Approximately 22% of Women Who Have Breast Cancer Die of the Disease

Chapter 35 Breast Cancer

HISTORY  William Halsted perfected the technique of radical mastectomy at the end of the nineteenth century  Approximately 22% of women who have breast cancer die of the disease

EPIDEMIOLOGY  Breast cancer is the most common malignant disease in American women o Every woman has approximately a one in eight chance of developing breast cancer over her lifetime  The second major cause of cancer death, preceded only by lung cancer  The incidence rate has steadily risen since the 1980s

RISK FACTORS  Gender: the most significant risk factor for breast cancer o The female to male incidence ratio is 100:1  Age: older women have the highest probability of developing breast cancer (60-79) o Incidence rises steadily during the reproductive years after age 30 o The median age of onset is 55 o The predominant age group is between 40 and 70 o Slight decrease in the perimenopausal years attributed to hormonal changes that occur during menopause  Family history: o Female relatives of women with breast cancer have a higher incidence than the general population (genetic testing available) o The probability of developing breast cancer is highest (two to three times more) for women whose mothers and/or sisters (first degree relatives) have breast cancer, especially if the family members were premenopausal o The tumor suppressor genes BRCA1 and BRCA2 is associated with a near 100% likelihood of breast cancer development  Hormonal Factors: risk factors appear to reflect menstrual and childbearing history o Overall length of ovarian function is related to breast cancer risk . Early menarche (the beginning of menstruation) and late menopause (the ending of menstruation) increase breast cancer risk . Oophorectomy (removal of one or both ovaries) before age 50 appears to reduce risk o Women who have given birth to a child have less risk than women who have never been pregnant (nulliparous women) . Pregnancy later in life increases the risk more than nulliparity . Women who give birth to their first child after age 35 are twice as likely to develop breast cancer as women who give birth to their first child before age 20 o Women who are taking hormone replacement therapy (used to alleviate menopausal symptoms) are at an increased risk

1 o Women taking oral contraceptives (used to prevent ovulation) are at a slightly increased risk  History of malignancy o A history of either invasive or ductal carcinoma in situ (DCIS) (cancer confined to the breast) in one breast increases the risk for development of cancer in the opposite breast o Women with a history of malignant tumors of the colon, thyroid, uterus, ovary, or major salivary glands have an increased risk  History of benign breast disease o Women with atypical hyperplasia or lobular carcinoma in situ have an increased risk  Dietary and environmental Factors o Rates are higher in Europe, Canada, and the United States and lower in Asia and developing countries such as Mexico . White women have a higher incidence of breast cancer than nonwhite women o Moderate consumption of alcohol (more than two drinks per day) appears to increase the risk- has the greatest effect on breast cancer in women younger than 30  Radiation Exposure o Depends on type and quality of radiation, frequency of exposure and magnitude of dose o Imaging used to monitor tuberculosis or treatments of benign conditions such as postpartum mastitis or fibroadenomas of the breast

PROGNOSTIC INDICATORS  Lymph node status, tumor extent, histology, Estrogen and Progesterone Receptor status (ER/PR), flow cytometry Lymph node status  The primary spread of tumor cells in breast tissue o Lymph nodes in the axillary and IM areas are the most likely sites of regional involvement of breast cancer o The supraclavicular nodes are only occasionally involved o 70% of the lymphatic drainage of the breast occurs to the axilla, with 30 percent going to the IM nodes- also drain to the supraclavicular nodes, liver and contralateral IM nodes  Axillary nodes: o Lymph nodes located in the axilla represent the primary lymphatic drainage of the breast o Half of all patients with breast cancer have microscopic involvement of the axillary nodes . Size of the primary tumor: as tumor size increases so dose the likelihood of axillary node involvement . Quadrant location of the primary tumor: lesions located in the upper outer or lower outer quadrants have a greater chance of axillary node involvement o Between 10 and 38 lymph nodes are in each axilla- divided into 3 sections (I, II, and III) based on location o The number of nodes involved by a tumor is the most important prognostic indicator . A higher number of involved nodes correlate with an increased recurrence rate and a decreased survival rate

2 . At least 10 axillary nodes must be evaluated to separate low risk (> 3 nodes positive) from high risk (< 4 nodes positive) the prognosis for patients with more than 10 axillary nodes positive for tumor is extremely poor

 Internal mammary (IM): o The second most common nodal site of involvement from breast cancer . Of all breast cancer patients 20% have IM nodes positive for tumor . The incidence of IM involvement is directly related to axillary node involvement and the size of the primary tumor o The involvement of IM lymph nodes by cancer, with or without axillary lymph node involvement, further reduces disease free survival rates o The average person has four IM lymph nodes located near the edge of the sternum on each side o CT and lymphoscintigraphy are used to image the IM nodes  Supraclavicular o The involvement of IM and supraclavicular nodes is considered a grave prognostic indicatory in breast cancer Tumor extent & Progression  Breast cancer tends to grow locally, involving the ducts and adjacent tissues, and may spread to local and regional lymphatics  Larger tumors increase the likelihood of involvement of the skin, muscle, chest wall, and regional lymph nodes, resulting in a worse overall prognosis  Left untreated, the cancer can become fixed in position, and the overlying skin may become infiltrated by the tumor, eventually causing ulceration o Fixation of a mass to the chest wall involves significant negative staging and prognostic implications Recurrence  Breast cancer can recur in the breast (local: treated with surgery) in the lymphatics (regional- surgery and chemo) or at distant metastatic sites  Patients may relapse up to 20 years or more after treatment  Few options are available for cure after relapse Histology/Pathology  Two basic methods are used for obtaining pathologic information o Gross examination is performed to record the dimensions of the specimen, the size of the tumor and the tumors relationship to the excisional margin o Microscopic examination  Carcinoma in situ o Is characterized by a proliferation of malignant epithelial cells that do not invade the basement membrane  Infiltrating ductal carcinoma o The most common histologic type of breast malignancy, accounting for 70% o Components of DCIS and tend to spread to the axillary

3  Infiltrating lobular carcinoma o The next most common type, comprising about 5-10% of breast cancer

 Inflammatory breast cancer o Less than 1% of all breast cancer o Diagnosis is based on pathologic evidence of malignancy and clinical findings of breast tenderness and enlargement, peau d’ orange appearance, erythema, thickening, increased warmth and diffuse induration caused by dermal lymphatic involvement o An extremely poor prognosis with a survival time of less than 2 years o Aggressive and fast growing o Combined modality treatment is used  Others include mucinous or colloid, tubular and papillary carcinoma- yield a favorable prognosis Estrogen and Progesterone Receptor status  Tissue is analyzed to determine the effect of estrogen and progesterone on the cells- indicate the potential response to hormonal therapy  Patients who are receptor positive are more likely to respond and have a better outcome than those with receptor negative tumors. Flow Cytometry  DNA form breast cancer cells is routinely evaluated for prognostic information  The content of the DNA is studied for ploidy (pertaining to a cell that has the complete set of chromosome sets) status because aneuploid (pertaining to a cell that does not have an exact multiple of the normal number of chromosomes) have a poorer prognosis Survival  The overall 5-year survival is 85% o Regional spread: 77% o Distant metastasis at the time of diagnosis: 21%  10-year survival: 75%  15-year survival: 57%

ANATOMY  The protuberant portion of the adult breast is located between the second and sixth ribs in the sagittal plane  Breast tissue is also in the axilla, which is referred to as the axillary tail of Spence  In close proximity to several functionally important muscles: the pectoralis major and minor, serratus anterior, and latissimus dorsi  The breast lies over the pectoralis major and serratus anterior muscles and is attached to them by a layer of connective tissue called Cooper’s suspensory ligaments which support the breast  Site of origin o Approximately 48% of breast cancers arise in the upper outer quadrant o 15% in the upper inner quadrant 4 o 11% in the lower outer quadrant o 6% in the lower inner quadrant o 17% in the subareolar area (around the nipple where the ducts converge o 3% are multicentric

 Multicentric: tumors that appear in several areas of the breast  Multifocal breast cancer denotes a situation in which elements of a tumor are contained in tissue near the primary lesion in the same quadrant o Multifocal breast cancer is more common than multicentric cancer and is prognostically more favorable

ROUTES OF SPREAD  Cancer of the breast is a relatively slow disease process with distant metastasis sometimes occurring decades after definitive treatment of the primary tumor  Direct: local extension in the breast: o Direct invasion into surrounding breast tissue and skin- ulcerations o Extension via the duct system o Spread along the lymphatic channels in the breast  Regional: Lymphatics  Distant metastasis (hematogenous): o Breast cancer has a propensity to metastasis to distant sites via invasion of the blood vessels, followed by hematogenous spread to other sites . Embolization: spread via tumor cells entering the circulatory system and traveling to a distant organ o Distant metastatic sites include bone, brain, liver, lung, eyes, ovaries, and adrenal and pituitary glands may be present at the time of the diagnosis o Patients with distant metastasis (stage IV) have an extremely poor prognosis

CLINICAL PRESENTATION  Most changes of the breast are benign o 20% of all masses are malignant  Breast mass o The most common presentation of breast cancer is a painless lump . By the time a breast lesion is palpable it has already grown to about 0.5 cm o Benign breast conditions (including cysts) are rare postmenopausally  Axillary lymph node enlargement o Occasionally the first sign of breast cancer o Arm edema may also be a sign of lymph node involvement  Nipple discharge or retraction o Nonlactational serous discharge from one breast is the second most common symptom of breast cancer o Nipple retraction and tenderness or pain in the nipple  Skin Changes and Alterations in Breast Contour

5 o Changes in skin texture, dimpling, irritation, increased warmth scaling pain and ulceration of the skin require evaluation o Distortion of the normal breast contour, swelling and thickening of subcutaneous tissues o Peau d’orange, a condition in which the skin develops an orange peel appearance is a clinical sign of inflammatory breast cancer  Mammographic abnormality or distant metastasis

DETECTION AND DIAGNOSIS  Important features of breast cancer screening and detection methods include cost effectiveness, accuracy, specificity (the probability that a test will be negative for an instance when no disease if present) safety and availability  A three-step breast health program is recommended: o Monthly self-examination . At the same point each month relative to the menstrual cycle o An annual clinical examination by a qualified medical professional . Can detect tumors as small as 0.5 cm . The 5-year survival rate for patients with lesions less than 0.5 cm is 99% . The skin is evaluated for color and textural changes o A routine mammographic examination . The ACS recommends:  A baseline mammogram be obtained between ages 35 and 39  Women between 40 and 49 should have a mammogram every other year  Women older than 50 are advised to get annual mammograms . Mammography remains the only modality that routinely detects breast cancer if the lesion is too small to feel during a clinical examination . Mammograms miss 10 to 15% of small and moderate size breast cancer . Clusters of calcifications are biopsied  As few as one biopsy positive for tumor for every seven performed . The standard low dose film mammogram involves exposures in two views  A cranio-caudal and medial lateral view . The average optimally performed procedure delivers only 0.002 Gy . Xerography is a technique of mammography that provides greater visualization of the area close to the chest wall but lacks the detail of good quality film mammography  Ultrasound: currently used as an adjunct to mammography for its ability to distinguish between cystic and solid masses and to guide biopsy procedures o Not suitable screening modality for breast cancer . It cannot detect microcalcifications . It is not sensitive enough to detect small breast cancers . Can miss subtle structural irregularities indicative of breast malignancy  MRI: used in women with silicone breast implants, extremely dense breast tissue or changes in the breast secondary to radiation treatment o Limitations – inability to detect microcalcifications and high cost  CT: regional disease in patients who have an established diagnosis of breast cancer

6 DIAGNOSIS  Fine needle biopsy: small gauge needle evacuated blood and or tissue  Core needle biopsy larger gauge needle are used to aspirate a core of tissue from the breast mass  Incisional biopsy: an incisional biopsy involves the partial removal of a breast mass  Excisional biopsy: (lympectomy) removes the mass in its entirety with or without a portion of surrounding normal tissue

TREATMENT MANAGEMENT  Decisions regarding treatment are influenced by the extent of the primary tumor, the patient’s general medical condition and the patient’s personal preference  Management depends on the patient’s stage of disease, lymph node status, estrogen receptor and progesterone receptor (ER/PR) status and menopausal status SURGERY:  If the breast is small relative to the tumor or multicentric tumor involvement is present, then a mastectomy may be the best treatment choice  Limited surgery is not an option for patients with advanced breast cancer  Radical mastectomy: o Involves the removal of the breast with its overlying skin, all the axillary lymph nodes and the pectoral muscles o Concave chest wall, arm weakness, shoulder stiffness and lymphedema  Modified radical mastectomy o Involves removal of the breast and some or all of the axillary lymph nodes may include removal of the pectoralis minor muscle, lymph nodes are sampled through a separate axillary incision o Modified to preserve muscle, some skin, lymphatics and blood vessels, thereby improving cosmetic results, reducing arm edema and improving arm strength  Lumpectomy: o Involves removal of the tumor with a margin of normal appearing tissue, overlying skin and underlying tissue are left intact lymph nodes are sampled through a separate axillary incision  Axillary dissection: o Involves removal of a sample of axillary lymph nodes in the axilla on the side of the involved breast – necessary for staging Endocrine therapy: (ER/PR) used to deprive cancer cells of the hormones needed for growth  The most commonly used agents are tamoxifen (causes menopause, effective only 5 years- then switch to letrosol) and Megace CHEMOTHERAPY  Chemotherapy has been used increasingly to address microscopic, lymphatic, and systemic disease  The goal of systemic treatment is the destruction, prevention or delay of tumor spread to distant sites in the body

7  cyclophosphamide (C), 5-fluoraouracil (F), methotrexate (M), (CMF) and doxorubicin (Adriamycin) (A) o Stage I: how incidence of relapse therefore chemotherapy is reserved o Stages II and III systemic therapy is useful in reducing relapse rates and increasing overall survival rates o Stage IV: a combination of systemic and local treatment is usually required for patients with advanced disease o For some patients chemo is used as a palliative measure

 Side effects o Endocrine and chemotherapeutic agents cause nausea and vomiting, loss of appetite, fatigue, change in menstruation, mouth ulcers and hair loss o Most side effects are acute resolving after the completion of treatment o Small chance exists that the chemo will cause a second cancer

RADIATION THERAPY  The aim of radiation therapy is the complete eradication of tumor cells with minimal structural and functional damage to normal tissue  When indicated, radiation therapy is usually delivered postoperatively o The tumor size and location, o Number of axillary nodes positive for tumor o Tumor involvement of the skin o Supraclavicular lymph nodes o Hormone receptor status  Contraindications: o First or second trimester pregnancy o Multicentric disease o A history of prior breast irradiation of significant dosage is absolute contraindications of breast conservation treatment  Potentially contraindicating the use of a conservative approach to treatment o A history of vascular disease o A large tumor in a small breast o An extremely large or pendulous breast o The specific location of the tumor in the breast TANGENTIAL FIELDS:  The purpose of tangential fields is to maximize coverage of the tissues at risk and minimize the radiation dose to underlying structures primarily the lung and heart  Immobilization/Positioning o Start of therapy should be delayed 2-4 weeks until scar heals and the patients arm moves appropriately . One of the key elements involves the mobility of the patients arm

8 . Many postoperative patients experience initial difficulty in raising the arm to an acceptable position for radiation treatment o The ipsilateral arm is raised and supported far enough in a cephalad direction to allow the tangential radiation beam to treat the breast or chest wall while avoiding the patients upper arm . Reduce or eliminate skin folds in the axilla and supraclavicular areas o The arm on the uninvolved side should rest on the tabletop with the palm down o Custom molded foam casts, boards with arm and head supports used o Supine, body must be straight in the sagittal plane and level from side to side o The head should be turned slightly to the contralateral side o A sponge may be placed under the patients knees

o Patients with large or pendulous breasts can be positioned on an incline board useful in keeping the breast tissue in a more normal location can also help alleviate the problem of deep skin folds in the supraclavicular area (thermoplast, elastic netting, rings, radiation brassiere, and Styrofoam crutches used as well)  Borders: o Superior, at the most cephalad of the following points . First intercostal space . As far up as possible without including the arm . Cephalad- more than 2 cm to original location of mass o Inferior . Caudad 1-2 cm to the inframammary fold o Medial . Midline of patient determined by palpation of suprasternal notch and xiphoid process o Lateral . Corresponding to midaxillary line . Including drain sites or incisions  Treatment o Lower megavoltage beam energies (4 to 8 MV) and tissue compensators are used to improve dose homogeneity o The amount of lung protected at the center of the tangential fields should be limited to between 1 and 3.4 cm thereby reducing the risk of radiation pneumonitis o An isocentric method of tangential field irradiation, in these techniques the isocenter is placed at some depth in the patient’s breast or chest wall o An important feature of the tangential field arrangement is the coplanar nature of the deep margin of the ports . This is important in ensuring a dose as homogenous as possible throughout the treatment volume (decreases overlap in the lung)  Dose: o Fields are treated daily with standard fractionation (180 to 200 cGy per fraction) o To a total dose of 4500 to 5000 cGy o A boost dose may be delivered with an electron beam or interstitial technique, increasing the total dose to the primary tumor site to 6000 to 6600 cGy 9 IM FIELD  Treating the IM nodes combines photons and electron treatments helping to limit cardiac dose  One method is to extend the tangential field to include the IM nodes, not popular due to increasing normal tissue dose  Involves the use of an enface (perpendicular to the skin surface with a combination of electrons and photons  Match line fibrosis (abnormal formation of fiber like scarring or local recurrence SUPRACLAVICULAR FIELD  The central ray is placed at the cephalad borders of the tangential fields and the inferior half of the beam is blocked  Slight oblique: the gantry is angled 10 to 15 degrees mediolaterally to avoid exiting through the spinal cord Breast boost  May be delivered with electrons (more convenient, less expensive) or brachytherapy  Tumor mass is located using fluoroscopy and or radiography to locate surgical clips placed by surgeon Posterior axillary boost field:  Sometimes used to increase the midaxillary dose to the prescribed level Side effects  Combination radiation and chemotherapy may intensify toxicity o Doxorubicin may cause cardiac damage o When used concomitantly, radiation and doxorubicin may be hazardous o If doxorubicin is given after radiation therapy, then a recall phenomenon may occur in previously treated areas, displayed by exacerbation of reactions of the esophagus, skin, lungs and heart  Skin changes: variables that affect the skin dose include the type of radiation, beam energy, boost technique, wedge, bolus, fraction size, total dose, and physical conformation of the patient o Skin folds tend to intensify skin reactions because of the bolus effect and therefore the most sensitive areas . Eythema (dryness and redness) of the skin are common after a skin dose of about 3000 cGy 3-4 weeks into treatment . Dry desquamation, which involves flaking of superficial layers of the epidermis, may appear after the delivery of about 4000 cGy to the skin . Moist desquamation, involving the loss of superficial and deep epidermal layers, occurs when doses to the skin exceed 5000 cGy  Management: o The treatment area must be kept clean through normal, gentle cleaning, and sun exposure should be avoided o Cornstarch is often recommended as a soothing agent for early skin reactions and as a substitute for commercial deodorant- should never be used in areas of moist

10 desquamation because it may promote fungal growth and increase the risk of wound infection o The use of lotions creams, deodorants or powders in the treatment area should be discouraged because they may contain irritating agents such as perfumes, alcohol, or metals o Shaving under the arm is not recommended, and clothing should be soft and loose fitting o Extreme temperatures should also be avoided  Most chronic skin changes include hyperpigmentation (excessive coloration) hair loss, epidermal thinning, telagiectasia and subcutaneous fibrosis (decreased elasticity of the skin- 6000 cGy) o Rare cases of delayed wound healing, ulceration, and necrosis may occur after skin doses of over 70 Gy

 Cardiac: the myocardia is relatively radioresistant o The incidence of pericarditis is less than 5% for small heart volumes treated to 60 Gy or 40 Gy for large volumes  Pneumonitis o Some degree of radiation pneumonitis and fibrosis can be expected after the administration of more than 2500 cGy to any portion of the lung via standard fractionation o These effects are directly related to the total dose, fraction size, and irradiated lung volume o Symptoms may appear after a latent period of 1 to 3 months  Lymphedema o The severity and risk of lymphedema may be further complicated by radiation and chemotherapy o Approximately 25 to 30 of patients receiving radiation experience arm edema  Osteoradionecrosis o Tangential treatment fields of the chest wall may incidentally deliver a relatively high dose of radiation to the ribs o The incidence of a resulting rib fracture is relatively low (less than 1%)