogen-receptor modulator tamoxifen (Jaiyesimi, 1995). As discussed in Chapter 27, important side effects of tamoxifen include menopausal symptoms, increased risks of thromboembolic events, and higher rates of endometrial polyps and endometrial cancer. Although this cancer risk is increased, surveillance of the endometrium with routine transvaginal sonography or endometrial biopsy is not recommended. Endometrial evaluation is reserved for those with abnormal bleeding and follows that outlined in Chapter 8.
In postmenopausal women, aromatase inhibitors may be used. FDA-approved agents include anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) (Kudachadkar, 2005). In postmenopausal women, most circulating estradiol is derived from the peripheral conversion of androgens by the enzyme aromatase. Administration of aromatase inhibitors reduces circulating estradiol to nearly undetectable levels in these women. The addition of an aromatase inhibitor after tamoxifen is associated with a 23- to 39-percent improvement in the disease-free survival rate and a nearly 50-percent reduction in the contralateral breast cancer rate (Geisler, 2006). Although tamoxifen is commonly used as an initial antihormonal therapy in postmenopausal women, transition to an aromatase inhibitor and 10 years of treatment improves outcome (Johnston, 2014).
Unlike tamoxifen, aromatase inhibitors are associated with greater rates of bone loss and fractures. Accordingly, baseline bone mineral density testing and periodic monitoring is recommended. For women with mild or moderate bone loss, exercise and supplementation with vitamin D and calcium are encouraged. Various agents are available for managing severe loss, and a discussion of these drugs is found in Chapter 22.
Bisphosphonates such as zoledronic acid (Zometa) are often used to prevent cancer-treatment-induced bone loss (Hadji, 2011). In addition, the combination of aromatase inhibitors and zoledronic acid appears to improve outcome in hormone-receptor-positive breast cancer (Coleman, 2013).
Therapies that target specific biological pathways are becoming available. However, only HER2-targeted therapies are currently used routinely in early-stage breast cancer and only in HER2-amplified tumors. Targeting the mTOR pathway with everolimus (Afinitor) is now an FDA-approved strategy for advanced or metastatic hormone-receptor-positive breast cancer and is also being investigated for trastuzumab-resistant HER2-positive breast cancer (Andre, 2014; Dhillon, 2013). Comprehensive molecular profiling of tumors to identify targets for intervention is becoming more common (Frampton, 2013). Biologic agents for targeting cancer are described more fully in Chapter 27.
Long-term surveillance of breast cancer patients after treatment includes periodic history and physical examination. Women who elected breast conservation are counseled that the remaining breast tissue requires surveillance indefinitely. Ipsilateral, second primary breast cancers develop at a rate of approximately 1 percent per year and contralateral breast cancers at approximately 0.7 percent per year (Fatouros, 2005; Fisher, 1984; Gao, 2003). Laboratory and imaging tests are obtained to further evaluate specific signs or symptoms. Screening tests other than mammography to identify asymptomatic recurrences are not recommended (Khatcheressian, 2013).
Inflammatory Breast Cancer
Inflammatory breast cancer accounts for 1 to 5 percent of breast cancers (Chang, 1998; Dawood, 2010). This cancer presents with skin changes that can range from a faint red blush to a flaming-red rash associated with skin edema (peau d’orange change) (Fig. 12-15). It is distinguished from a neglected advanced primary breast cancer by its rapid onset and progression within just a few weeks. The cancer spreads rapidly throughout the entire breast and creates diffuse induration. As a result, the breast may enlarge to two to three times its original volume within weeks (Taylor, 1938).
Photographs of inflammatory breast cancer. A. Subtle erythematous blush and edema in inflammatory breast cancer. B. Classic inflammatory breast cancer. (Used with permission from Dr. Marilyn Leitch.)
Although mastitis or even congestive heart failure can produce a similar clinical appearance, inflammatory breast cancer must be definitively excluded. This always includes diagnostic mammography and punch biopsy of the skin. However, it also may require multiple biopsies and additional imaging such as MR imaging. Treatment begins with induction chemotherapy, followed by modified radical mastectomy (total mastectomy and axillary dissection), and then postoperative chest wall irradiation with or without additional chemotherapy (Cariati, 2005). The 5-year survival rate is 30 to 55 percent, which is significantly worse than for neglected advanced primary breast cancer (Brenner, 2002; Harris, 2003).