Breast Cancer– A Review for African Surgeons

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1. Introduction  
2. History  
3. Anatomy of the Breast  
4. Epidemiologic Risk Factors/Etiology  
  -Lifestyle Risks  
  -Family History and Genetics  
  -Risk Assessment  
5. Pathology  
6. Diagnosis  
  -Examination  
  -Imaging  
  -Biopsy  
7. Screening  
8. Treatment  
  -DCIS/LCIS  
  -Early Breast Cancer  
-Locally Advanced Breast Cancer  
  -Metastatic/Recurrent Breast Cancer  
  Treatment of Complications  
9. Prognosis  
  -Natural History  
  -Prognostic Indicators  
10. Prevention  
11. Breast Cancer and Pregnancy
12. Breast Cancer in Males
13. Future Trends and Controversies

14. Conclusion

15. Recommendations

1. INTRODUCTION
Breast Cancer constitutes a major public health issue globally with over 1 million new cases diagnosed annually, resulting in over 400,000 annual deaths and about 4.4 million women living with the disease. It is the commonest site specific malignancy affecting women and the most common cause of cancer mortality in women worldwide.(1;2)

There is an international/geographical variation in the incidence of Breast Cancer.
Incidence rates are higher in the developed countries than in the developing countries and Japan. Incidence rates are also higher in urban areas than in the rural areas.
In Africa, Breast Cancer has overtaken cervical cancer as the commonest malignancy affecting women and the incidence rates appear to be rising. (3;4) In Nigeria for example, incidence rate has increased from 13.8–15.3 per 100,000 in the 1980s, to 33.6 per 100,000 in 1992 and 116 per 100,000 in 2001. (5) These increases in incidence are due to changes in the demography, socio-economic parameters, epidemiologic risk factors, better reporting and awareness of the disease. While mortality rates are declining in the developed world (Americas, Australia and Western Europe) as a result of early diagnosis, screening, and improved cancer treatment programs, the converse is true in the developing world as well as in eastern and central Europe.(6-8)

Breast cancer and its treatment constitute a great physical, psychosocial and economic challenge in resource limited societies as found in Africa. The hallmarks of the disease in Africa are patients presenting at advanced stage, lack of adequate mammography screening programs, preponderance of younger pre-menopausal patients, and a high morbidity and mortality. (3;6)

This Review is meant to provide practical guidance for the surgeon working in the developing world. We have relied on the Chapter on Breast Cancer by Bland et al in Schwartz’s Principles of Surgery, 8th Edition. (9)

Material which is of interest but not immediately applicable has been placed in smaller print. In the Recommendations we have followed the principles developed in the Breast Health Global Initiative. (10-12)

2. HISTORY
Breast cancer is one of the oldest known forms of malignancies. The earliest known documentation on breast cancer was the Smith Surgical Papyrus (3000-2500 B.C.) written in Africa (Egypt). It described 8 cases of tumors or ulcers of the breast that were treated by cauterization, with a tool called "the fire drill." The writing says about the disease, "There is no treatment." At least one of the described cases is male. There were few other historical references to breast cancer until the first century when Celsus recognized the relevance of operations for early breast cancer.
In the second century, Galen inscribed his classical clinical observation: "We have often seen in the breast a tumor exactly resembling the animal the crab. Just as the crab has legs on both sides of his body, so in this disease the veins extending out from the unnatural growth take the shape of a crab's legs. We have often cured this disease in its early stages, but after it has reached a large size, no one has cured it. In all operations we attempt to excise the tumor in a circle where it borders on the healthy tissue."(13)

Halsted and Meyer reported their operations for the local treatment of breast cancer in 1894. Both Halsted and Meyer advocated complete dissection of axillary lymph node levels I to III and removal of pectoral muscle along with the breast. By demonstrating locoregional control rates after radical resection and providing the first opportunity for cure, these surgeons established radical mastectomy as state-of-the-art treatment in the early part of the 20th century. Later in the century, there was a transition from the Halsted radical mastectomy to the modified radical mastectomy (MRM) as the surgical procedure most frequently used for breast cancer. This procedure maintained the en bloc dissection of the breast and lymph nodes, but left the pectoralis major muscle intact.

The recognition in the 1950s that breast cancer was often a systemic disease at presentation shifted the management of primary breast cancer away from a purely surgical approach to a multidisciplinary one that uses systemic therapy, surgery and radiation. As a result surgery for breast cancer may now be managed with more conservative and less locally ablative procedures such as lumpectomy. The past three decades has witnessed an enormous growth in the knowledge and understanding of the basic science of the disease especially the genetic and molecular basis of the disease.

3. ANATOMY OF THE BREAST
The breast is a modified sweat gland and therefore ectodermal in origin. It is present in all mammals and becomes particularly prominent in females as the hallmark of pubertal development. It lies cushioned in adipose tissue between the subcutaneous fat layer and the superficial pectoral fascia. It extends from the clavicle above to the upper border of the rectus sheath below and from the midline to the posterior axillary line. It overlies the second to the sixth ribs, the pectoralis major, serratus anterior and the upper part of the rectus sheath. The area covered is wider than the visible protuberant breast. An axillary extension of the breast (axillary tail of Spence) always exists and its size is proportional to the total volume of the main breast mass. The innervation of the breast is derived from the anterior branches of the intercostal nerves 2 through 6 with the nipple receiving its innervation from the 4th intercostal nerve. The major blood supply, in order of importance, are the internal mammary branches, the lateral thoracic, and the thoracodorsal perforating vessels from the pectoral branch of the throacoacrominal branch of the axillary artery, and small intercostals branches. The venous and lymphatic drainage parallel the blood supply.

The glandular tissue consists mainly of epithelium, fibrous stroma, and fat. The breast is organized into roughly 20 lobular units made up of terminal ducts surrounded by fat and fibrous tissues and efferent ductules. These terminal ducts coalesce and drain towards the areola forming the 15-20 ducts of the nipple areolar complex.
The lymphatic drainage is primarily to the axillary nodes (75%), divided into three levels by the Pectoralis minor muscle (level I nodes lie lateral, level II nodes behind and level III nodes medial to the muscle). Usually, but with some exceptions, lymphatic drainage is progressive through these levels. Drainage also occurs to the internal mammary chain of lymph nodes which lie in the intercostal spaces, the supraclavicular nodes, the opposite breast and axilla, and to the liver via the rectus abdominis muscle.

4. EPIDEMIOLOGIC RISK FACTORS/ETIOLOGY
The precise etiology of breast cancer is largely unknown, but several risk factors have been identified. Table 1 lists the known risk factors.(14)
The risk factors include:
Age: The incidence of breast cancer increases with age and is rare before the age of 20 years. The breast cancer incidence in Caucasians is highest at age 50-59, after menopause, dropping after age 70. In Africa and African-Americans the peak age incidence is about one decade less, so that the majority of the patients are pre- menopausal. While numerous theories have been proposed to explain this difference, including age at menarche, time of first delivery, parity, socio-demographic factors, body mass index, and underlying genetic difference, none are completely satisfactory and more research is needed in this area.(3-5;15-17)

Sex: Breast Cancer is 100 times more common in women than in men with male breast cancer accounting for <1% of all breast cancer cases in the United States and 0.1% of cancer mortality in men (18-20).However in Africa this situation may be different as from 5-15% of breast cancer in Uganda and Zambia may occur in males.(18;21-24)

Geographic variation: A wide difference in age adjusted incidence and mortality for breast cancer exists between different countries (up to five fold). Figure 1 shows the difference which may be explained by environmental and genetic factors.(25-28)

Hormone/Pregnancy related factors: The role of estrogen in the causation of breast cancer has been extensively studied and the general opinion is that estrogen is the primary stimulant for breast epithelial proliferation. Factors that increase exposure to high or prolonged level of estrogen are therefore associated with an increased risk of developing breast cancer (29-33). These include early menarche, late menopause, use of contraceptives and exogenous estrogen, nulliparity and increased age at first term pregnancy. Induced abortion and spontaneous abortion do not increase the risk. Prolonged lactation and breast feeding reduce the risk. As the living standard and health care facilities in Africa improve, it is probable that age at menarche will decrease while that of menopause increases. The demands for education and a career may increase the number of women who delay childbearing, have fewer children, use contraceptives and breast feed for a shorter time. These will likely impact on the increase in the incidence of breast cancer as African countries meet the minimum development goals.

Previous Breast Disease: Individuals who have a prior history of invasive carcinoma or ductal carcinoma in situ have a 0.5%-1% per year risk of developing a new invasive breast carcinoma. Women with atypical ductal or lobular hyperplasia have a four to five times higher risk of developing breast cancer. Proliferative lesions without atypia, such as moderate hyperplasia and sclerosing adenosis, are associated with a slightly increased risk (1.5-2%). Other common non-proliferative changes such as palpable cysts, fibroadenomas and duct papillomas are not associated with a significantly increased risk. (34)

Enviromental Exposures: Exposure to ionizing irradiation increases the risk of developing breast cancer. Excess breast cancer has been observed in patients given multiple fluoroscopies, radiotherapy for ankylosing spondylitis, Hodgkin’s disease, or enlargement of the thymus gland and in survivors of the atomic bombings, painters of radium watch faces and X-ray technicians (28). Environmental exposures to organic chlorines and other environmental/synthetic estrogens like cosmetics and phytoestrogens found in food have also been postulated to increase the risk, but so far there are no conclusive evidence linking organic chlorines to breast cancer. (31;35;36)

LIFESTYLE RISKS
Anthropometric indices and physical activity: Height, obesity and high body mass
index are risk factors especially in post menopausal women. In pre-menopausal women, obesity and high body mass index has an insignificant but inverse relationship to breast cancer risk that is reduced by physical activity. (37-39)

Diet, Alcohol and Smoking: Alcohol and Diets rich in fat especially saturated fat raises the risk while smoking does not appear to affect the risk. (40-42)

FAMILY HISTORY AND GENETICS
A family history of breast cancer increases a woman's risk of developing the disease. A woman is considered to be at increased risk if the family member is a first degree relation with early age of onset (< age 50), if both breasts are involved, or if she has multiple primary cancers (such as breast and ovarian cancer). Women with one, two, and three or more first-degree affected relatives have an increased breast cancer risk when compared with women who do not have an affected relative (risk ratios 1.8, 2.9 and 3.9, respectively) (43) Such women are recommended to begin breast cancer screening at an age 10 years younger than the age at which the affected relative was diagnosed.
Hereditary breast cancer caused by an underlying inherited gene mutation accounts for a small proportion (5-10%) of all breast cancers. The majority is accounted for by 2 germline mutations BRCA-1 (50%) and BRCA-2 (32%), which are inherited in an autosomal dominant fashion with varying penetrance. These tumor suppressor genes are important in the processing of DNA damage and preservation of genomic integrity. BRCA-1 is located on chromosome 17q while BRCA-2 is located on chromosome 13q. (44) They are most commonly found in the European Ashkenazi Jewish population and their descendants, accounting for their relatively high prevalence in the developed world. In Europe and North America, BRCA1 is found in 0.1% of the general population, compared with 20% in the Ashkenazi Jewish population and is found in 3% of the unselected breast cancer population and in 70% of women with inherited early-onset breast cancer. (9) Up to 50-87% of women carrying a mutated BRCA1 gene develop breast cancer during their lifetime. Risks for ovarian and prostate cancers are also increased in carriers of this mutation. BRCA2 mutations are identified in 10-20% of families at high risk for breast and ovarian cancers and in only 2.7% of women with early-onset breast cancer. The lifetime risk of developing breast cancer in female carriers is 25-30%. BRCA2 is also a risk factor for male breast cancer; male carriers have a lifetime risk of 6% for developing the cancer. BRCA2 mutations are associated with other types of cancers, such as prostate, pancreatic, fallopian tube, bladder, non-Hodgkin lymphoma, and basal cell carcinoma.

Risk management strategies for BRCA-1 and BRCA-2 carriers include:
• Prophylactic mastectomy and reconstruction;
• Prophylactic oophorectomy and hormone replacement therapy;
• Intensive surveillance for breast and ovarian cancer; and
• Chemoprevention using Tamoxifen or raloxifene (post-menopausal women)
In contrast, less is known about genetic mutations as a cause of breast cancer in the non-Caucasian population. Studies that have been done of African-Americans, whose genetic history includes Caucasians, have identified BRCA-1 and -2 mutations but of a different pattern.(17;45;46) In native Africans, a wide range of BRCA-1 and BRCA-2 mutations and sequence variations have been found which are unique. This suggests that there may be significant differences in the genetics of hereditary breast cancer in Africa.

A screening of 206 black South African women with breast cancer revealed 3 common BRCA1 mutations: 185delAG in exon 2, 4184del4 in exon 11, and 5382insC in exon 2022. A second study of the coding regions of BRCA1 and BRCA2 genes from 70 Nigerian patients diagnosed with breast cancer before the age of 40 years revealed 2 novel BRCA1 truncating mutations, Q1090X and 1742insG; four BRCA1 missense variations; one BRCA2 truncating mutation, 3034del4, previously unreported in anyone of African descent; and 20 nontruncating variants were detected in BRCA2.45 BRCA1 and BRCA2 mutations and sequence variations are potentially significant in cases of early-onset breast cancer within Africa. However, only a small portion of the mutations were protein truncating, fewer than those observed among white women.(47)

Other rare genetic changes that account for predisposition to breast cancer include Li Fraumeni syndrome (TP53 gene mutation), Cowdens syndrome, Peutz-Jeghers and Muir-Torre syndromes, Ataxia Telangiectasia syndrome (caused by the ATM gene). (48-51) New breast cancer susceptibility genes are being reported and they include the CHEK2 or CHK2 gene, cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk but the degree of penetrance of these genes are far less than the BRCA1 and BRCA2 genes (43;51)

RISK ASSESSMENT
Several statistical models are currently in use in North America to predict the risk of breast cancer, based on the above risk factors identified in the American Caucasian population. The universal applicability of these models can not, however be taken for granted as the data on which they rely on were generated from predominantly American Caucasian population and have not been tested for African women (43;52;53)

The most prominent statistical models are the Gail and the Claus models. Gail and colleagues developed the most frequently used model, which incorporates age at menarche, the number of breast biopsies, age at first live birth, and the number of first-degree relatives with breast cancer. It predicts the cumulative risk of breast cancer according to decade of life. To calculate breast cancer risk with the Gail model, a woman's risk factors are translated into an overall risk score by multiplying her relative risks from several categories. This risk score is then compared to an adjusted population risk of breast cancer to determine a woman's individual risk. A software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc.
Claus and colleagues, using data from the Cancer and Steroid Hormone Study, a case-control study of breast cancer, developed the other frequently used risk-assessment model, which is based on assumptions about the prevalence of high-penetrance breast cancer susceptibility genes. Compared with the Gail model, the Claus model incorporates more information about family history, but excludes other risk factors. The Claus model provides individual estimates of breast cancer risk according to decade of life based on knowledge of first- and second-degree relatives with breast cancer and their age at diagnosis. Risk factors that are less-consistently associated with breast cancer (diet, use of oral contraceptives, lactation), or are rare in the general population (radiation exposure), are not included in either the Gail or Claus risk-assessment models.(54)


5. PATHOLOGY
Breast cancers are derived from the epithelial cells that line the terminal duct lobular unit. Cancer cells that remain within the basement membrane of the elements of the terminal duct lobular unit and the draining duct are classified as in situ or non-invasive. An invasive breast cancer is one in which there is dissemination of cancer cells outside the basement membrane of the ducts and lobules into the surrounding adjacent normal tissue.

Classification of Primary Breast Cancer
Noninvasive Epithelial Cancers
Lobular Carcinoma in situ (LCIS)
Ductal Carcinoma in situ (DCIS) or intraductal carcinoma: Papillary, cribriform, solid and comedo types
Invasive Epithelial Cancers (percentage of total)

Invasive lobular carcinoma (10-15)
Invasive ductal carcinoma
Invasive ductal carcinoma, (NOS) Not Otherwise Specified (50-70)
Tubular carcinoma (2-3)
Mucinous or colloid carcinoma (2-3)
Medullary carcinoma (5)
Invasive cribriform (1-3)
Invasive papillary (1-2)
Adenoid cystic carcinoma (1)
Metaplastic carcinoma (1)
Pagets disease (<1)
Mixed Connective and Epithelial Tumors
Phylloides tumors, benign and malignant
Carcinosarcoma
Angiosarcoma

Paget’s disease of the breast is a rare manifestation of breast cancer characterized by neoplastic cells in the epidermis of the nipple areolar complex. It most commonly presents with eczema of the areola, bleeding, ulceration, and itching of the nipple. The diagnosis is often delayed because of the rare nature of the condition and confusion with other dermatologic conditions. Because of this, it is recommended that any ulcerated or irritated lesion on the nipple areolar complex undergo a punch biopsy under local anesthesia. There is an associated cancer elsewhere in the breast in up to 80% of cases.

LCIS originates from the terminal duct lobular units and only develops in the female breast. It is 12 times more frequent in white women than in African American women. Invasive breast cancer subsequently may develop in 25 to 35% of women with LCIS over their lifetime, and may develop in either breast, regardless of which breast harbored the initial focus of LCIS

DCIS: predominantly seen in the female breast, it accounts for 5% of male breast cancers. The risk for invasive breast cancer is increased nearly fivefold in women with DCIS. The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the DCIS that was originally detected, suggesting that DCIS is an anatomic precursor of invasive ductal carcinoma.

Tumor Grade
The degree of differentiation of the tumor can be graded by these parameters: tubule formation, nuclear pleomorphism, and frequency of mitoses. These are scored from 1 to 3. For example, a tumor with many tubules (the cells are more differentiated, closer to normal breast tissue and therefore less aggressive) would score 1 whereas a tumor with no tubules would score 3. These values are combined and converted into three groups: grade I (score 3-5), grade II (scores 6 and 7), and grade III (scores 8 and 9). This derived histological grade—often known as the Bloom and Richardson grade or the Scarff, Bloom, and Richardson grade after the originators of this system—is an important predictor of both disease free and overall survival. (See Prognosis)

Staging
Staging of Cancer is an attempt to define characteristics that would reliably define tumors based on the extent of the disease. It is useful for choosing treatment options, selection of patients and comparing the outcome of treatment and clinical trials and for prognosticating. In Africa, where over 70% of breast cancer patients present late, staging of breast cancer patients can provide revealing epidemiological information about opportunities for improving breast cancer screening and management.
The first staging method for Breast Cancer was proposed by Steinthal, a German Physician in 1904, and since then staging method has been evolving, with the TNM (Tumor, Node, Metastasis) method being universally adopted by the UICC (The International Union Against Cancer) and the American Joint Committee on Cancer (AJCC). Tables 2 and 3 show the latest TNM staging for Breast Cancer (AJCC classification (6th edition or revision) (55), which incorporates both clinical information and changes related to the growing use of new technology (e.g., sentinel lymph node biopsy, immunohistochemical staining, reverse transcriptase-polymerase chain reaction). Patients with bilateral or multicentric breast cancer are staged according to the size of the largest tumor.

6. DIAGNOSIS


1. Examination: Early breast cancer causes no symptoms and is usually painless. The commonest symptom is a painless lump in the breast. Examination of the breast should be done in such a way to show respect for the privacy and comfort of the patient. A systematic approach to breast examination is important. Initial examination should start with the patient in an upright position with careful visual inspection of masses, skin and nipple changes, and asymmetries. Palpation should be done to include all the breast quadrants, the nipple-areola complex, the axillary tail and the axilla. Simple maneuvers like stretching the arms high above the head, tensing the pectoralis muscles may help accentuate asymmetries and dimpling.
Other less frequent presenting signs and symptoms of breast cancer include (1) breast enlargement or asymmetry; (2) nipple changes, retraction, or discharge, including Paget’s disease; (3) ulceration or erythema of the skin of the breast including inflammatory carcinoma; (4) an axillary mass; and (5) systemic symptoms such as fatigue, cough, ascites or new musculoskeletal discomfort.
2. Imaging: Mammography, Ductography, Ultrasonography, MRI are imaging techniques useful in the screening and diagnosis of breast cancer.
Mammography is the most useful test to differentiate between benign and malignant lesions and is the one that is recommended for breast cancer screening. Specific mammography features that suggest a diagnosis of a breast cancer include a solid mass with or without stellate features, asymmetric thickening of breast tissues, and clustered microcalcifications Mammography may also be used to guide interventional procedures, including needle localization and needle biopsy.
Xeromammography techniques are identical to those of mammography with the exception that the image is recorded on a xerography plate, which provides a positive rather than a negative image Details of the entire breast and the soft tissues of the chest wall may be recorded with one exposure.
Ductography and Ductoscopy
Mammary ductoscopy (MD) is a newly developed endoscopic technique that allows direct visualization and biopsy examination of the mammary ductal epithelium where most cancers originate. When combined with ductal lavage and cytology , it may reveal early carcinoma.(56-59) The primary indication for ductography is nipple discharge, particularly when the fluid contains blood. Radiopaque contrast media is injected into one or more of the major ducts and mammography is performed. Intraductal papillomas are seen as small filling defects surrounded by contrast media .Cancers may appear as irregular masses or as multiple intraluminal filling defects.
Ultrasonography is an important method of resolving equivocal mammography findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities. Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle localization of breast lesions. It is highly reproducible and has a high patient acceptance rate, but does not reliably detect lesions that are 1 cm or less in diameter and when used alone is a poor screening test (60;61)
Magnetic Resonance Imaging is a non invasive, non radiating imaging technique. In the process of evaluating MRI as a means of characterizing mammography abnormalities, additional breast lesions have been detected. However, in the circumstance of both a negative mammogram and a negative physical examination, the probability of a breast cancer being diagnosed by MRI is extremely low. There is current interest in using MRI to screen the breasts of high-risk women and of women with a newly diagnosed breast cancer. In the first case, women with a strong family history of breast cancer or who carry known genetic mutations require screening at an early age, but mammography evaluation is limited because of the increased breast density in younger women. In the second case, a study of MRI of the contralateral breast in women with a known breast cancer showed a contralateral breast cancer in 5.7% of these women. (62-64)
Plain X-rays and Bone Scan are useful in the detection and diagnosis of metastasis especially to the bones.
MRI, PET, CT Scans and bone scans are not readily available in most centers in the developing world, and when available, the cost of these procedures makes them virtually unrealistic for many of the patients. Ultrasonography and X-rays are however readily available and many patients will end up with these minimal investigations and the standard history and physical examination.

3. Biopsy
Pathologic diagnosis of a breast lesion can be achieved using a number of biopsy techniques. With a larger biopsy sample, greater accuracy and more information are obtained, but this is at the expense of increased invasiveness. Ideally, needle biopsies should be performed after imaging to help prevent distortions of imaging due to hematoma. The various needle biopsy techniques can be divided into two groups
1. Fine needle aspiration will provide cytology which will allow a diagnosis of malignant cells but will not differentiate between in situ or invasive disease.
2. Tissue biopsy for histology which include Tru cut biopsy, Biopty cut, Mammotome. These relatively larger tissue samples will allow the diagnosis of invasive versus in situ cancer.
Table 4 compares the accuracy of needle biopsy techniques.

Open Biopsy (Excision or Incision biopsy) The ultimate diagnostic biopsy is open biopsy of a lesion, normally performed under general or local anesthetic. Open excisional biopsy should be reserved for lesions for which some doubt remains regarding diagnosis after less invasive assessment or for benign lesions that the patient wants removed. A wide clearance of the lesion is usually not the goal in diagnostic biopsies, thus avoiding unnecessary distortion of the breast. It is also useful for excision of mammographic lesions when percutaneous biopsy has failed or is equivocal. Where frozen section is available, open excisional biopsy may be performed at the same time the as definitive breast cancer surgery. Incisional biopsy is used only in cases where the lesion is very large and a percutaneous biopsy has been unsuccessful.

7. SCREENING
Annual screening mammography has been demonstrated to reduce breast cancer mortality among women older than 50 years by 20 -39%. The benefit in younger women is not yet established. For Caucasian women aged 40–49, the results of RCTs are consistent in showing no benefits at 5–7 years after entry, a marginal benefit at 10–12 years, and unknown benefit thereafter. This is primarily because when used as a screening tool, the detection rate per screened individual is lower because of denser breasts and an overall lower incidence. The controversy over the effectiveness of screening mammography among younger women (i.e., 40–49 years) has led to varying recommendations about its use for this age group. In patients with high risk factors a yearly mammography assessment from the age of 40 years is advisable.(65-67). Considering the younger demographic pattern of Breast Cancer in Africa, it is not clear what role screening mammography should have in Africa.

Other methods of early breast cancer screening like Self Breast Examination and Clinical Breast Examination have not been demonstrated to improve mortality in patients; rather SBE has resulted in more breast biopsies due to false positive results, more physician visits and apprehension in patients (68). It is pertinent to state that most of the studies that evaluated the role of SBE and CBE have been done in developed societies where cancers are small at diagnosis and this may not be relevant in Africa where the majority of patients present late. Incorporation of Breast Awareness programs and health education into the Primary Health Care of African countries may very well be a useful option to allow for a diagnosis at an earlier stage. Cultural attitudes play important roles in the acceptance of screening programs.(69)

8. TREATMENT

Treatment strategy will depend on the stage of the disease.

In situ Breast Cancer (DCIS and LCIS)

LCIS: Observation alone with or without tamoxifen is the preferred option for women diagnosed with LCIS because their risk of developing invasive carcinoma is relatively low (approximately 21% over 15 years) and is equal in both breast..(70) Follow-up of patients with LCIS includes physical examinations every 6 to 12 months for 5 years and then annually. Annual diagnostic mammography is recommended in patients being followed with clinical observation.

DCIS: Treatment options for DCIS are mastectomy, breast-conserving surgery (BCS) plus radiotherapy or BCS alone. The goal of treatment for DCIS is to reduce local recurrence, because 50% of the time that DCIS recurs it recurs as an invasive cancer. Factors that may modify treatment are (1) the grade of the lesion, with higher-grade lesions more likely to recur in a short time; (2) the youth of the patient, with many more years at risk for recurrence and (3) the size of the lesion. For years the traditional surgical management of DCIS was mastectomy, with or without axillary dissection. Breast conservation technique and irradiation is now a preferred alternative where local breast radiation is available. Only small, low grade DCIS that has been excised with a large margin may be considered for BCS alone. Axillary lymph node staging is discouraged in women with apparent pure DCIS. However, a small proportion of patients with apparent pure DCIS will be found to have invasive cancer at the time of their definitive surgical procedure which will require a further axillary dissection. (71) Addition of Tamoxifen reduces the risk of developing contralateral breast cancer.(72;73). Follow-up of women with DCIS includes a physical examination every 6 months for 5 years and then annually, as well as yearly diagnostic mammography.

Early Breast Cancer (Stages I and II or T1-3N0-1 M0):
Staging for metastatic disease is standard for most patients diagnosed with early breast cancer and include a chest X-ray, bone scan and ultrasound of the abdomen. If negative, treatment intent is curative, and involve modalities that fight the cancer locally (surgery and radiation) and systemically (chemotherapy and endocrine therapy).

Loco-regional Treatment:
Local treatment requires the treatment of the entire breast and the axillary lymph nodes with surgery, radiation, or a combination of both. Surgery can be breast conservation therapy (BCT) and axillary staging (SLNB or axillary dissection) or simple or total mastectomy with axillary staging (modified radical mastectomy).

The surgical procedure for the excision of the breast in BCT goes by several names (Partial mastectomy, tylectomy, segmental resection, quadrantectomy or lumpectomy).
The goal of breast-conserving surgery is to minimize the risk of local recurrence while leaving the patient with a cosmetically acceptable breast. The selection of BCT versus mastectomy depends on the size of the tumor relative to the rest of the breast and the availability of radiation. BCT and breast radiation together offers equivalent survival to total mastectomy provided the BCT removes the entire tumor with negative margins.
Generally a tumor less that 1/4 of the breast is amenable to BCT; anything much larger will result in significant breast distortion after surgery and radiation.
The procedure can be done safely with local anesthesia and sedation unless axillary dissection is part of the procedure. A curvilinear incision lying parallel to the nipple-areola complex is made in the skin overlying the breast cancer. Radial scars are avoided because of poor cosmetic results. Skin encompassing any prior biopsy site is excised, but skin excision is not otherwise necessary. The breast cancer is removed with an envelope of normal-appearing breast tissue. Meticulous hemostasis is important because a large hematoma distorts the appearance of the breast and makes re-excision and follow-up more difficult.
The excised specimen is orientated for the pathologist using sutures, clips, or dyes. Additional margins (superior, inferior, medial, lateral, superficial, and deep) can be taken from the surgical bed to confirm complete excision of the tumor. These six margins are marked with titanic clips as this may help the Radiotherapist in planning the boost. In addition, it helps the surgeon to do an adequate re-resection if the margins are not free of cancer cells at definitive paraffin-embedded histology sections.
Attempts to re-approximate the cavity in the breast should be avoided, because this will usually distort the breast contour, which may not be apparent when the patient is supine on the operating table. Similarly, drains are not used. Allowing the cavity to fill with serum and fibrin maintains contour in the early postoperative period and helps to avoid deformity. The procedure is completed with two-layer closure of the deep dermis and the subcuticular layer, and a light dressing is used.

There is no firm consensus on the extent of the excision or margins required. The main benefit of BCT is preservation of body image for the woman, which greatly improves her quality of life. Several randomized controlled trials have shown that BCT and radiation has a similar survival advantage as mastectomy as there were no significant differences in the two groups in disease-free survival, distant-disease-free survival, or overall survival and even in loco regional control.(74-80)
Contraindications to breast conservation therapy (BCT) can be divided into absolute or relative. Absolute contraindications include lack of mammography facilities to ensure all tumors have been removed, adequate pathology facilities to ensure tumor- free resection margins and/or lack of radiotherapy facilities.(10;11) Other contraindications include pregnancy (first or second trimester because of the risk of radiotherapy to the fetus), patient’s preference, diffuse suspicious calcifications, inflammatory breast carcinoma, previous radiation to the region, and inability to achieve negative margins particularly with extensive intraductal carcinoma (EIC). Relative contraindications also include two or more gross tumors (multicentric disease) in different quadrants, tumor greater than 5 cm initially or after neoadjuvant chemotherapy, large tumor-breast ratio for cosmesis, and collagen vascular disease.(74)
In Africa, many of the factors above make the practice of BCT difficult and these include lack of adequate diagnostic oncology services like mammography and surgical pathology, lack of adequate therapeutic oncology services like radiotherapy, advanced stage disease and poor follow up culture.(5) Thus the majority of the patients with early breast cancer in Africa should still undergo total mastectomy and axillary clearance.
In a total or simple mastectomy, the patient is placed in the supine position with the ipsilateral arm extended horizontally. General anesthesia is used. The incision is in the form of an ellipse is designed to include the skin overlying the tumor or biopsy scar and the nipple–areola complex. Superior and inferior skin flaps are then raised. The plane between the subcutaneous tissue and breast tissue is not always obvious and is most easily identified at the medial superior flap; it is therefore easiest to begin here. The skin flaps must be thin, to ensure that all the breast tissue is removed, and yet enough subcutaneous fat to ensure adequate blood supply to the skin. Superiorly the dissection must include the tail of Spence laterally. Inferiorly, the dissection ends at the inframammary fold. The entire breast, the skin ellipse, nipple-areola complex are then dissected off the pectoralis fascia. The procedure is completed with an en bloc excision of the axillary lymph nodes level I and II (see description below). The mastectomy site and axillary nodal basin are then irrigated with saline solution, and meticulous hemostasis is achieved. The wound is closed with a closed suction drainage bottle fixed to a catheter brought out through a separate stab incision.

Modified radical mastectomy can be done alone or in association with breast reconstruction. Reconstruction, using implants or myocutaneous flaps, provides many women with an enhanced body image and self-esteem, and better psychosocial adjustment, but it does not impact on the probability of disease recurrence or survival. (81;82) One method becoming widely used is the skin-sparing mastectomy (SSM) that conserves an extensive section of skin, as well as the more recent skin and nipple-sparing mastectomy that preserves the nipple-areolar complex. (83-85). SSM is clearly contraindicated in patients with direct involvement of the skin by the underlying tumor. Nicotine, previous radiotherapy, diabetes and obesity increase the risk of skin envelope ischemia, skin necrosis and infection.
However, the additional cost of reconstruction is an issue especially in resource poor countries.

Treatment of the Axilla

Axillary lymph node dissection (ALND)
The status of axillary and internal mammary lymph nodes is the most significant prognostic factor for survival in patients with breast cancer. In breast cancer, the status of axillary and internal mammary lymph nodes is the most significant prognostic factor for survival. The axillary nodal basin has been the main target in lymphatic staging in breast cancer because over 75% of the lymphatic flow from the breast is directed to the ipsilateral axilla. Axillary clearance (ALND) has been the gold standard in axillary staging in breast cancer, providing valuable information about the planning of adjuvant therapy, prognosis and an excellent regional disease control as well. Removal of 10 or more nodes as assessed by the pathologist provides accurate information about the axillary nodal status of the patient.

The most accepted surgical axillary clearance procedure is a level I and II axillary dissection, detecting 98.5% of cases with positive axillary nodes. (86) Either at the time of mastectomy, or through a separate incision (if BCT), the lateral border of pectoralis major muscle is identified. The clavipectoral fascia, extending laterally from the edge of this muscle, is divided parallel to the edge of the muscle to allow entry into the axilla. The superior border of the dissection is the lower border of the axillary vein; dissection above the vein runs the risk of damage to the brachial plexus. The nerves to latissimus dorsi (thoracodorsal) and to serratus (long thoracic) are identified and are the posterior border of the dissection. The lateral border is the floor of the axilla, consisting of skin and subcutaneous tissue. Retraction of the pectoralis minor muscle medially allows for the removal of level II nodes. All the fatty tissue within these borders is removed. The sensory intercostal brachial nerve runs through the axilla and may or may not be preserved.

Sentinel node biopsy

Although long considered the standard management of the axilla for breast cancer, ANLD is associated with significant arm morbidity (20-25% risk of lymphedema) and risk of damage to the axillary vein, nerve to the latissimus dorsi and serratus anterior and hypoesthesia of the arm and the thorax. For these reasons, other less invasive but accurate methods have been sought for axillary staging in breast cancer, especially in the developed world, where ¾ of patients present with early node negative disease . Clinical examination of the axilla and available diagnostic imaging techniques like US, CT and PDG-PET are manifestly inaccurate for axillary staging.

Less invasive than ALND, sentinel lymph node biopsy (SLNB) is now accepted as an alternative to routine ALND for the detection of occult lymph node metastases in patients with clinically node-negative breast cancer. (87;88) SNLD is based on the observation that specific areas of the breast drain by way of afferent lymphatics to a specific ‘sentinel’ node. This node can be detected by injecting vital blue dye (isosulfan blue dye, methylene blue or patent blue V dye) or a radioactive suspension (Tc99m radioisotope labeled colloids). The route of injections include intra parenchymal (peri-tumorally), intradermal or subareolar.(88;89). The use of vital dye is resource efficient (cheaper and less time consuming) and safer, but may miss non axillary sites and also carries the risk of anaphylactic reactions while radioactive agents are more expensive, carries the risk of exposure to staff, and requires that the hospital have a nuclear medicine department.

There are five principal aims for the excision and histopathological analysis of the SN: (1) minimally invasive assessment of the nodal status; (2) selection of patients with positive SNs for elective lymph node dissection (ELND) or adjuvant therapy; (3) prevention of lymph node dissection and associated morbidity in SN negative patients; (4) detection of aberrant or alternative lymphatic drainage; (5) improvement of sensitivity of histopathological detection of lymph node metastasis.(90)
Further surgery of the axillary nodes now depends on the results of the sentinel lymph-node biopsy—if negative, ALND is avoided. While SLNB is becoming widely used in the developed world as a method to assess the axilla, ALND remains the recommended management for treatment in any hospital that does not have access to a nuclear medicine department or a dedicated breast pathologist able to use specialized immunohistochemistry markers.

Radiotherapy in early breast cancer: The aim of radiotherapy to the whole breast after BCT is to establish local control. Numerous studies have shown reductions in local recurrences from 12-35% to 2-10% at 5-10 years. This compares to local recurrence rates after mastectomy of 5%.(91) In most developed countries, the current standard of care for patients with early-stage breast cancer consists of breast-conserving surgery, followed by 5–6 weeks’ postoperative radiotherapy used on the whole breast. Probabilities of adequate local control rates and good cosmetic results are high with the use of conventional fractionation. Patients who cannot receive radiation are treated with mastectomy. Some recent papers suggest a small survival advantage which was rather offset by the long term toxicity from radiotherapy resulting in deaths from vascular and cardiac injuries.(92).

Some data support the effectiveness of an additional dose applied to the tumor bed (i.e., boost irradiation) to reduce local recurrence. However, delivery of the boosting dose raises the rate of morbidity, which reduces cosmetic outcome.

Recent advances in radiotherapy includes partial breast irradiation using various techniques such as such as low or high-dose rate brachytherapy (interstitially or with an intracavitary balloon), conformal external-beam irradiation (including intensity modulated radiotherapy), and intraoperative radiotherapy (Electron Intra Operative Therapy-ELIOT).(93;94)

Most reports of partial breast irradiation have provided results much the same as those achieved with conventional external beam, even though some caution is needed until the safety and efficacy of such irradiation have been shown in appropriate patients and analysis of long-term treatment outcomes.(95-97)

Systemic Treatment
More than half the women with operable breast cancer who receive only locoregional treatment die from metastatic disease. This indicates that breast cancer is a systemic disease and that the micrometastatic process can occur early even independently from lymphatic spread. (76;98) The way to improve survival is to give these women systemic medical treatment, including endocrine therapy, chemotherapy, or targeted therapy with trastuzumab along with surgery/radiotherapy.

Systemic treatment may be given after (adjuvant) or before (neoadjuvant, primary, or preoperative) locoregional treatment. Adjuvant treatment has been shown to be effective in randomized clinical trials, whereas the evaluation of neoadjuvant systemic therapy is ongoing.

It is important to realize, especially in the African context, that any systemic therapy including hormonal therapies, will at least temporarily interrupt child bearing. The current recommendations of at least 5 years of Tamoxifen after diagnosis will significantly impact on the ability of a woman to bear many children. Chemotherapy will cause most women to stop menstruating and permanent premature menopause is common. These recommendations listed below, based on the culture of the developed world, may not be acceptable or applicable to African women.

The choice of systemic adjuvant therapy in early breast cancer will depend on the following factors; estrogen (ER)/progesterone (PR) receptor status, menopausal status and over-expression of HER2. It will also depend significantly on the risk of recurrence and therefore the potential benefit of the treatment. Any systemic therapy carries with it a risk of toxicity, and can be quite expensive. A woman at high risk of recurrence will benefit significantly from treatment while for a woman at low risk the benefit will be small yet she will be exposed to the same toxicity. For example, a 20% reduction with chemotherapy for a patient with a baseline 50% risk of recurrence will result in an absolute reduction to 10% (from 50% to 40%) where as a woman with a 10% recurrence risk reduces her risk of recurrence to 8%, only a 2 % absolute reduction. Some women would not choose chemotherapy for a 2% risk reduction and others might. The decision to take systemic therapy therefore is therefore very much dependent on the woman and her understanding of these risks. (99)

Adjuvant endocrine therapy is effective in ER and/ or PR positive tumors. The most commonly used endocrine therapy is the Selective Estrogen Receptor Modulator (SERM) Tamoxifen, used in premenopausal women. Other SERM agents like Toremifene and Raloxifene are equally effective. There is strong evidence to support the superiority of a 5 year Tamoxifen therapy over shorter durations. Tamoxifen in addition helps to maintain bone mineral density in post menopausal women and reduces the risk of developing cancer in the contralateral breast. The side effects of Tamoxifen include hot flashes, risk of thrombo-embolic disease, endometrial carcinoma and cataracts.

For post-menopausal women, third generation selective aromatase inhibitors have been shown in recent trials to be more effective than Tamoxifen and have become the standard of care. Examples include non steroidal type (anastrozole and letrozole) and the steroidal type exemestane. Patients using aromatase inhibitors have less gynecological symptoms such as endometrial cancer, vaginal bleeding, and vaginal discharges. Fewer cerebrovascular events and venous thromboembolic events were also observed with patients receiving aromatase inhibitors. However, musculoskeletal effects (arthritis, arthralgia, and/or myalgia) and bone toxicity (bone fractures) are associated with aromatase inhibitors.

The combination of endocrine therapy and cytotoxic chemotherapy provides benefits greater than the benefits from either therapy alone. They are therefore usually offered sequentially, with chemotherapy given right after surgery, local radiation therapy is then given, and endocrine therapy commenced. Premenopausal women are given Tamoxifen for five years. The optimal duration of the aromatase inhibitors has not yet been determined and postmenopausal women remain on them indefinitely.
Ovarian ablation (e.g., surgical oophorectomy or radiation ablation) or suppression (e.g., use of the gonadotropin- releasing hormone or luteinizing hormone-releasing hormone analogues) is another effective way to reduce estrogen in premenopausal women. It can be used as an adjuvant treatment alone or to induce menopause in very high risk premenopausal women to allow the use of adjuvant aromatase inhibitors.

Chemotherapy: Chemotherapy has been shown to substantially improve the long-term, relapse-free, and overall survival in both premenopausal and postmenopausal women up to age 70 years with lymph node-positive and lymph node-negative disease irrespective of the hormone receptor status.
The administration of polychemotherapy (two or more agents) is superior to the administration of single agents. Four to six courses of treatment (3–6 months) appear to provide optimal benefit, with the administration of additional courses adding to toxicity without substantially improving overall outcome. Popular regimes include CMF (cyclophosphamide, methotrexate,fluorouracil) , CAF, AC, FEC. Anthracycline based adjuvant therapy (with doxorubicin or epirubicin) result in a small(4-5%) but statistically significant improvement in survival compared with non-anthracycline-containing regimens.(100).

Trials using accelerated or dose dense chemotherapy (two weekly interval instead of the standard three weeks) with granulocyte colony stimulating factor (GCSF) support to overcome the risk of neutropenic sepsis has been demonstrated to improve both disease free survival and overall survival with fewer neutropenic crises.
Trials using high dose chemotherapy with haemopoietic stem cell rescue on the other hand showed high morbidity and no benefit from this approach.

Around 20% of breast cancers over express HER2, and this is associated with an adverse prognosis. Trastuzumab is a humanised monoclonal antibody directed against the external domain of the receptor with clinical activity as a single agent inpatients whose cancers over express HER2.
Trastuzumab in combination with Taxanes and other drugs have shown considerable improvement in metastastic breast cancer. Its role in the adjuvant setting in early breast cancer has been so successful in HER2 positive breast cancer showing significant DFS and OS. Unfortunately, the cost implication is a drawback to its use in countries with limited resources.

Bisphosphonates are drugs that inhibit osteoclast mediated bone resorption induced by tumors. Some adjuvant trials indicate that two years of oral clodronate reduces the incidence of bone metastases. One trial showed a small, but significant, improvement in overall survival. Further trials are underway with clodronate and the newer, more potent bisphosphonate zoledronate to define their long term effectiveness.
They are very useful in patients taking Aromatase inhibitors because of the risk of bone loss and fractures.

Advanced Breast Cancer (Stages III and IV):

This includes Locally Advanced Breast Cancer (LABC), metastastic cancer and recurrent cancer. (see photos)

Photo 1

Photo 2

Photo 3

Photo 4

Photo 5


LABC:

LABC refers to Stage III tumors according to the TNM staging. Locally advanced breast cancer (LABC) accounts for at least half of all breast cancers in countries with limited resources and has a poor prognosis (12). Locally advanced tumors include tumours that present with palpable lymph node metastases, ulcerations, tumors greater than 5 cm etc.
A subtype of LABC that deserves some further discussion is Inflammatory Breast Cancer (IBC). Inflammatory breast cancer is a rare but aggressive subtype of breast cancer, which historically was considered uniformly fatal. Clinically, inflammatory breast cancer is characterized by the rapid onset of breast warmth, erythema, and edema (peau d’orange) often without a well-defined mass.
Along with extensive breast involvement, women with inflammatory carcinoma often have early involvement of the axillary lymph nodes. In general, women with inflammatory breast cancer present at a younger age are more likely to have metastatic disease at diagnosis, and have shorter survival than women with non-inflammatory breast
cancer.(101-103)
The management of LABC requires a combined modality treatment approach involving surgery, radiotherapy and systemic therapy.

Radiotherapy in LABC:
Radiotherapy after MRM or mastectomy to the chest wall or axilla is restricted to patients with high risk of recurrence. These include tumors larger than 5 cm in maximum diameter and those with four or more involved axillary lymph nodes, those with positive surgical margins on resection, and those with involvement of the skin or underlying chest wall. (12) It can also be a very effective local modality in controlling or shrinking tumors that are not amenable to surgical therapy.

Preoperative and locoregional treatment:
The initial management should be neoadjuvant chemotherapy with Doxorubicin- or
Epirubicin-based or Paclitaxel- or Docetaxel based chemotherapy. Patients with HER2 positive tumors should be considered for preoperative chemotherapy incorporating Trastuzumab.
The advantages of neoadjuvant therapy include down staging of the tumor, improving operability of tumors and increasing the chances of BCT
For patients that respond to neoadjuvant chemotherapy, the following options are recommended (71;104-108): modified radical mastectomy, radiotherapy to the chest wall and supraclavicular nodes (plus internal mammary nodes if involved) with or without delayed breast reconstruction. In those women with LABC who do not have access to neoadjuvant chemotherapy because of economic constraints or radiotherapy, mastectomy with node dissection, when feasible, may still be considered in an attempt to achieve local-regional control. (12) The second option is BCT with surgical axillary staging, radiotherapy to the breast, supraclavicular nodes (plus internal mammary nodes if involved).
However, for patients who fail to respond to preoperative chemotherapy, recommended treatment is to consider additional systemic chemotherapy and/or preoperative
radiation.

Adjuvant treatment:
Chemotherapy should contain an anthracycline. Acceptable regimens are 6 cycles of 5 Fluorouracil, Doxorubicin, Cyclophosphamide (FAC) or Cyclophosphamide, Epirubicin, 5Fluorouracil (CEF). Sequential addition of Taxanes has also proven very effective.
Tamoxifen for 5 years should be recommended to pre- and postmenopausal women whose tumours are hormone responsive.
Aromatase inhibitors like Letrozole, Anastozole and Examestane can be used in post menopausal patients.
Surgical oophorectomy causing ovarian ablation is a very effective therapy in the treatment of locally advanced and metastatic ER positive breast cancer in premenopausal women. This therapy is one that would be very feasibly applied in Africa provided that it was acceptable to the woman.

Metastastic and Recurrent Cancer
The standard evaluation procedure for this group of patients includes history and clinical examination, full blood count, liver function test, platelet count , chest X-ray, limited skeletal survey especially of any long or weight bearing bones that are painful, biopsy of recurrence, evaluation of hormone receptor status, ultrasound of the abdomen or CT where available.

Others include bone scans, MRI, PET, and determination of HER2 status of the tumor. These are however tall orders in countries with limited resources and where there are no medical insurances to cover the cost of these investigations. Pragmatism is required in this setting.

Treatment of Local Recurrence

Local recurrence can occur in two settings; post BCT or MRM.
Post MRM local recurrence should undergo local resection of the recurrence where feasible without unnecessarily endangering the lives of the patients. In addition, radiotherapy of the involved area should be done if the chest wall was not previously irradiated or if it could be done safely.
Post BCT patients should undergo a total mastectomy. Systemic therapy for local recurrence could be adjuvant chemotherapy or endocrine therapy as in LABC.

Addition of Hyperthermia to radiotherapy has been shown in some trials to cause a statistically significant increase in local tumor response and greater duration of local control. This is however technically demanding and resource intensive.

Systemic disease
Systemic recurrence and metastatic cancers are incurable, so the goals of therapy are to prolong survival, improve quality of life with minimal morbidity or toxicity from the therapy.
Minimally toxic endocrine therapy is therefore preferred to the use of cytotoxic therapy whenever indicated. Endocrine therapies are indicated in women with hormone receptor status, bone or soft tissue disease only and those with limited asymptomatic visceral disease. For post menopausal women, the choice is between Tamoxifen and aromatase inhibitors, with aromatase inhibitors having a slight edge especially in those who have taken anti-estrogen previously.
For premenopausal women who are anti-estrogen naïve, anti-estrogen with or without LHRH agonist is the preferred choice. Oophorectomy is an excellent cheap alternative where drugs are not available.
Since the majority of African women with breast cancer are hormone receptor negative, few will benefit from endocrine therapy, chemotherapy will be the option in most cases.
Premenopausal patients who have taken anti-estrogen previously have a choice of either surgical or radiotherapeutic oophorectomy or luteinizing hormone-releasing hormone (LHRH) agonists with or without an antiestrogen.

Endocrine therapies in postmenopausal women include selective, nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); pure antiestrogens (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). In premenopausal women, therapies include LHRH agonists (goserelin and luprolide); surgical or radiotherapeutic oophorectomy; progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol).
Chemotherapy is the best option in women with estrogen and progesterone receptor-negative tumors, symptomatic visceral metastasis, or endocrine therapy refractory disease.
The higher rates of objective response and longer time to progression of combination chemotherapy are at the expense of increased toxicity with little survival benefit.
Therefore, there is no significant advantage of combination chemotherapy over sequential single agents.
Preferred first-line chemotherapies include sequential single agents or combination chemotherapy. Among preferred first-line single agents, are doxorubicin, epirubicin, pegylated liposomal doxorubicin, paclitaxel, docetaxel, capecitabine, vinorelbine (all
category 2A), and gemcitabine (category 2B). Among preferred first-line
combination regimens are cyclophosphamide, doxorubicin, and fluorouracil (FAC/CAF); fluorouracil, epirubicin, cyclophosphamide (FEC); doxorubicin, cyclophosphamide (AC);
epirubicin, cyclophosphamide (EC); doxorubicin in combination with either docetaxel or paclitaxel (AT); cyclophosphamide, methotrexate, fluorouracil (CMF); docetaxel, capecitabine; gemcitabine, paclitaxel.
Patients with tumors that are HER2-positive may derive benefit from treatment with trastuzumab as a single agent or in combination with selected chemotherapeutic agents. 27% of patients treated with a combination of Trastuzumab and doxorubicin/cyclophosphamide chemotherapy develop significant cardiac dysfunction making this regime unsafe and unpopular. (71)

 

Treatment of Complications
In Africa, a good number of women present with fungating/ ulcerating masses and many of them are so ill that they can not undergo surgery or radiotherapy immediately. The following are some useful supportive measures:

1. Dressing of the wound with honey and metronidazole cleanses and remove the odor. This measure in addition to the use of neoadjuvant chemotherapy has largely reduced the need for toilet mastectomy.
2. Clean malignant ulcers are prone to secondary hemorrhage; topical formalin is effective in this setting.
3. Pain is another significant problem and this may be due to the disease, therapy or depression. Optimal pain management is very crucial to improving the quality of life. If pain occurs, there should be prompt oral administration of drugs in the following order: non-opioids (aspirin and paracetamol); then, as necessary, mild opioids (codeine); then strong opioids such as morphine, until the patient is free of pain. To calm fears and anxiety, additional drugs – “adjuvants” – should be used. To maintain freedom from pain, drugs should be given “by the clock”, that is every 3-6 hours, rather than “on demand” This three-step approach (see figure 2) of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective. Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective.(109)
4. Anemia as a result of the disease or chemotherapy is often under treated and underestimated in patients. It has a negative impact on quality of life and survival. It will require blood transfusion in some women. The introduction of recombinant human erythropoietin (epoetin) has provided an effective and convenient treatment of anemia without the risks of blood transfusion. Epoetin is also effective for the prevention of anemia and reduction of transfusion requirements in patients with a high risk of developing anemia during chemotherapy.(110-112)
5. Lymphedema of the arm is a very distressing complication which may occur as a result of the disease itself or as a result of surgery or radiotherapy in the treatment
of breast cancer. Treatment options include compression treatments (using compression bandage or garments and pneumatic compression devices),
therapeutic exercises and pharmacotherapy (antibiotics, flavonoids, hyaluronidase, and selenium). Diuretics have not been found useful. (113;114)
6. Respiratory distress in advanced breast cancer may be as a result of pleural effusion or deposits in the lungs. Closed thoracostomy tube drainage with
pleurodesis using Tetracycline or Bleomycin is an effective treatment. Lung metastasis can be treated with steroids inhalers, bronchodilators, diuretics,
anxiolytics, chest physiotherapy and oxygen.(5)
7. Neurological complications include cerebral metastases, spinal, leptomeningeal, cranial and peripheral nerve metastases.(115) Treatment includes steroids,
radiotherapy and surgery for localized metastases.
Younger women with breast cancer are more prone to physical and psychological distress which makes them have poorer quality of life outcomes. These arise as a result of the disease and the complications of treatment. Gonadal toxicity leading to irregular menses, amenorrhea and premature menopause is especially disturbing for African patients, the majority of whom are in their reproductive age group. Other problems like Alopecia, fertility problems and the cost of treatment may severely affect relationship especially among young couples. In this context, a multi disciplinary approach is important which will involve psychologists, social welfare/support groups and various advocacy groups where survivors of breast cancer can share their experiences and support one another.(116-120)

9. PROGNOSIS

Natural History: The natural history of breast cancer in 250 untreated women revealed the following statistics; Median survival of untreated breast cancer was 2.7 years after initial diagnosis. The 5- and 10-year survival rates were 18.0 and 3.6%, respectively. Only 0.8% survived for 15 years or longer. Autopsy data confirmed that 95% of these women died of breast cancer, while the remaining 5% died of other causes. Almost 75% of the women developed ulceration of the breast during the course of the disease. The longest surviving patient died in the nineteenth year after diagnosis. (121)
With modern treatment, the 5-year survival rate for stage I patients is 94%; for stage IIa patients, 85%; and for stage IIb patients, 70%, while for stage IIIa patients the 5-year survival rate is 52%; for stage IIIb patients, 48%; and for stage IV patients, 18%.

Prognostic Iindicators:
Tumor size
Prognosis deteriorates with increasing tumor size, which is an independent predictor of survival in node-negative patients and correlates with the incidence of nodal metastases.
Staging
The status of the axillary lymph nodes is one of the most useful prognostic indicators for breast cancer, with average 10-year survival rates of 60-70% for node-negative patients, dropping to 20-30% in node-positive patients.
Histopathology


Histologic type
o Carcinoma in situ, because it is a preinvasive condition, is curable if completely removed, although 16% of patients with carcinoma in situ develop invasive recurrence after local excision of ductal carcinoma in situ, usually high grade. Similarly, 18% of patients develop invasive recurrence after lobular carcinoma in situ excision.
o Well-differentiated invasive cancers have a relatively good prognosis if they are tubular, mucinous, cribriform, or secretory.
o Medullary carcinoma is probably of intermediate prognosis, but different studies have used different criteria for its definition.
o Invasive ductal and invasive lobular carcinomas have a less favorable prognosis but are influenced heavily by other factors.
• Cytologic grade
o Cytologic grade is the best predictor of disease prognosis in carcinoma in situ but is dependent on the grading system used, such as the Van Nuys classification (high-grade, low-grade comedo, low-grade noncomedo).
o The grading of invasive carcinoma is also important as a prognostic indicator, with higher grades indicating a worse prognosis. Microscopic criteria for grading are shown in Table 5.
• Lymphovascular: Lymphatic invasion, vascular invasion, microvessel quantification, and lymphoplasmacytic infiltration are associated with a worse prognosis.
• Hormone receptor status: With the aid of gene expression studies using DNA microarrays and immunohistochemistry, several distinct biologic breast cancer subtypes have been identified. These subtypes differ markedly in prognosis and in the number of potential therapeutic targets they express.

The intrinsic subtypes include 2 main subtypes of estrogen receptor (ER)–negative tumors (basal-likeand human epidermal growth factor receptor-2 positive/ER- [HER2_/ER-] subtype) and at least 2 types of ER+ tumors (luminal A and luminal B). The basal like subtype carries poor biologic (worse grade) and clinical prognostic indicators like positive axillary nodes.
This subtype was found to be more prevalent in pre-menopausal African –American women compared to post menopausal African –American women and other races (122)This finding may be one of the reasons why African- American women with breast cancer have high grade, late stage tumor and with poor prognosis and poor survival outcome.
The similar clinical outcome of native African women with breast cancer may tempt one to extrapolate these findings seen in African-American women. To lend credence to this fact, the few studies on hormone receptor status of breast cancer in native African women show that the majority of them are Estrogen or Progesterone negative (123-125).
There are also several other provocative parallels between African-American and native African breast cancer patients which include a younger age distribution and a greater prevalence of high grade, estrogen-receptor-negative disease among breast cancer patients in the Ghanaian and Nigerian populations of western Africa similar to the patterns of breast cancer reported among African-American women. Western African populations served as the source for most of the slave trade to colonial North America, and therefore share a common ancestry with present-generation African Americans. These parallels suggest the possible contribution of founder effects.(16)
However, further research needs to be done in this area before reaching any conclusion is reached as the African-Americans are a heterogeneous group with mixed genetic heritage consisting of Hispanics, Caucasians and Africans. In addition other socioeconomic factors and environmental factors may contribute to the clinical outcome seen.(126;127)

• Immunohistochemistry
o The most widely used tests are for the estrogen receptors (ER) and progesterone receptors (PR). Immunohistochemistry analysis of heat-treated paraffin sections has largely superseded the enzyme-linked immunosorbent assay (ELISA) ligand-binding assay. ER- and PR-positive status (ie, >10 fmol on ELISA; >15 H-score on immunohistochemistry) predict improved response to endocrine treatment, time to relapse, and overall survival.
o Immunohistochemical positivity for c-erb-B2 and p53 is associated with a worse prognosis.
o HER-2 status: The human epidermal growth factor receptor-2 (HER-2/neu) is a well-characterized biomarker in the biology of breast carcinoma that has had immediate impact on clinical medicine. The positive status of HER-2/neu is associated with a younger age and several adverse prognostic factors, i.e., advanced stage, absence of estrogen and progesterone receptors, metastasis to axillary lymph nodes, and high nuclear grade. In addition, women diagnosed with positiveHER-2/neu breast carcinoma generally have relative resistance to anthracycline-based chemotherapy, tamoxifen therapy, and have shorter disease-free and overall survival. (128)


Other prognostic indicators
Advances, in the knowledge of the molecular mechanisms that influence normal and aberrant cell growth, have led to the identification of an increasing number of surrogate biomarkers, which have been correlated with prognosis or used as predictors of response to specific treatments. These novel prognostic markers can be classified as follows:


• Oncogene products
o Bcl-2
o p53
o HER-2/neu
o Cyclin D1
o Nm23
• Proteases
o uPA
o Cathepsin D
o Tenascin C
• Markers of proliferation - Ki-67


HER-2/neu identifies patients with a poor prognosis. These patients are likely to respond to treatment with trastuzumab (Herceptin).
Tumors positive for Ki-67 have a high metastatic potential and warrant the possible use of early aggressive therapy.
uPA and cathepsin D identify poor prognosis node-negative tumors. In these cases, chemotherapy can be offered.
The use of gene expression profiling to detect breast carcinoma has already shown that the differential expression of specific genes is a more powerful prognostic indicator than traditional determinants such as tumor size and lymph node status. These molecular assays are awaiting clinical validation.

10. PREVENTION

Screening as currently practiced can reduce mortality but not incidence, and then only in a particular age group. Advances in treatment have produced significant but modest survival benefits. A better appreciation of factors important in the etiology of breast cancer would raise the possibility of disease prevention. Currently, prevention strategies fall into two groups: chemoprevention and surgical prophylaxis.

Chemoprevention is defined as the systemic use of natural or synthetic chemical agents to reverse or suppress the progression of a premalignant lesion to an invasive carcinoma.(129). Tamoxifen is currently the only agent that has been approved clinically for use in women with high risk of developing cancer. Raloxifene, selenium, retinoids, aromatase inhibitors and cyclo-oxygenase 2 inhibitors require further clinical investigation before adoption in this context.

Surgical prophylaxis: by either a bilateral mastectomy or oophorectomy, is another avenue of prevention. Some studies have demonstrated that women with definite BRCA1 or BRCA2 mutation may have an overall reduction in their breast cancer risk profile after such operation.(130)

Dietary intervention If specific dietary factors are found to be associated with an increased risk of breast cancer dietary intervention will be possible. However, reduction of dietary intake of such a factor in whole communities may well be difficult to achieve without major social and cultural changes. Dietary fat reduction and exercise decrease the circulating serum oestradiol level, but whether this in turn leads to a reduction in the incidence of breast carcinoma has not been determined conclusively.(131)

11. BREAST CANCER AND PREGNANCY

Pregnancy associated breast cancer is defined as breast cancer diagnosed during pregnancy or lactation or one year post partum. Breast cancer and pregnancy can be classified into three main situations; these are (a) breast cancer that is detected during the evolution of pregnancy, (b) breast cancer that is detected during lactation or postpartum, and (c) pregnancy in patients who have had a previous breast cancer. Cancer complicates approximately 1 per 1000 pregnancies and accounts for one-third of maternal deaths during gestation. The prevalence of breast cancer during pregnancy is increasing due to delayed onset of childbearing. Breast cancer is diagnosed in approximately 1 in 3000 pregnancies. The incidence ranges from 0.76% to 3.8% of breast cancer cases. The median age of pregnant women affected with breast cancer is 33 years. In a recent review in Nigeria, 12% of the patients with Breast Cancer were pregnant or lactating and 74% were premenopausal , making it the most frequently occurring malignancy during pregnancy, along with cancer of the uterine cervix.(5) Treatment decisions for breast cancer patients during pregnancy become most difficult because not only the mother but also the fetus is involved. The final advice should be based upon the following considerations: (1) the parents’ decision whether or not to continue with the pregnancy, (2) the period of pregnancy when the breast cancer is diagnosed, and (3) the stage of the breast cancer.
A detailed guideline on the management of breast cancer in pregnancy can be found in the NCCN Clinical Practice Guidelines in Oncology™ Breast cancer V.1.2007 at www.nccn.org.
Early studies have indicated that the prognosis of breast cancer in pregnancy is very poor; however, more recent studies with more careful consideration of age and the stage of the disease show no significant differences. Evidence is lacking that termination of pregnancy changes the outcome of breast cancer. Pregnancy after breast cancer does not alter the outcome of treatment. The ideal interval between treatment for breast cancer and subsequent pregnancy is unknown. (132)

12. BREAST CANCER IN MALES
Male breast cancer is an uncommon disease although the incidence has increased over the past 25 years. Less than 1% of all breast cancer patients are male. Rates of male breast cancer vary widely between countries: in Uganda and Zambia the annual incidence rates are 5% and 15%, respectively of all breast cancer cases. These relatively high rates have been attributed to endemic infectious diseases causing liver damage, leading to hyperestrogenism. By contrast, the annual incidence of male breast cancer in Japan is less than five per million, in parallel with the lower than average incidence of female breast cancer in that country. Jewish men are the only racial group with a higher than average incidence (2•3/100 000 per year), irrespective of living in Israel or the USA.(133) Risk factors for Breast Cancer include Genetic (BRCA2, Klinefelter’s syndrome), Lifestyle (Obesity, Alcohol, Estrogen intake), Work (High ambient temperature, Exhaust emissions), and Disease (Testicular damage, Liver damage, Radiotherapy to chest) The predominant histological type of disease is invasive ductal, which forms more than 90% of all male breast tumors.

Much rarer tumour types include invasive papillomas and medullary lesions. Lobular carcinoma of the male breast has been reported not only in men with Klinefelter’s syndrome, but also in genotypically normal men with no previous history of oestrogen exposure or gynaecomastia. In large studies of male breast cancer, oestrogen receptor positivity has been reported in more than 90% of tumours, with 92–96% being progesterone-receptor positive.

Some studies suggested that breast cancer has a worse prognosis in men than in women, but if age- matched and stage-matched breast cancer is compared, there is no difference between the sexes (18;134;135)

FUTURE TRENDS AND CONTROVERSIES
Diagnosis and early detection:
Several new technologies, apart from mammography are being evaluated to improve the early detection of breast cancer. These include non ionizing imaging techniques like Ultrasonography and MRI. Other imaging tools being evaluated include scintimammography, positron emission tomography, magnetic resonance spectroscopy, optical imaging, thermo-acoustic computed tomography, microwave imaging, Hall effect imaging etc.
Molecular targets and new drugs
HER-2

Pertuzumab (also known as 2C4, Omnitarg) is a new recombinant humanised monoclonal antibody that also binds the extracellular portion of HER2, which causes steric hindrance and impairs receptor dimerisation. Ongoing phase-I testing has shown activity in patients with breast cancer that is either HER2-negative and trastuzumab-refractory HER2-positive.
Tyrosine kinase, cyclines, and proteosoma
Most tyrosine-kinase inhibitors are in preclinical investigations and only a few have been tested in patients with advanced breast cancer. Gefitinib is an inhibitor of the tyrosine kinase of human epidermalgrowth-factor receptor (HER1) and has shown some antitumour activity in preclinical studies and a phase II trial of patients heavily pretreated for metastatic breast cancer.
Insulin-like growth factor (IGF)
IGF is an interesting therapeutic target in breast cancer because its ligands and receptors are often overexpressed and are implicated in proliferation, transformation, and metastasis. The IGF system includes ligands IGF-I and IGF-II, receptors IGF-IR and IGF-IIR, and six known IGF-binding proteins. These binding proteins are promising targets for the manipulation of endocrine responsiveness and resistance to Trastuzumab.
Angiogenesis
Bevacizumab is a recombinant, humanised monoclonal antibody to vascular endothelial growth factor that has shown some efficacy when used alone in phase II clinical trials.
Several anti-angiogenic drugs have been tested for efficacy, including thalidomide, endostatin, angiostatin, SU6668, SU11248, and cyclo-oxygenase 2 (COX-2) inhibitors. COX-2 also improves the efficacy of
Receptors as targets for radionuclides
Efficacy of targeted therapy depends on the biologically relevant quality and quantity of the specific compound. This treatment needs to reach the target efficiently and accurately and exert a selective therapeutic effect. The development of biomarkers to assess in-vivo responses and the ability to use such biomarkers as targets for specific radionuclide treatment represent great challenges in cancer medicine.
IN SITU ABLATION
In situ ablation of the primary tumour has been suggested as an alternative to surgery. There are preliminary reports on methods using cryosurgery, or coagulating with heat,
delivered by a laser fiberoptic technique .

WHO WILL PERFORM BREAST SURGERY?
Within the next decade the number of patients undergoing axillary surgery will diminish as a result of improved staging by sentinel node biopsy. A greater part of the patients will have only breast resection, and these operations can be performed as day-case surgery, even under local anaesthesia. The surgical challenges during the next decade will be immediate breast reconstruction and various oncoplastic procedures. Therefore breast surgery will increasingly be performed by plastic surgeons. General surgeons will not be so interested in carrying out all the other rather undemanding breast procedures.(136)

Controversies
1. Relevance.
2. The place of post mastectomy radiotherapy in early breast cancer especially in women with T1 ,T2 and one to three positive lymph nodes.
3. Sequencing of post mastectomy radiotherapy and breast reconstruction(137)
4. The impact of mammographic screening in reduction of mortality in breast cancer

14. CONCLUSION

Management of breast cancer is a major challenge in resource limited countries.
Efforts should be geared towards early diagnosis, prompt and standardized treatment to reduce the burden of advanced disease in African women, majority of who are worse hit in the most productive part of their life time.
Our knowledge about breast cancer is evolving, but is still limited with respect to its etiology and biology, and with respect to its features in individual countries and
cultures.
Further research is needed to understand the role of genetics and environment in the etiology of breast cancer in Africa.

15. RECOMMENDATIONS
In high-resource countries, evidence-based guidelines outlining optimal approaches to early detection, diagnosis, and treatment of breast cancer have been defined and
disseminated. These guidelines unfortunately are not applicable in countries with resource constraints as they are not economically feasible or culturally appropriate.
The following recommendations might be considered appropriate in the resource-poor countries of Africa. Following the Breast Health Global Initiative we have stratified the recommendations into Basic, Limited, Enhanced and Maximal. (10-12;138)
Definition of Stratification terms
Basic level—Core resources or fundamental services absolutely necessary for any breast health care system to function. By definition, a health care system lacking any basic-level resource would be unable to provide breast cancer care to its patient population. Basic-level services are typically applied in a single clinical interaction.
Limited level—Second-tier resources or services that produce major improvements in outcome, such as increased survival, but which are attainable with limited financial means and modest infrastructure. Limited-level services may involve single or multiple clinical interactions.
Enhanced level—Third-tier resources or services that are optional but important. Enhanced-level resources may produce minor improvements in outcome but increase the number and quality of therapeutic options and patient choice.
Maximal level—High-level resources or services that may be used in some high-resource countries, but nonetheless should be considered lower priority than those in the basic, limited, or enhanced categories on the basis of cost or impracticality for limited-resource environments. In order to be useful, maximal-level resources typically depend on the existence and functionality of all lower-level resources.

Recommendations are presented in tabular form and are reproduced with permission from the BHGI.

Our own recommendations include:
1.Early Detection and Diagnosis: Possible less resource-intensive methods for earlier diagnosis of breast cancer like education in breast awareness, training in breast self-examination (BSE), regular clinical breast examination (CBE) by experienced personnel and diagnostic ultrasound may be the option in resource limited countries as mammography screening may be resource intensive. (69)
2. To improve breast pathological capacity and services in Africa, the following approaches may be explored; including training pathologists, establishing pathology services in centralized facilities, and organizing international pathology services. In particular it is important that estrogen and progesterone receptor status of tumors be identified.
3. As staging is crucial to treatment decisions and prognosis, a thorough clinical evaluation after the diagnosis of breast cancer to check for clinically obvious indications of metastases to the lymph nodes and other areas is crucial. In addition, tests to assess the presence of metastases to the lungs, liver, and bone provide valuable information, if available. Hormone receptor testing of pathology specimens should be part of the pathology services
4. More training for surgeons in BCT and Sentinel node biopsy.

Adisa Adeyinka Charles MD,FWACS, FICS
Director, Residency Training Program
Abia State University Teaching Hospital
Aba, Nigeria

Alexandra M. Easson, MSc , MD , FRCSC, FACS
Assistant Professor, Department of Surgery
General Surgery and Surgical Oncology
Mount Sinai Hospital and Princess Margaret Hospital
610 University Avenue Toronto , Ontario M5G 2M9


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