SECTION IV

SPECIAL MANAGEMENT TOPICS

ROBERT D. LEGARE DON DIZON JENNIFER S. GASS TREVOR TEJADA-BERGES MARGARET M. STEINHOFF C. JAMES SUNG SUSAN KOELLIKER HANAN I. KHALIL JARSLOW HEPEL WILLIAM SIKOV BACHIR SAKR

INTRODUCTION

Breast cancer, a worldwide problem, remains the most common cancer diagnosis in women, affecting more than 1.2 million women diagnosed each year. Treatment paradigms require an understanding of the natural history of the disease, including the various patterns of metastases and recurrence, and both the prognostic and predictive factors that may influence both response to treatment and overall survival (OS). In addition, the complexities that govern medical and surgical decisions make the management of breast cancer far more complicated than that of other disease sites. This chapter will provide the essential information regarding breast cancer, with an emphasis on recent developments. It stresses an interdisciplinary view of disease management by providing the foundational aspects of breast disease and treatment.

EPIDEMIOLOGY

In 2012, an estimated 226,870 women and 2,190 men will be diagnosed with breast cancer in the United States (1). It is estimated that 1 in 8 women will be diagnosed with breast cancer in their lifetimes. Beginning in the late 1990s, a shift in the incidence of breast cancer in the United States was noted. The steady increase in breast cancer diagnoses seen in the 1950s started to decline in 1999 and continued to decline into 2003. The decline in the annual incidence between 2002 and 2003 was limited to women over 50 years of age. Whether the declining use of hormone replacement therapy following publication of the Women’s Health Initiative study results, the utilization of mammographic screening, and earlier diagnosis of disease, or whether a combination of these factors, explains this trend continues to be an area of investigation. Mortality from breast cancer has been steadily declining since 1990, at a rate of 3.1% per year in women under 50 years of age and 2.1% per year in older women (1). Still, over 40,000 women will succumb to breast cancer this year, making it second only to lung cancer.

RISK FACTORS

Risk factors for breast cancer have been well characterized. Breast cancer is 100 times more frequent in women than in men. Factors associated with an increased exposure to estrogen have also been elucidated, including early menarche, late menopause, late age at first pregnancy, or nulliparity. The use of hormone replacement therapy has been confirmed as a risk factor, although mostly limited to the combined use of estrogen and progesterone, as demonstrated in the Women’s Health Initiative (WHI) study (2). Analysis showed that the risk of breast cancer among women using estrogen and progesterone was increased by 24% compared to placebo. A separate arm of the WHI study randomized women with a prior hysterectomy to conjugated equine-estrogen (CEE) versus placebo, and in that study, the use of CEE was not associated with an increased risk of breast cancer (3). Unlike hormone replacement therapy, there is no evidence that oral contraceptive use (OCP) increases risk. A large population-based case-control study examining the risk of breast cancer among women who previously used or were currently using OCPs was conducted and included over 9,000 women 35 to 64 years of age (half of whom had breast cancer) (4). The reported relative risk was 1.0 (95% confidence interval [CI], 0.8–1.3) among women currently using OCPs and 0.9 (95% CI, 0.8–1.0) among prior users. In addition, neither race nor family history was associated with a greater risk of breast cancer among OCP users.

Apart from endocrine risk factors, sociodemographic risks have also been established. Breast cancer is an age-related phenomenon, with peak incidence after 40 years of age. Family history is also a strong epidemiologic risk factor. Clinical models can now be employed to predict the risk of breast cancer. Among those in common use are the Gail and Claus models (Table 28.1) (5,6). Although they have been widely used in the African-American population and other minority populations, they have not been validated sufficiently.

Beyond classification of risk based on family history (familial risk), the identification of genetic mutations that are passed in an autosomal dominant fashion (hereditary risk) has been an important scientific finding. Among the most significant was the identification of mutations at BRCA1, localized to chromosome 17q21, and BRCA2, on chromosome 13q12–13, both of which confer a risk for breast cancer as high as 80% among carriers (7,8). A specific BRCA1 mutation, 185delAG, has been identified in over 20% of Jewish women younger than 40 years of age at the time of breast cancer diagnosis. Other mutations known to carry an increased risk are those involving p53 in Li-Fraumeni syndrome (associated with other cancers, including sarcoma, leukemia, melanoma, gastrointestinal carcinomas, and brain tumors); CHEK-2, PTEN mutations associated with Cowden syndrome (associated with macrocephaly, intellectual disability and hamartomas with an increased incidence of endometrial cancer, benign and malignant thyroid disease, and noncancerous brain tumors); and STK-11 mutations associated with Peutz-Jeghers syndrome (associated with hamartomatous polyps of the gastrointestinal tract, dark-colored spots on lips, mucous membranes and palms/soles, and an increased incidence of gastrointenstinal, ovarian, and cervical malignancy).

^aGail MH, et al. Projecting individualized probabilities of developing breast cancer for White females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879–1886.
^bClaus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer. 1994;73(3):643–651.
^cRisk defined for invasive breast cancer only.

Work evaluating the long-term effects of environmental factors has established prior radiation exposure as an additional risk factor. The therapeutic use of mantle-field radiation in women with Hodgkin’s disease and the sequelae of the atomic bombing of Japan in World War II identified the heightened risks of breast cancer, particularly in young women (9,10).

Among modifiable risk factors, obesity, weight gain in later life, and the consumption of alcohol have been identified in prospective observational studies (11). The association of environmentally found trace elements and breast cancer risk has also been evaluated, with unconvincing results in general.

An association has been made between breast cancer risk and breast findings. Among the best-described risk factors is the association between breast cancer and a history of biopsies for benign breast disease. In a study by Hartmann et al. the relative risk for breast cancer ranged from 1.27 for nonproliferative lesions, to 1.88 for proliferative lesions without atypia, to 4.24 in lesions with atypia, and this risk persisted for as long as 25 years after biopsy (12). A recent report from Worsham et al. evaluated the same risks in an intercity clinic and reported that African-American women with benign breast lesions faced similar risks in developing breast cancer (13). More recently, Boyd et al. reported on the association between risk and breast density (measured in percentage of the total breast). Using 1,112 matched case-control pairs, they determined the association between risk and reported that women with density of 75% or greater had a significantly increased risk of breast cancer (odds ratio, 4.7; 95% CI, 3.0–7.4), with younger women notably at greatest risk (14).

ANATOMY

The breast is a modified sweat gland composed of 2 components—the large ducts and the terminal duct-lobular unit (TDLU)—surrounded by adipose and fibrous tissue, lymphatics, nerves, and blood vessels. The surface of the breast is attached to the underlying fibrous tissue via Cooper’s ligaments, and the mammary gland lies over the pectoralis major muscle extending vertically along the second to sixth ribs, and horizontally from the sternum to the anterior midaxillary line. The axillary tail comprises mammary tissue as well and extends laterally from the chest wall into the axilla. The large duct system of subsegmental, segmental, and lactiferous ducts converges and empties onto the nipple. The TDLU is the most distal part of this branching ductal system and is felt to be the site of origin of most pathologic entities of the breast, including fibrocystic changes, ductal hyperplasias, and the majority of carcinomas (15,16). It is connected to the subsegmental ducts and represents the secretory unit of the gland.

Mobility of the breast tissue over the chest wall is through the retromammary bursa that lies between the superficial and deep fascia. The lymphatic system of the breast is vast, comprising a network over the entire surface of the chest, neck, and abdomen, with increased density under the axilla. There are 3 main lymphatic pathways of the breast: (a) the axillary pathway, which drains the upper and lower halves of the breast into the lateral axillary nodal chain; (b) the transpectoral pathway, which drains into the supraclavicular nodes; and (c) the interal mammary pathway, draining the inner halves of the breast, into the nodes of the internal mammary chain.

NATURAL HISTORY OF BREAST CANCER

Breast cancer can occur with predictable features. For example, it is more likely to be diagnosed in the central or outer quadrants of the breast than in the inner regions (17). It has also been reported to be more commonly involving the left breast. One study of 2,139 cases of breast cancer in Iceland showed 13% more breast cancers occurred in the left breast versus the right (18).

Within the breast, cancer travels along ducts (intraductal carcinoma), and the process of invasion begins when the tumor erodes through the basement membrane. Continued growth results as the tumor spreads along adjacent lobules, breast lymphatics, perineural tumors, and vascular spaces. When it involves the dermal lymphatics, the overlying dermis becomes edematous and red with the classic appearance of peau d’orange. Continued growth of the primary tumor can result in the involvement of the pectoralis and intercostal muscles, ribs, and the clavicle.

While less frequently encountered, locally advanced or metastatic disease at diagnosis still occurs in clinical practice. Tumor spread can occur locally by direct extension, lymphatically, or via intravascular means. Lymphatic spread of tumor from the breast travels to the locoregional nodes of the chest—the axillary, intramammary, and supraclavicular nodal basins—and increasing tumor size is a well-known predictor of nodal involvement. A medial or central lesion of the breast is more likely to metastasize to the internal mammary nodes than outer quadrant lesions, and this has been theorized to explain their worse prognosis compared to upper outer breast tumors (17). Vascular invasion can be observed, even with small tumors.

Metastatic disease from breast cancer can occur in any organ site. Lee reviewed the published autopsy series involving over 2,000 women who had died of breast cancer (19). The most commonly involved organs were the lungs, bones, nodes, and liver. The pleural space, adrenal glands, and brain represented the next most commonly involved sites. Bloom et al. compared a group of women with untreated breast cancer to a cohort of patients treated with radical or modified radical mastectomy, with or without irradiation, and reported an overall 10-year survival of 3.6% in the untreated cohort versus 34% in the treated group.

Theories on the spread of breast cancer have been used as a foundation for subsequent treatment and have evolved over time. Dr. William Halsted defined the notion that cancer arose from one location and travelled contiguously by lymphatics to reach local and distant locations. Hence, treatment with the en bloc resection of the breast and lymphatics was felt to present the best opportunity for cure. Still, it was clear that even with aggressive surgery and removal of the lymphatics from the breast, women still died of breast cancer. In a seminal paper by Valagussa et al., the OS was reported to be 60% among women with node-negative disease, 54% in those with up to 3 nodes positive, and 26% in those with more than 3 positive nodes. This showed that contiguous lymphatic spread alone could not explain survival outcomes (20).

The theory of breast cancer as a systemic disease was brought forward in 1980 by Dr. Bernard Fisher (21). Breast tumors were seen as a marker of this systemic syndrome, just as neuropathy would be a marker of advanced diabetes mellitus. Hence, nodal disease was not simply an extension of a primary breast cancer process, but rather a marker of disease already spread. This theory holds that achieving local control will not impact OS and argues for the use of systemic treatment in order to affect the best outcome. Recently, however, a meta-analysis on the use of adjuvant radiation by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has called this theory into question. In that analysis, the use of adjuvant radiation not only improved local control but also reduced annual mortality by 13% after the second year of follow-up (22).

It is likely that breast tumors express variable degrees of malignancy. Hellman argued that “synthesis” between Halsted and Fisher’s theories was required (23). Recognizing that tumor size is proportional to the risk of metastases, he argued that small and large tumors behave differently, and carried different prognoses. Small tumors were a manifestation of a locoregional process and therefore were curable with treatment. Larger tumors, on the other hand, comprised cells more likely to proliferate and be more malignant—features that made them more likely to metastasize. As such, these were likely to be associated with systemic disease. Defining cure as “that proportion of the treated group that has the same survival as an age-adjusted peer population,” he estimated that over 80% of women with tumors less than 1 cm in size were curable and that this was manifest at 10 years of follow-up. In summary, he once again stressed the importance of local control for small tumors, while emphasizing the importance of systemic control in breast cancer.

CLINICAL PRESENTATION OF BREAST CANCER

Today the most common presentation is with an abnormal mammogram, although patients continue to present with a painless or slightly tender breast mass. In younger women, a delay in diagnosis may be attributed to benign causes, such as recent trauma or changes with pregnancy, or due to breast-feeding. For those women presenting with a mass, the patient may ultimately present with breast tenderness, skin changes, bloody nipple discharge, or changes in the shape and size of the breast, with or without axillary adenopathy. Rarely will women present with axillary nodal disease but no evidence of a breast primary, otherwise known as occult breast carcinoma. Lastly, inflammatory breast cancer (IBC) presents as a tender, red, and swollen breast, often mistaken for mastitis. A crusting rash emanating from the nipple is sine qua non for Paget’s disease of the breast, which is almost uniformly associated with an underlying malignancy. Fortunately, with the increase in screening following publication of the NIH Consensus Statement in 1978, patients rarely present with metastatic disease (24).

IMAGING STUDIES OF THE BREAST

Introduction

Breast imaging can be performed as a screening tool in asymptomatic women to detect early cancer, in high-risk women, or as a diagnostic examination in women suspected of having breast cancer or previously treated for breast cancer. Mammography, an X-ray examination of the breast obtained either by conventional film or by digital technique, remains the most widely used technique for screening and is the only modality proven to decrease mortality. The benefits of screening mammography and the differences between film and digital technique will be discussed. The reported benefits of digital mammography in selected groups of women will be presented. Computer-aided detection (CAD), a tool designed to help the radiologist improve the detection of breast cancer, is frequently used by interpreting radiologists; the benefits and consequences will be reviewed.

Stay updated, free articles. Join our Telegram channel

Join