The male breast is subject to almost all the lesions that are seen in the female beast, However, by comparison, the incidence of breast lesions in men is very low. The explanation for this low incidence may be that the male breast does not undergo the cyclic physiologic stimuli that the female breast undergoes during menstruation, pregnancy, and lactation.

OVERVIEW OF COMMON LESIONS IN THE MALE BREAST

Anatomically and histologically, the male breast is similar to that of a prepubertal girl. It has ducts, but lacks lobules. Fibroadenomas and cysts – lesions that originate in the lobules – are therefore not seen in men. On the other hand, ducts being the main component of the male breast, ductal lesions are more common. The ductal lesions are gynecomastia, ductal papilloma, ductal carcinoma, and infiltrating ductal carcinoma. Because breast examination in men is usually neglected, and because screening mammography is simply not done on the male population, breast carcinoma is usually more advanced in men than in women when it is diagnosed.

Papillomas of the male breast are usually reported as papillary cystadenomas. As in women, papillomas in men are usually found in the major ducts, and nipple discharge is the most common clinical manifestation.

The malignant lesions most commonly found in the male breast are (in order of frequency) cystic papillary carcinoma, infiltrating duct carcinoma, and ductal carcinoma.

Cancer is the second most common breast lesion after fibrocystic changes of the breast.

Breast cancer is asymptomatic. Malignant tumors are usually found on breast self-examination or during a routine physical examination. To be palpable, a tumor has to reach a size of 1 cm. In patients with large, pendulous breasts, detection of a tumor that size is difficult; the tumor may even be completely missed. But the increased use of screening mammography has resulted in more breast cancers being diagnosed in the subclinical stage – either as small, nonpalpable tumors or as microcalcifications.

BREAST CANCER OVERVIEW

In women, among all lesions of the breast, the incidence of cancerous lesions is 28%–30%. Although beast cancer has been diagnosed in patients in their late teens, the incidence at that age is low. Breast cancer reaches its highest incidence in patients between the ages of 45 and 50. The incidence declines somewhat in patients between the ages of 50 and 59, but then peaks again as the patient ages beyond 59 years.

CLINICAL PRESENTATION

Breast cancers are most commonly located in the upper outer quadrant of the breast – chiefly because that quadrant contains the greater volume of breast tissue. In order of decreasing frequency, the next most common locations are the upper inner, lower outer, and lower inner quadrants.

The role of the surgeon in a multidisciplinary approach to breast disease is unique because the surgeon interacts with the clinician, the radiologist, and the pathologist. Yet often, the surgeon is the first to see a patient with a breast problem.

Like any other physician, the surgeon must be aware of the incidences of the most common breast lesions and their clinical presentations. Using that information, he or she can determine the most appropriate surgical management. The surgeon should also know the limitations of mammography and should not rely simply on a negative mammogram in the presence of a palpable lesion.

Today's surgeon not only must know the relevant anatomy and possess the appropriate surgical skills, but must also be prepared to communicate with the radiologist and the pathologist. With the radiologist, the surgeon must be able to discuss mammography and ultrasound findings and guide-wire placement (in cases of imaging-guided needle biopsies). With the pathologist, the surgeon must seek to better understand the lesion so as to choose the most appropriate surgical treatment. (Seventy years ago, Bloodgood, a famous breast surgeon, said that the surgeon should also be his own pathologist. While that statement probably was true then, today it simply is not possible.)

The procedures that a surgeon has in the surgical armamentarium to diagnose and treat a breast lesion are

• fine-needle aspiration biopsy,

• core biopsy,

• incisional biopsy, and

• excisional biopsy.

Introduction

In spite of numerous advances that have been made in the screening and management of patients with breast cancer, an unacceptable number of patients die of this disease even though they may have had optimal therapy and management. It is therefore necessary to assess the possible impact of different treatment modalities currently used more in other tumour types and consider this application to the treatment of breast cancer. These include immunotherapy (active: vaccines, and passive: antibodies), gene therapy, antisense technology and antiangiogenic agents.

Cancer and the immune system

Macfarlane Burnet (1970) postulated that the immune system kept potential cancer cells under surveillance and could detect and kill thousands of emerging cancer cells every day. This concept had gradually fallen out of favour as regards the common solid tumours as they do not appear to be increased in conditions where the immune system is compromised, such as autoimmune deficiency syndrome (AIDS) and renal transplant patients. However, both of these conditions have an increased incidence of viral driven cancers such as Epstein–Barr Virus (EBV) associated lymphomas and HHV-8-associated Kaposi's sarcoma. In these conditions there is a foreign viral antigen(s) which can be detected and contained by a healthy immune system and the failure to do so leads to viraldriven proliferation and oncogenesis. The absence of increased breast, lung and bowel cancer in HIV infection however, does not mean that the immune system has no role in containment of tumour progression.

Introduction

The definition of locally advanced breast cancer includes patients with large tumours, extensive regional lymph node involvement, or direct involvement of the skin or underlying chest wall. These tumours thus include stage IIIA and IIIB breast cancer as well as inflammatory breast cancer and involvement of the supraclavicular nodes (stage IV). Haagensen & Stout (1943) were the first to describe the clinical signs and then confirmed that these patients had a uniformly poor prognosis with no cures at 5 years in 120 patients treated with radical mastectomy (and 49% developing a local recurrence by 5 years) (Haagensen, 1971). Radiotherapy alone then became the standard treatment (Baclesse, 1949), with a local tumour control rate of 28% to 74% at 5 years and a 5-year survival of between 12% to 38% (Bouchard, 1965; Fletcher, 1972; Zucali et al., 1976; Langlands et al., 1976; Bruckman et al., 1979; Treurniet-Donker et al., 1980; Bedwinek et al., 1982; Balawajder et al., 1983). Some of these more recent studies compared radiation alone with a combination of surgery and radiotherapy and confirmed that the 5-year survival could be improved to between 35% and 55% (Fletcher, 1972; Zucali et al., 1976; Bruckman et al., 1979; Bedwinek et al., 1982; Balawajder et al., 1983).

Since the early 1980s there has been an increasing trend to offer systemic chemotherapy (so-called primary medical therapy or neoadjuvant therapy) as part of the multimodality approach. As a result of this it was found that a proportion of women could be offered conservative surgery and thus avoid a mastectomy.

Introduction

Resistance to chemotherapy invariably occurs in breast cancer patients being treated for metastatic disease. As with hormonal therapy, resistance may be either ‘intrinsic’, manifest as a failure to respond to initial therapy, or ‘acquired’, seen as progression after a variable length of time in patients who initially respond to cytotoxic therapy. In the adjuvant setting resistance to chemotherapy is inferred by rapid relapse following completion of therapy. In vitro models have established that cancer cells exhibit varying degrees of intrinsic drug-specific resistance, but may also acquire the same phenotype following long-term exposure to a given agent. Many of the established mechanisms of resistance are associated with genetic abnormalities such as activation of dominantly active oncogenes, or loss of tumour suppressor genes. Both patterns of intrinsic and acquired resistance are consistent with a model of cumulative genetic change during the development and progression of breast cancer.

Although many of the mechanisms involved in chemoresistance have been investigated extensively in vitro, other factors such as systemic drug metabolism and bioavailability may influence the likelihood of tumour response/resistance in vivo. Clinical studies have been used to verify whether a given genetic or biochemical change observed in experimental studies of drug resistance is relevant to clinical practice. There are several limitations in this approach when studying biological markers of resistance, not least the methodologic problems in analyzing clinical specimens (for example, protein vs. RNA analysis, type of antibody used, tissue fixation) and sampling errors due to heterogeneous expression within human tumours.

The rationale for systemic adjuvant therapy

Up until approximately 25 years ago, it was considered that breast cancer metastases developed according to the anatomical and mechanistic principles first proposed by Halstead (1907). Metastases spread in a predictable fashion from the breast to the regional lymph nodes and subsequently to distant sites. Consequently, the aim of early breast cancer treatment was extensive surgery to remove local and regional disease. However, the Halstead principles were subsequently challenged by laboratory findings, biological hypotheses and clinical observations which have formed the rationale for systemic adjuvant chemotherapy. There is no orderly pattern of cancer cell dissemination, and the blood stream is of considerable importance as a route of dissemination (Fisher & Fisher, 1966), and so regional lymph nodes are of prognostic rather than anatomical significance. The high recurrence rate, especially during the first three years after a Halstead radical and extended radical mastectomy, suggest that micrometastases, which are not clinically detectable, are present at the time of surgery for the primary tumour and are unaffected by local treatment (Valagussa et al., 1978). Several studies have evaluated breast-conserving surgery alone or with radiotherapy (Fisher et al., 1991; Veronesi et al., 1993; Liljegren et al., 1994). A higher local recurrence rate among women who underwent lumpectomy did not adversely affect survival.

Introduction

The cessation of menstruation is termed the menopause, the median age of which is 51 years in the United Kingdom, whereas the climacteric (or perimenopause) is the transitional period leading up to this during which ovarian function ceases and symptoms of ovarian failure may become manifest. This usually predates the menopause by approximately two to three years in the majority of women. Ovarian failure arises as a result of a reduction in ovarian responsiveness to gonadotrophin stimulation combined with an exhaustion of viable oocytes. As oestradiol production is predominantly dependent on oocyte maturation with an increase in anovulatory cycles, serum levels subsequently fall, endometrial stimulation fails to occur and amenorrhoea results. The short and long-term sequelae of this decline in ovarian oestrogen production are summarized in Table 4.1.

Vasomotor symptoms and their psychological sequelae can severely impair a women's quality of life (Daly et al., 1993). Symptoms are experienced by 75% of climacteric and early postmenopausal women but are usually self-limiting, lasting two to three years, although they can be life-long in a minority of women (Belchetz, 1994). Vaginal dryness and the subsequent superficial dyspareunia experienced by a proportion of women may contribute to loss of libido. Coronary artery disease is the most common cause of morbidity and mortality in women in many countries including the United Kingdom (Office for National Statistics Population and Health Monitor, 1997) and is the most frequent non-neoplastic cause of death in node-negative breast cancer survivors (Rosen et al., 1993).

Introduction

At present we are in an era of controlled clinical trials evaluating chemoendocrine agents in the prevention of breast cancer. Although breast cancer deaths (in the UK and USA) have now started to decline (Peto et al., 2000), the commitment to this approach originated in the recognition that early diagnosis and improvements in treatment had not translated into an order of magnitude step-down in mortality figures. Research directed at primary prevention of breast cancer has become a priority, especially for those women who are at increased risk of developing the disease. This is further enhanced by the emerging detail of breast cancer genetics, heralded with the identification of BRCA1 and BRCA2, and the consequent ability to refine risk assessment, along with developments in the understanding of breast cancer biology, the oestrogen receptor (ER) and the availability of new selective oestrogen receptor modulators (SERMs).

In the early months of the year 2000 there was intense pressure on these prevention trials. Tamoxifen in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 Breast Cancer Prevention Trial has been reported to reduce the incidence of invasive (and noninvasive) breast cancer when compared to placebo (Fisher et al., 1998), and as a consequence the Food and Drug Administration (FDA) have approved tamoxifen for breast cancer risk reduction in high-risk women. In contradistinction, the preliminary analyses of the Royal Marsden, London, UK and Italian tamoxifen randomized chemoprevention trials (Powles et al., 1998a; Veronesi et al., 1998) yielded null results.

History of surgery for breast cancer

Introduction

Breast cancer is an ancient disease and was described by the Egyptians 3000 years before Christ. Subsequently various articles about breast cancer and its treatment were written by Greek and Roman physicians. Surgery is the oldest method of treating breast cancer with different operations described which sometimes reflected beliefs held about its causes and natural history. However, a variety of ‘medical’ therapies have also been described, especially in the Middle Ages, which to the modern observer were more akin to witchcraft than the application of scientific knowledge to the treatment of the disease. Changing fashions in the treatment of breast cancer have reflected not only changes in beliefs regarding its pathogenesis but also a growth in knowledge about the disease as well as advances in science and technology. Thus four periods can be discerned in the evolution of treatment over the centuries. The first period could be described as the Empiric era of the pre-Galen period. Subsequently, breast cancer was regarded as a systemic disease and this characterized the Pessimistic period. By the eighteenth century, breast cancer was thought to be a local disease leading to the Optimistic era in which it was believed that larger operations than performed previously could eradicate the disease. By the twentieth century, knowledge about the biology of breast cancer had started to grow which led to a realization that breast cancer was a more complex disease than previously had been supposed and led to the establishment of the Realistic era in which we now find ourselves.

Introduction

Adjuvant radiotherapy (RT) has an established role in the reduction of risk of locoregional breast cancer recurrence, both postmastectomy and after breast-conserving surgery (BCS). Importantly, results of recent clinical trials also suggest that locoregional RT may impact on overall survival, adding to the benefits accruing to systemic adjuvant therapy. This chapter will review the evidence base for current recommendations for adjuvant RT, highlight areas of ongoing research activity and indicate directions for future treatment optimization.

Radiotherapy and breast conservation

The aims of breast-conservation therapy using tumorectomy and adjuvant radiotherapy are to ensure survival equivalent to mastectomy, whilst optimizing the cosmetic outcome and minimizing risks of disease recurrence in the conserved breast. Since the 1970s, there have been six prospective randomized trials in which breast-conserving surgery has been compared with mastectomy. These studies have confirmed the efficacy of BC + RT with respect to survival (Table 8.1). Differing surgical and RT techniques lead to varying rates of recurrence in the breast from 4% to 20% at 10 years. Importantly, despite undergoing a more radical surgical procedure, associated with significant rates of psychosexual morbidity, it was observed that mastectomy still conferred a risk of local recurrence of 2–9%.

As a result of these randomized studies, and many retrospective large single-centre studies of BCT and RT, this approach has become the standard of care for women who wish to opt for BCT.