BREAST CANCER

General considerations

Structurally, the mammary gland is a group of 12 to 20 specialized apocrine glands connected by

ducts to the nipple. The ducts are lined with single layers of epithelial cells and dilate as they approach the

nipple. Each lobular unit is surrounded by fibrous septae, which eventually connect the pectoral fascia to the

skin (Cooper's ligaments).

The structural composition of the breast changes with age. There is also significant change in the

mammary gland secondary to hormonal stimulation during the menstrual cycle. In the preovulatory phase,

histologically, the breast cells are more compact and ductal epithelium predominates secondary to estrogen

stimulation.

The postovulatory phase, or the proliferative phase, demonstrates an increase in the acinar

epithelium. During this phase, there is an increase in glandular cells and ductal cells with the woman

experiencing increased nodularity and painful engorgement of the breast.

It is recommended to plan routine breast examinations and routine mammograms after menses to

reduce discomfort to the patient and allow more thorough examination.

Dramatic histologic changes accompany pregnancy and lactation. There is an increase in the size

of the mammary lobule and in the numbers of gland fields. During pregnancy, increasing amounts of

estrogen, progesterone and HPL produce active growth of functional breast tissue.

Estrogens directly interact with human breast cells to stimulate growth. There are other trophic

substances aside from estrogens. These include glucocorticoids, epidermal growth factor, insuline like

growth factor I, prolactin, transforming growth factor alpha.

For women between the ages 9f 35 and 54, breast cancer is the number one cause of cancer

mortality. Breast cancer may be diagnosed in 12% of all women and of that group 30% ultimately die of the

breast cancer.

Clinical breast cancer research has focused on effective methods to detect the disease at its earliest

stages and standardized treatments to cure it.

Risk factors

Age is an important risk factor. Although one in nine women will eventually develop breast cancer,

this is a cumulative risk estimate, with half of a woman's risk occuring after age 65 years.

About 85% of all breast cancer are detected in women over the age of 40. Of these, 67% are diagnosed

after the age of 50 years.

An early age at menarche is associated with a higher risk of breast cancer. Women whose menarche

occured before the age of 12 have about a twofold increase in relative risk.

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An early age first pregnancy exerts a protective effect against breast cancer, but only a full-term

pregnancy provides this protection. A late age at first pregnancy and nulliparity carry a three and twofold

risk of breast cancer respectively.

Women who become menopausal after the age of 45 years have a twofold breast cancer risk

compared with those whose menopause occured earlier.

Family histoty is probably the most widely recognized risk factor for breast cancer. When assessing

the risk conferred by a family history of breast cancer it is important to distinguish between a genetically

inherited predisposition to breast cancer and increased familial incidence of the disease.

Only 5% to 10% of breast cancers are thought to be due to a specific inherited mutation that confers an

extremely high risk of breast cancer development. The Li-Fraumeni syndrome is associated with a high risk

for development of breast malignancy in young women. Germline mutations of the tumor suppressor gene

p53 have been detected in patients with Li-Fraumeni syndrome and it is estimated that mutations of the p53

gene may accont for 1% of all breast cancers in women younger than 40 years of age.

Another gene believed to be associated with a genetic predisposition to cancer is the BRCA 1 gene,

isolated on chromosome 17q21. Mutation of BRCA 1 is believed to occur in 45% of cases of genetically

transmitted breast cancer and 80% of cases where the family has a history of both breast and ovarian cancer.

A woman with a first degree relative (mother or sister) with breast cancer has an increased risk of 2.5

times greater than'for a woman with no family history. If the history of breast cancer is a second degree

relative (aunt or grandmother) the relative risk is increased 1.5 times more than for a woman with no family

history.

Personal history of benign breast diseases. Nonproliferative lesions (account for 70% of breast

biopsies done for palpable masses) are associated with no increase in the risk of breast cancer development.

Proliferative lesions without atypia have a relative risk of 1.5 to 2.0 and atypical hyperplasia, whether

lobular or ductal, increases a woman's relative risk to 4.6 to 5.0.

Lobular carcinoma in situ (LCIS) has traditionally been regarded as a malignancy. However, current

evidence suggests that LCIS is a risk factor rather than the precursor of invasive carcinoma. Estimates of the

relative risk of cancer development after a diagnosis of LCIS range from 6.9 to 12.0.

A positive relationship has been observed for postmenopausal women between obesity and risk of

developing breast cancer. Whether this effect is related to high caloric intake or increased consumption of

specific nutrients such as dietary fat, remains to be clarified.

The use of oral contraceptives, cigarettes and alcohol does not increase the risk of breast cancer. A

woman with benign breast disease who uses birth control pills has no increased risk of breast cancer. In

addition, the number of years a woman uses contraceptives does not increase her risk of breast cancer. There

is also no increased risk in the postmenopausal woman on estrogen replacement therapy.

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Natural history

The biology of breast cancer has been characterized as a relatively stereotyped, time related

progression of events. This concept conveys the idea that cancer grows with time, subsequently spreads to

the regional lymph nodes and then, with time, spreads systematically. Therefore, interruption of the cycle

before the cancer spreads to the regional lymph nodes or prior to systemic dissemination from these

structures should effect a cure. Such a belief justifies the value of the so-called early detection and treatment

but, unfortunately, this point of view is erroneous and misleading.

It is true that primary tumors take time to grow. However, accepting a stereotyped natural history leads

to an inaccurate understanding of breast cancer. Growth, in the breast represents a heterogenous group of

neoplasms and recent evidence suggests biologic heterogeneity of cells constituting individual breast

cancers.

Most breast cancers cannot be palpated until they are at least 1cm in size. Kinetic studies indicate that

such a size requires 30 cell population doublings. A doubling time might encompass 30 to 200 or more days.

It becomes apparent that a tumor that is regarded as clinically early is in truth biologically late, requiring

only 10 to 20 more doublings before causing death of the host. A small 0.5cm breast cancer, detected by

mammography, although clinically regarded as early, has already traversed through 27 doubling and is biologically a late tumor.

Most studies suggest that when metastases occur, they do so within the first 10 to 20 doubling times

that is at a stage undectable by prevailing methodologies. It has been estimated that 50% of women with

breast cancer measuring 1cm have already systemic disease.

Diagnosis

The diagnosis of breast cancer involves differentiating benign from malignant changes in the breast

and determining the nature and extent of those changes that are malignant.

Breast cancer screening is the detection of breast cancer before it is palpable, in asymptomatic women.

Breast self-examination and physical examination by the clinician are proven methods of breast cancer

detection. However, using only these methods, the cancers are often not discerned before there has been

spread out of the breast.

Mammography provides an important supplement to physical examination and its value in early breast

cancer detection is now universally accepted. With screening mammography occult breast cancer can often

be found in asymptomatic women, when it is still confined to the breast.

The diagnostic approach to breast cancer patients includes the systematic evaluation of breast changes,

beginning with the history and physical examination, and concluding with assigning an appropriate stage to

the cancer and making treatment recommendations.

The history and physical examination, by defining the breast changes, will indicate the additional

procedures to be performed to further characterize the abnormalities. These studies may be noninvasive or

invasive and may be directed at the breast or at distant organs and tissues.3

Noninvasive procedures evaluating the breast include mammography, ultrasonography, thermography and

computerized tomography.

Invasive procedures are almost always necessary to establish the diagnosis of the breast abnormality and

are performed after noninvasive procedures are completed. Available invasive procedures include fine

needle aspiration and cytologic anslysis, percutaneous needle biopsies and open incisional or excisional

biopsies.

The evaluation of any patient suspected of having breast cancer must begin with a complete history

and physical examination.

The history should determine the chronology and characteristics of the patient's breast symptoms and

the presence or absence of any factors known to increase the risk of breast cancer.

All breast symptoms should be defined in terms of chronology, location and periodicity. The most

frequent signs and symptoms of breast cancer are:

=> palpable mass, the most common (more than 70%);

pain in the breast (6-8%);

nipple discharge; => nipple retraction or erosion;

skin dimpling, ulceration, edema or erythema; => breast enlargement; => axillary tumor.

The history should begin with the date of onset of the symptom,whether it is persistent, intermittent or

progressive. The appearance of a painless palpable mass is the most common presenting symptom in women

with breast cancer. The persistence of any mass should increase concern.

The presence of risk factors not only may increase the probability that a specific symptom represents a

malignancy but also emphasizes the importance of examining the remaining breast tissue and the

contralateral breast. Patients at high risk include:

- women older than 40 years of age;

- those with family histories of breast cancer;

- nulliparous women or those with first parity after age 34;

- those with previous histories of cancer in one breast;

- those with precancerous mastopathic fibrocystic disease;

- history of endometrial or ovarian cancer;

- patients with excessive breast exposure to ionizing radiation.

Information from previous evaluations should be carefully reviewed, including mammograms,

cytologies from aspirations or secretions, biopsy material and the response to any treatment regimens. In this

manner, the diagnosis of breast changes can be facilitated and unnecessary repetition of procedures avoided.

The physical examination will define the location and extent of the breast changes and whether they

are associated with any abnormalities in regional tissues or distant sites.

The entire breast and adjacent lymph node areas should be examined for all breast complaints. Breast

tissue extends from the second or third rib superiorly to the sixth or seventh costal margin inferiorly and 4

from the lateral border of the sternum to beyond the anterior axillary fold. Both breasts should be

systematically inspected and palpated in the supine and sitting positions.

Inspection

•Any asymmetry, skin edema, erythema and retraction, previous biopsy scars should be noted as well

as any nipple retraction or excoriation.

Skin retraction may become evident when the patient is placed in the sitting position with her arms

raised. Skin retraction signs may also be accentuated by retraction of the pectoral muscles.

Subtle changes in the nipple, in addition to retraction, may be manifestations of malignancy (Paget's

disease). These changes may include: eczema, crust formation, ulceration and a bloody nipple discharge.

Carcinoma should be considered in the differential diagnosis of any eczematoid lesion of the nipple. A

palpable tumor in the breast may be present in 25 to 44% of such cases.

Palpation

The characteristics of any palpable breast mass should be determined and accurately recorded. The

location, size and mobility of the mass and whether it is associated with skin ulceration, inflammation or

satellite nodules are major determinants for tumor classification.

Fixation of the mass to pectoralis fascia or muscle should be distinguished from fixation to the chest

wall. Masses that are fixed to the chest wall are completely immobile. The tumor should be accurately

measured in its greater dimension.

Breast cancer frequently metastasizes to regional lymph nodes, including axillary, internal mammary

and supraclavicular areas. Approximately 20% of patients with Tl lesions and 40 to 50% of cases with T2

lesions will have metastases to axillary lymph nodes at presentation.

Examination of these areas is important for staging purposes and for detecting evidence of locally

advanced disease. The axilla is best examined with the patient in the sitting position and the arm relaxed.

The presence of any palpable lymph nodes, their size, whether they are thought to be matted or fixed, should

be noted.

The finding, at presentation, of palpable supraclavicular lymph node metastases is uncommon and

their presence represents advanced disease (stage IV).

The history and physical examination should also include an evaluation for distant metastatic disease.

Approximately 10% of patients with breast cancer will have distant metastases at presentation. The most

common sites for metastases from breast cancer are, in order of decreasing frequency, lung, bone, liver and

adrenal gland.

Signs and symptoms of distant metastases noted on history and physical examination will serve as

indicators for specific investigations.

The stage of a breast malignancy describes the extent to which the malignancy involves the breast

tissue locally and the extent to which it has spread to regional lymph nodes and to distant organs and tissues.

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The importance of any staging classification lies in its ability to define the treatment options that are

appropriate and effective for a given patient.

Clinical - diagnostic staging system of the American Joint Commitee for cancer staging and end - results reporting

TNM classification

Primary tumor T

Tx Tumor cannot be assessed TO - No evidence of primary tumor

Tis Paget disease of the nipple with no demonstrable tumor; carcinoma in situ

Tl Tumor of 2cm or less in greatest dimension Tla 0.5cm or less in greatest dimension Tib

more than 0.5cm but not more than 1cm Tic more than 1cm but not more than 2cm

T2 Tumor more than 2cm but not more than 5cm in its greatest dimension

T3 Tumor more than 5 cm in its greatest dimension

T4 Tumor of any size with direct extension to chest wall or skin

T4a extension to chest wall

T4b edema (including peau d'orange) or ulceration of the skin of the breast or satellite skin

nodules confined to the same breast

T4c both (T4a and T4b)

T4d inflammatory carcinoma

Regional lymph nodes N

Nx regional lymph nodes cannot be assessed

NO no regional lymph node metastasis

Nl metastasis to movable ipsilateral axillary lymph node (s)

N2 metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures

N3 metastasis to ipsilateral internal mammary lymph nodes

Distant metastasis M

Mx presence of distant metastasis cannot be assessed

MO no distant metastasis

Ml distant metastasis (includes metastasis to ipsilateral supraclavicular lymph nodes)

Noninvasive procedures for the evaluation of the breast

While the history and physical examination will provide information about the nature of the breast

mass, noninvasive studies are useful for further defining the mass and the remaining breast tissue.

Mammography has been the most widely used noninvasive procedure and the one in which the

greatest experience has been gained. Breast lesion abnormalities suggestive of malignancy that are detected

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by mammography may be : microcalcifications, irregular mass with spiculated borders, asymmetry of the

breast, venous dilatation, retraction of the skin.

The increased density of breast tissue in younger women may compromise interpretation of the

mammograms. The reliability of mammography for detecting carcinoma in women over 60 years of age is

90%. In addition to defining a palpable mass, mammography may detect occult lesions elsewhere in the

same breast or in the opposite breast.

Mammography is useful to localize lesions for which biopsy is recommended. The increased use of

mammography as a screening procedure has led to the detection of anomalies that may not be associated

with any symptoms or findings on physical examination.

A mammogram obtained to evaluate a mass should be done to support the diagnosis of malignancy. A

negative mammogram should never be a substitute for cytologic or histologic evaluation of a palpable mass.

Ultrasonography has been used with increasing frequency to evaluate breast abnormalities. The breast

changes are, in general, less subtle than those detected by mammography. As an imaging procedure, US is

most useful for distinguishing solid from cystic masses. It is also useful for evaluating palpable masses in

women under 30 years of age, pregnant and post partum women and patients with inflammatory conditions

of the breast. Finally, it may be used to guide needle aspiration of cysts and to determine whether complete

resolution has been achieved following aspiration of cysts.

Ultrasound is less reliable than mammography when used either for detection and early diagnosis of

breast cancer or for distinguishing benign from malignant lesions. US does not successfully visualize

microcalcifications and has difficulty with lesions less than 1cm in size.

Some authors reported that whereas mammography detected over 90% of cancers of all categories,

sonography detected only 48% of the cancers that had not yet spread to axillary lymph nodes, only 30% of

the nonpalpable malignancies and only 8% of the cancers less than 1cm in diameter.

Thermography is based on the principle that inflammatory and neoplastic processes produce an

increase in local temperature that can be detected at the skin surface. Thermography is more accurate for

larger tumors and for those that are rapidly growing but because of its inability to diagnose smaller tumors

is, generally, not considered to be a useful technique for breast evaluation.

By computerized tomography, breast tissue is evaluated in 1cm slices, thus, smaller lesions, such as

microcalcifications, can easily be missed. Because of the limitations (it delivers a higher dose of radiation, is

time consuming) CT scans of the breast is not recommended as a standard procedure.

Summary

Noninvasive studies may provide important information in the evaluation of breast symptoms. These

studies should be obtained prior to invasive procedures. Mammography and ultrasonography are the most

useful of these studies. Mammography is the only reliable method for detecting occult lesions in the breast.

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Invasive studies for the evaluation of a breast mass

Aspiration of breast masses and cytologic analysis

Fine needle aspiration of breast masses may provide information regarding the cystic or solid nature of

the mass and, especially in the case of solid masses, may provide material for cytologic examination.

In case of a benign cyst, aspiration should result in complete resolution of the mass without

reaccumulation in a 2 to 3 week period. A cystic breast mass should be excised to exclude the possibility of

malignancy if aspiration of the mass does not result in complete resolution, if the cyst reaccumulates or if

the aspirate is bloody.

Aspiration cytology has been used extensively to diagnose solid breast masses. There are false-

negative and false-positive cytologic findings. If there is any question about the diagnosis from the aspirate,

a biopsy of the mass should promptly be performed.

The use of a pozitive cytologic finding to plan definitive therapy will depend on the degree of

confidence in the nature of the sample and on the expertise of the cytologist. Cytology may be practised in

nipple secretions.

Incisional or excisional biopsies

These techniques remain the definitive means for establishing the diagnosis of breast lesions. Frozen

section review of the specimen may provide an immediate diagnosis.

Occult lesions can be localized for biopsy by X-ray guidance with a small-gauge needle or with a

nonabsorbable dye to stain the tissue. For tumors smaller than 2 to 3cm biopsy may be excisional.

Outpatient breast biopsies can be performed safely with a negligible complication rate.

Differential diagnosis

Cancer of the breast is usually on the left side, most in the upper outer quadrant (more than 50%), in

women without children and women who have not breast fed.

The most common type of breast lesions and their frequency are fibrocystic disease (34%), cancer

(27%), fibroadenoma (19%), intraductal papilloma (6%), duct ectasia (4%) and others (11%). So, the

differentiation between benign and malignant breast lesions is crucial.

Fibrocystic disease

It is commonly bilateral and multiple. It is characterized by dull, heavy pain, a sense of fullness and

tenderness. Changes with menses are common (increase premenstrually). The lumps are cystic to palpation,

tender, well delineated, slightly mobile. Aspiration reveals a typical turbid, nbnhemorrhagic fluid that has a

yellow, green or brown tint.

Deeply embedded cysts, a cluster of cysts, or dominant areas caused by sclerosing adenosis or dense

fibrous dysplasia can produce a mass that clinically mimics cancer. Fibrocystic disease occurs in women

between 20 to 50 years of age.

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Fibroadenoma

Another common benign lesion is the fibroadenoma which appears predominantly in young women

and occasionally in adolescents. It is initially seen as a firm, painless, mobile mass and may be very large,

particularly in adolescents. Fibroadenomas are multiple and bilateral in about 14% to 25% of patients.

A fibroadenoma grows slowly and does not change with menses.

Cystosarcoma phyllodes

This is a rare variant of fibroadenoma. It may cause massive enlargement of the breast. The skin is

seldom involved and the axillae are usually clear. Venous engorgement and skin inflammation may be

present.

Intraductal papilloma

It manifests as a serous, serosanguineous or watery type of nipple discharge, hi the absence of a mass,

the most common cause of bloody nipple discharge is an intraductal papilloma. The discharge is usually

spontaneous and from a single duct and is commonly unilateral.

Intraductal papillomas are generally smaller than 1cm. There has been considerable debate in the

literature regarding the malignant potential of solitary intraductal papillomas. Available evidence suggests

that these lesions rarely undergo malignant transformation.

Galactocele

It typically occurs following lactation. It is usually found beneath the areolar zone. It is occasionally

tender and a milky discharge is sometimes found.

Mammary duct ectasia

It commonly manifests with nipple discharge which is usually multicolored, sticky, bilateral and from

multiple ducts. The patient may experience a burning, itching or dull, pulling pain aroud the nipple and

areola, and there may be palpable tortuous tubular swelling under areola.

Nipple retraction, skin retraction and a diffuse mass may be present. There may be edema and axillary

adenopathy. It is very difficult to differentiate it from cancer.

Fat necrosis

It usually results from trauma. Skin dimpling and a firm, indistinct mass are characteristic. The

differential diagnosis from cancer is difficult.

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Inflammatory carcinoma

Initially appears to be an acute inflammation with redness and edema. Inflammatory cancer should be

diagnosed when more than one third of the breast is involved by erythema and edema and when biopsy of

this area shows metastatic cancer in the subdermal lymphatics.

There may be no distinct palpable mass, because the tumor infiltrates through the breast with ill-

defined margins or there may be a dominant mass. There may even be satellite nodules within the

parenchyma.

Except for biopsy of the lesion, surgery usually should not be used in the initial management of

inflammatory carcinoma. The best results are achieved with a combination of chemotherapy and radiation

therapy. Mastectomy may be indicated for patients who remain free of distant metastatic disease after initial

chemotherapy and radiation.

Pathology

Breast cancer may arise in the intermediate-sized ducts or terminal ducts and lobules. The cancer may

be either invasive (infiltrating ductal carcinoma, infiltrating lobular carcinoma) or in situ (ductal carcinoma

in situ or lobular carcinoma in situ). These carcinomas do not invade the surrounding tissue and

theoretically, lack the ability to spread. 25-30% of patients are with lobular carcinoma in situ. Most women

with lobular neoplasia are premenopausal.

Ductal carcinoma in situ tipically occurs in postmenopausal women.

Infiltrating ductal carcinoma on nonspecified type accounts for 60-70% of the breast cancers.

Other types of invasive ductal carcinoma are far less common. Medullary carcinoma, which accounts

for approximately 5-8% of breast carcinomas, arises from larger ducts within the breast and has a dense

lymphocytic infiltrate.

Mucinous (colloid) carcinoma accounts for less than 5% of all breast cancers. Infiltrating comedo

carcinoma accounts for less than 1% of breast malignancies.

Treatment of breast carcinoma

Preoperative evaluation

The extent of preoperative workup varies with the initial stage of the disease. For most patients with

small tumors, no palpable lymph nodes (TNM stage I) and no symptoms of metastases, the preoperative

evaluation should consist of mammography, chest X-ray, comlete blood count-screening blood chemistry

tests.

A bone scan and computed tomography scan are not necessary unless symptoms or abnormal blood

chemistry suggest bone or liver metastases. For patients with clinical stage II disease, a bone scan should be

obtained, but a CT scan of the liver is not necessary unless symptoms or liver function tests suggest liver

metastasis.10

Local-regional treatment Surgery

Radical surgery has lost popularity in the past decades. Modified radical mastectomy has become the

most frequently performed operation.

Breast conservation procedures have become acceptable alternatives for many women with primary

breast cancer. Adequate local control and improved cosmesis can be obtained without jeopardizing survival.

Patients treated by total mastectomy or with breast conservation surgery must have a level I and II

axillary dissection. Adequate tissue can be obtained while preserving the pectoralis muscles. A level III

dissection should be considered in patients with clinically positive nodes to obtain optimal local control.

The axillary contents are divided anatomically into three levels. Level I represents the tissue between

the latissimus dorsi muscle and the lateral border of the pectoralis minor muscle. Level II is that axillary

tissue between and inferior to the lateral and medial borders of the pectoralis minor muscle. Level III is that

tissue internal of the pectoralis minor medial border (the apex of the axilla).

The optimal surgical approach is determined by the stage of disease, tumor size and location, breast

size and configuration, the presence of multicentricity clinically or mammographically, available surgical

and radiotherapeutic expertise and patient wishes.

Specific procedures

Radical mastectomy (Halsted's operation) (1894)

This procedure involves en bloc removal of the breast, pectoral muscles and axillary contents. This

operation is not indicated today except, perhaps, for the removal of very large, fixed tumors.

Modified radical mastectomy (Patey or Madden operations)

Through a horizontal incision, the breast and axillary contents are removed with preservation of the

pectoralis muscles. The cosmetic result is improved by the more normal appearance of the upper chest wall.

Retrospective studies found that survivals were similar regardless of any of the modified approaches.

Partial mastectomy, axillary dissection and breast irradiation

This breast-preserving procedure involves excision of the tumor with an adjacent rim of normal breast

tissue. Lumpectomy is a modification that entails excision of gross tumor only. An axillary dissection

through a separate incision is required for accurate staging and local control.

Radiotherapy is used to treat the remaining breast tissue to reduce the chance of local recurrence.

Treatment consists of external beam radiation therapy plus an optional boost to the local tumor site with

either external beam or interstitial radiation.

Conserving the breast is one of the main objectives in treating patients with mammary carcinoma

today. However, this objective must be made compatible with good local control of the disease so as to keep

the risk of local recurrences as low as possible.

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Total (simple) mastectomy and axillary dissection

The total mastectomy removes all of the breast tissue, both the pectoralis major and the pectoralis

minor muscles are preserved, A transverse incision is" used. Dissection of the skin flaps is performed in the

same manner as for the radical mastectomy. Postoperative catheter drainage is routinely employed.

Axillary dissection (levels I and II) is performed through a separate incision. Removal of axillary

lymph nodes is necessary to accurately quantitate the number of positive nodes. An axillary dissection of at

least levels I and II is the minimal procedure that should be performed to reliably obtain staging and

prognostic information.

Breast reconstruction

Patients who desire, can obtain an acceptable cosmetic result with immediate or delayed breast

reconstruction after mastectomy.

Reconstruction may be realised using silicone prosthesis, tissue expanders or local flaps

(thoracoepigastric or latissimus dorsi musculocutaneous flaps).

Postmastectomy radiation therapy

It is now reserved for patients with a high risk of local recurrence. Risk factors include:

- tumors greater than 5cm in diameter with positive lymph nodes;

- tumor involvement at the margin of surgical resection;

- invasion of the pectoral fascia or muscle.

Systemic treatment

About 50% of all patients with operable primary breast cancer survive 10 years after surgery without

developing recurrent disease and presumably do not have viable distant micrometastases at the time of

diagnosis.

Identification of patients with established micrometastases who may benefit from adjuvant therapy is a

challenge. Currently, no tests or tumor marker studies are available to accurately identify patients who are

destined to relapse. Several prognostic indicators can be used to classify patients according to their relative

risk for recurrence:

> axillary lymph nodes positive

> ER/PR status negative

> tumor size > 2cm

> histopathology high nuclear grade

> D~NA content aneuploid

> proliferative index _ high S-phase fraction

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The most important factor is the axillary lymph node status. Although patients with negative nodes

have a relatively good prognosis, certain subsets such as those with receptor-negative, poorly differentiated

or large tumors and those with aneuploid DNA content or high S-phase fraction have a relatively high

recurrence rate and should be considered for adjuvant therapy.

Adjuvant chemotherapy

Chemotherapy delays recurrence and improves survival of women with positive axillary nodes. The

major benefit is observed in premenopausal cases where adjuvant has been estimated to cause a 30%

proportional reduction in mortality at 5 years.

Studies have demonstrated that combination chemotherapy is superior to single- agent treatment. The

most popular regimen is CMF (cyclophosphamide, methotrexate, 5-fluorouracil) repeated every 28 days, 6

cycles of treatment.

Several chemotherapy regimens have been used for adjuvant chemotherapy of breast cancer. There is

insufficient data available to strongly recommend one regimen over another.

The toxicity is acceptable and is dependent on the drug regimen as well as the judicious use of

preventive measures. Side-effects are: nausea, vomiting, mucositis, diarrhea, alopecia, myelosuppression,

cardiac toxicity.

Adjuvant endocrine therapy

Hormonal therapy may improve the results of adjuvant systemic therapy. Both, premenopausal and

postmenopausal patients who had ER-positive, node-negative disease benefited from the adjuvant use of

TAMOXIFEN (10mg, twice a day, for 3 to 5 years) after local treatment.

TAMOXIFEN is an antiestrogen and the greatest benefit is seen in postmenopausal patients.

In premenopausal patients, TAMOXIFEN therapy has replaced bilateral ovariectomy as the primary

method of hormonal manipulation. About 60% of premenopausal patients with ER-positive tumors respond

to either TAMOXIFEN or bilateral oophorectomy.

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