Breast Cancer

Breast cancer is a major cause of morbidity and mortality in elderly women. Each year about 50% of the 185,000 new cases of breast cancer in the USA occur in women >= 65 years. The risk of developing breast cancer is much greater than that of dying of it: 6.53% of white women and 4.70% of black women >= 65 develop breast cancer, but only 1.53% and 1.14%, respectively, die of it (see Table 121-1). Breast cancer in men, which also increases in incidence with age (mean age at diagnosis is about 65), accounts for 1% of all new cases.

The incidence of breast cancer increases up to age 80, plateaus between ages 80 and 85, and then declines. However, the measured decline after age 85 is difficult to interpret and may reflect the inadequacy of epidemiologic data.

Classification and Pathophysiology

Breast cancer may be classified pathologically as noninvasive (in situ) or invasive (infiltrating). The noninvasive carcinomas are generally thought to be antecedents of invasive carcinoma.

Intraductal carcinoma (ductal carcinoma in situ) is the most common noninvasive carcinoma among elderly women. It is generally multicentric, and <= 20% recur locally after partial mastectomy. Axillary lymph nodes are involved in < 2% of cases. Lobular carcinoma in situ, often multicentric and involving both breasts, is rare after menopause.

Of the invasive carcinomas, invasive ductal carcinoma is the most common among women of all ages, comprising about 70% of all cases. The incidence of mucinous (colloid) carcinoma, a slow-growing tumor in elderly women, increases with age. The incidence of medullary carcinoma, which is often bilateral, decreases with age. Inflammatory carcinoma of the breast, a very aggressive tumor, is equally prevalent among premenopausal and postmenopausal women.

Paget's disease of the nipple represents spread of a ductal carcinoma to the skin of the nipple; it is usually associated with intraductal carcinoma and less so with invasive carcinoma. A palpable breast lump is present in 50% of cases.

Risk Factors

The major risk factors for breast cancer are listed in Table 121-2. The influence of reproductive history, history of estrogen replacement therapy, and abdominal obesity suggest that estrogens play a role in the pathogenesis of breast cancer. An increased prevalence of android obesity among elderly women may partly explain the higher risk of breast cancer with age. Android obesity is defined as a ratio of >= 0.71 between the body circumference measured at the waist and at the hips (the "apple" vs. the "pear"). It is associated with an increased concentration of free estrogen.

Use of postmenopausal estrogen replacement therapy for 5, 10, or 15 years is associated with 2, 6, and 12 excess breast cancers diagnosed per 1000 women, respectively. Risk returns to normal 5 years after stopping estrogen replacement therapy. The risk of breast cancer associated with use of oral contraceptives disappears within 10 years after stopping use.

Symptoms, Signs, and Diagnosis

Breast cancers have the same clinical characteristics in elderly women as in younger women. Cancer is usually suspected when changes are observed on mammography or when a breast lesion is seen or felt. Lesions usually can be felt as firm nodules within the breast. Ulcerations may occur, and lesions within or near the nipple may produce discharge. Sometimes, breast cancer is discovered only after metastatic lesions cause bone fractures, neurologic changes, hypercalcemia, liver failure, or ascites.

When a tumor is detected by physical examination, bilateral mammograms should be obtained to rule out occult lesions. Certain radiographic images, such as speckled calcifications or tissue infiltration, suggest cancer, whereas a cystic appearance suggests a benign process. Even an apparently benign finding on a mammogram requires further evaluation, usually by fine-needle aspiration. This simple and safe procedure, which has 94% sensitivity, allows collection and cytologic examination of cystic fluid and is extremely helpful in planning definitive treatment of breast cancer. A positive result on fine-needle aspiration is diagnostic; a negative result usually should be followed by an open biopsy.

At the time of initial diagnosis, a chest x-ray, a CBC count, and liver enzyme studies are performed. More complex and costly tests should be reserved for specific indications, such as hepatomegaly or abnormal liver enzymes, bone pain and tenderness, nocturnal headache, 6th nerve paralysis, focal neurologic signs, or cranial hypertension.

Breast cancer commonly metastasizes to bone and may cause pathologic fractures, especially in osteoporotic women. Pathologic fractures can cause severe pain, especially when they lead to spinal compression. Bone metastases may also cause profound hypercalcemia, which can be the presenting symptom, most typically in women on bed rest. Breast cancer also frequently metastasizes to the brain, lungs, and liver.

Prevention

The goal of primary prevention is to prevent or halt the carcinogenic process before cancer develops. The goal of secondary prevention is to detect breast cancer at an early and curable stage.

Primary prevention: Chemoprevention is the usual method of primary prevention, and the drugs tamoxifen and raloxifene are promising, although their optimal use is not yet known. For women at high risk of breast cancer (including any woman >= 60), taking tamoxifen 20 mg daily for 5 years reduces the incidence of invasive cancer by 49%. The occurrence of osteoporotic fractures also decreases, but the rates of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer increase slightly, particularly in women >= 50. Hot flushes may limit its use in up to 15% of postmenopausal women. Raloxifene, a selective estrogen receptor modulator, may also reduce the incidence of breast cancer by as much as 45% and does not appear to increase the incidence of endometrial cancer.

Chemoprevention is also recommended for women with a history of invasive or in situ breast cancer, because the risk of developing a new breast cancer increases 0.5 to 1.0% per year. Adjuvant tamoxifen given for 5 years decreases contralateral breast cancer by 47% in all women. Preliminary data suggest that 4-hydroxyphenylretinamide, a retinoid, may provide similar benefit.

Secondary prevention: Elderly women often present with more advanced and symptomatic disease than do younger women. To prevent late diagnosis, health care practitioners should teach elderly women how to examine their breasts and encourage them to perform breast self-examination monthly. However, evidence is lacking concerning the benefit of breast self-examination.

Screening asymptomatic elderly women for breast cancer includes periodic mammography and clinical breast examination. Appropriate screening reduces breast cancer-related mortality among women aged 50 to 75 by 25 to 30%. Regular screening may also benefit women > 75, but this has not been proved. Screening guidelines have been developed by several organizations (see Table 121-3). There are no clear data indicating which method of screening is best.

Fewer than 50% of women >= 65 have ever undergone mammography, and an even smaller proportion undergo mammography regularly. The participation of elderly women in screening programs is determined mostly by the support of primary care physicians, who are in the best position to identify and to help patients overcome socioeconomic, cultural, and educational barriers.

Prognosis

It is unclear whether breast cancer in women > 65 has the same or a more indolent clinical course than in younger women. Pure mucinous, pure tubular, pure medullary, and pure papillary carcinomas are associated with longer survival than all other types of intraductal carcinoma.

Tumors found in elderly women are more likely to be well differentiated. Life-threatening hepatic, cerebral, and lymphangitic metastases are less prevalent. In addition, a tumor is more likely to be hormone receptor-rich as a patient ages, a good prognostic sign. Local and regional recurrences appear to decrease with age. However, elderly women often have more advanced, less asymptomatic disease at the time of diagnosis. Stage-specific relative survival is similar to that of younger patients and is worse for patients > 85.

Prognosis is determined by the stage of the disease (see Table 121-4) and by different factors within each stage. In the absence of systemic adjuvant therapy, recurrence within 10 years is 24% for node-negative patients and 76% for node-positive patients. Axillary lymph node dissection has therefore become a routine part of staging of invasive breast cancer for tumors > 1 cm, since tumors smaller than this have a < 10% risk of metastatic nodes being present. However, particularly when followed by radiation therapy, axillary node dissection is associated with significant chronic morbidity 1 year after surgery, including lymphedema, decreased grip strength, limitation in shoulder range of motion, shoulder or arm stiffness, pain or numbness, and an increased susceptibility to cellulitis.

In women with stage I or II disease, the number of axillary lymph nodes with tumor is the most important prognostic factor. Ten years after diagnosis, 60 to 70% of women with involvement of one to three lymph nodes are alive and free of disease, compared with only 15 to 25% of those with involvement of eight or more lymph nodes. However, 25 to 33% of patients with node-negative breast cancer have recurrent disease. Systemic adjuvant therapy may improve outcomes for these women. However many women are unnecessarily subjected to treatment and its adverse effects, because patients at high risk of disease recurrence cannot be well distinguished from those at low risk. Known prognostic factors for node-negative disease are the size of the primary tumor, negative status of estrogen and progesterone receptors, and a high histologic and nuclear grade (ie, poor differentiation). Plasminogen activator inhibitor type 1 (PAI-1) is a new marker that may indicate a better disease-free and overall survival.

In stage III disease, unfavorable prognostic factors include edema, ulceration, fixation to the chest wall, and inflammatory breast cancer.

In stage IV disease, the prognosis varies markedly with the metastatic sites: average survival is 3 to 6 months if the patient has liver or lymphangitic lung metastases, 24 months if the patient has nodular lung metastases or pleural effusions, and > 5 years if metastases are limited to bone.

Treatment

Treatment is guided by disease stage, the patient's general condition, and the patient's preferences. In the elderly, frailty, serious comorbidities, and dementia may make aggressive treatment inappropriate. In such cases, palliation might be a better option. Local treatment modalities include partial mastectomy (lumpectomy) or total mastectomy, axillary lymph node dissection, and external beam radiation.

Biopsy of the sentinel lymph node (the first node that receives drainage from the tumor) can decrease the need for axillary lymph node dissection. When the procedure is done by experienced surgeons, the sentinel node is identified in > 90% of patients, the positive predictive value is almost 100%, and the negative predictive value is 95%.

Systemic treatment includes hormonal therapy and cytotoxic chemotherapy (see Table 121-5).

Stage 0 breast cancer: Regardless of tumor size, 98% of ductal carcinoma in situ is cured by total mastectomy or partial mastectomy with radiation therapy. Axillary dissection and systemic adjuvant chemotherapy are not necessary.

Stages I and II breast cancer: The management of localized breast cancer includes local and systemic (adjuvant) treatment. Local treatment involves total or partial mastectomy and axillary lymph node dissection. Total or partial mastectomy may be performed under local anesthetic, with negligible risk even for women >= 90. Partial mastectomy is usually followed by postoperative radiation therapy to prevent local recurrence of cancer.

The choice of surgical procedure is the patient's prerogative. Partial mastectomy may be preferable in terms of body image and sexual attractiveness, but the adjuvant postoperative radiation therapy can be inconvenient (it must be given 5 days a week for 7 weeks) and costly. In addition, the benefits and risks of postoperative radiation therapy are unclear for elderly women. Radiation therapy may prevent local recurrences, but it is not known whether it affects survival. Elderly women, however, are less likely to have local recurrences. Radiation therapy may cause toxicity to breast tissue, skin burns, irritation, and heart or lung complications.

Most elderly women choose to use an external prosthesis rather than to have breast reconstruction after mastectomy. Reasons why women elect not to have breast reconstruction include concerns about increased time under anesthesia and increased risk of complications. However, age is not a contraindication to reconstruction. A new prosthesis that adheres to the chest wall and does not require a padded brassiere (and is therefore more comfortable) is being tested in Germany.

Systemic adjuvant treatment is recommended for women with invasive breast cancer and axillary node involvement, invasive ductal or lobular carcinoma >= 1 cm in largest diameter, or, with favorable histologic findings, invasive carcinoma >= 3 cm in largest diameter because of the high risk of recurrence after local therapy. Tamoxifen prolongs both the disease-free survival and overall survival of postmenopausal patients, even patients >= 70 and those whose regional lymph nodes are cancer-free. For women >= 70, recurrence is reduced from 42% to 25%. There is no advantage to continuing tamoxifen therapy beyond 5 years.

Women with estrogen receptor-negative (ER-) tumors do not generally benefit from tamoxifen. However, tamoxifen has a similar effect on reducing the incidence of contralateral breast cancer in women with ER- and ER+ tumors. Primary treatment of localized breast cancer with tamoxifen is recommended only for women who cannot or should not undergo surgery.

After treatment, patients with stage I or II breast cancer should be followed up every 3 to 6 months for the first 3 years; every 6 months for the next 2 years; and then annually. These women are at risk of new breast cancer as well as of recurrence of the original tumor. In addition to a general physical examination, patients should undergo clinical breast examination and mammography annually. Additional laboratory and radiologic testing does not improve survival or time to detection of recurrence.

Stage III breast cancer: Locally advanced breast cancer is best managed with a combination of systemic and local therapies. Preoperative systemic treatment with chemotherapy regimens containing doxorubicin or mitoxantrone is the first step. When tumor size is adequately reduced, total or partial mastectomy, radiation therapy, or both may be used. About 50% of patients are alive and disease-free 5 years after treatment. It is unclear whether adjuvant chemotherapy and hormonal therapy after preoperative chemotherapy and regional treatment in locally advanced breast cancer decrease further recurrence or prolong life. In the case of inflammatory breast cancer, hormonal therapy by itself is seldom effective; a combination of chemotherapy and hormonal therapy is advisable.

Stage IV breast cancer: Hormonal therapy is the best treatment for women >= 65 with ER+ tumors or tumors whose receptor status is unknown, a long disease-free interval, or metastases only to bone. Antiestrogens are first-line therapy, followed by aromatase inhibitors and progestins. Most practitioners prefer tamoxifen as initial hormonal treatment and use other drugs if the disease progresses or if complications with tamoxifen occur. In about 15% of patients with bone metastases, tamoxifen causes tumor flare-up resulting in hypercalcemia. This transient complication can be managed with IV fluids and furosemide and does not warrant stopping the drug. Patients sometimes respond to a second hormonal treatment after the first becomes ineffective.

For patients with hormone-unresponsive tumors or with life-threatening disease (hepatic or lymphangitic pulmonary spread), chemotherapy is indicated as first-line therapy. It has a much faster onset of action than hormonal treatment. Women with extensive comorbidity may not be appropriate candidates. Chemotherapy regimens are undergoing rapid change as new drugs and combinations of drugs become available (see Table 121-5). The mainstays include CAF (cyclophosphamide, doxorubicin [Adriamycin], 5-fluorouracil) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil). Taxanes (paclitaxel and docetaxel) prolong survival in women with anthracycline-resistant disease. Cytotoxic chemotherapy is usually well tolerated by patients >= 70. Randomized clinical trials have included few women with comorbidities or women > 80, thus adverse effects in such women are unknown. Elderly women are more likely to have preexisting heart disease, osteoporosis, and risk factors for delirium and falls (eg, if they become dehydrated) and are more likely to be taking other drugs. Therefore, elderly patients should be closely monitored, and risk factors should be identified and reversed or lessened when possible.

Trastuzumab, a monoclonal antibody that acts against the Her-2/neu oncogene, may be used as monotherapy for women refractory to chemotherapy or with paclitaxel as first-line treatment of metastatic breast cancer. The use of trastuzumab is limited to patients whose tumors overexpress Her-2/neu. The overexpression of Her-2/neu occurs in 20 to 30% of metastatic breast cancers and is associated with aggressive tumors and chemotherapy resistance. When combined with chemotherapy, trastuzumab improves 1-year response rate, median duration of response, and time to progression. The drug is administered intravenously weekly. Adverse effects are milder than those associated with standard chemotherapy, although about 40% of patients develop flu-like symptoms with the first dose. Cardiotoxicity occurs in 7% of patients when the drug is used alone.

Pathologic fractures of long bones may be prevented by prophylactic orthopedic pinning of bones with osteolytic metastases. Patients with lytic lesions develop skeletal complications (eg, pathologic fractures, cord compressions, hypercalcemia) less often and later in their disease when they receive IV pamidronate monthly. Bone pain may be managed with local radiation therapy, pamidronate, and strontium 89. Brain metastases are managed with corticosteroids and radiation therapy.

End-of-Life Issues

Palliative care, which provides physical, emotional, and spiritual relief, must be provided with attempts for curative therapy and becomes the exclusive goal when cure cannot be expected. At all stages of breast cancer, treatment needs to be modified for life expectancy. For patients with metastatic disease for which cure is not attainable, the physician should clarify the goals of care through frequent, clear discussions with the patient and, when appropriate, the family. All should recognize that cognitive impairment alone does not exclude the patient from participating in decision making, because some patients with impaired cognition are able to understand, explain the consequences of, and voice an opinion about certain treatment options. Pain from bony metastases should be treated as described above with nonsteroidal anti-inflammatory drugs, pamidronate, local radiation, and strontium 89 rather than with opioids if possible. Palliative chemotherapy may be useful when the tumor invades vital organs. Other details of palliative care are discussed in Ch. 13.