Breast Cancer : Symptoms, Pathophysiology, Diagnosis and Treatment
Breast cancer is a malignancy originating from breast tissue. This chapter distinguishes between early stages, which are potentially curable, and metastatic breast cancer, which is usually incurable.
Pathophysiology of Breast Cancer :
- The development of malignancy is a multistep process with preinvasive (or noninvasive) and invasive phases.
- The strongest risk factors are female gender and increasing age. Additional risk factors include endocrine factors (e.g., early menarche, nulliparity, late age at first birth, estrogen therapy), genetics (e.g., personal and family history, mutations of tumor suppresser genes [BRCA1 and BRCA2]), and environment (e.g., radiation exposure).
- Breast cancer spreads via the bloodstream early in the course of the disease, resulting in relapse and metastatic disease after local therapy. The most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.
- The likelihood of developing metastatic disease is related to prognostic factors as described below.
- The initial sign in more than 90% of women with breast cancer is a painless lump that is typically solitary, unilateral, solid, hard, irregular, and nonmobile. Less common initial signs are pain and nipple changes. More advanced cases present with prominent skin edema, redness, warmth, and induration.
- Symptoms of metastatic breast cancer include bone pain, difficulty breathing, abdominal enlargement, jaundice, and mental status changes.
- Approximately 80% of women first detect some breast abnormalities themselves.
- It is increasingly common for breast cancer to be detected during routine screening mammography in asymptomatic women.
Diagnosis of Breast Cancer
- Initial workup for a woman presenting with a localized lesion or suggestive symptoms should include a careful history, physical examination of the breast, three-dimensional mammography, and possibly other breast imaging techniques such as ultrasound.
- Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or a mass that is palpable on physical examination.
Breast Cancer Staging
Stage is based on the size of the primary tumor (T1-4, presence and extent of lymph node involvement (N1-3, and presence or absence of distant metastases (M). Simplistically stated, these stages may be represented as follows:
Early Breast Cancer
- Stage 0: Carcinoma in situ or disease that has not invaded the basement membrane.
- Stage I: Small primary tumor without lymph node involvement.
- Stage II: Metastasis to ipsilateral axillary lymph nodes.
Locally Advanced Breast Cancer
- Stage III: Usually a large tumor with extensive nodal involvement in which node or tumor is fixed to the chest wall; also includes inflammatory breast cancer, which is rapidly progressive.
Advanced or Metastatic Breast Cancer
- Stage IV: Metastases to organs distant from the primary tumor.
Pathologic Evaluation :
- The pathologic evaluation of breast lesions establishes the histologic diagnosis and presence or absence of prognostic factors.
- Most breast carcinomas are adenocarcinomas and are classified as ductal or lobular.
- Carcinoma in situ may be a preinvasive cancer or a marker of unstable epithelium that represents an increased risk for developing aggressive cancer.
- Tumor size and the presence and number of involved axillary lymph nodes are primary factors in assessing the risk for breast cancer recurrence and subsequent metastatic disease.
- Hormone receptors are used as indicators of prognosis and to predict response to hormone therapy.
- The rate of tumor cell proliferation, nuclear grade, and tumor (histologic) differentiation are also independent prognostic research factors.
- Additional potential prognostic factors include overexpression of erb-B2 oncogene (or HER-2/neu), cathepsin-D, angiogenic growth factors, and mutations in the tumor suppressor p53 gene. HER-2/neu status is of interest because targeted therapy is available; however, the testing method is controversial. The widely used method, immunohistochemistry (IHC), can yield false-positive results at the 2+ level, which should be confirmed by fluorescence in situ hybridization (FISH) testing.
TREATMENT of BREAST CANCER :
- The treatment of breast cancer is rapidly evolving. Specific information regarding the most promising interventions can be found only in the primary literature.
- Treatment can cause substantial toxicity, which differs depending on the individual agent, administration method, and combination regimen. Because a comprehensive review of toxicities is beyond the scope of this chapter, appropriate references should be consulted.
- EARLY BREAST CANCER
- Surgery alone can cure most patients with in situ cancers and approximately half of those with stage II cancers.
- Breast conservation is appropriate primary therapy for most women with stages I and II disease; it is preferable to modified radical mastectomy because it produces equivalent survival rates with cosmetically superior results. Breast conservation consists of lumpectomy (i.e., excision of the primary tumor and adjacent breast tissue) followed by radiation therapy to prevent local recurrence.
- Primary systemic or neoadjuvant therapy, which is administered before surgery, is gaining favor. Advantages include shrinking the tumor, making inoperable tumors resectable, assessing in vivo response to chemotherapy, and, in patients with complete pathologic response, prolonging disease-free survival.
- Simple or total mastectomy involves removal of the entire breast without dissection of underlying muscle or axillary nodes. This procedure is used for carcinoma in situ where the incidence of axillary node involvement is only 1%, for local recurrence following breast conservation therapy, or to avoid the inconvenience of radiation therapy and preserve the option for future breast reconstruction.
- Axillary lymph nodes should be sampled for staging and prognostic information. Lymphatic mapping with sentinel lymph node biopsy is a new, less invasive alternative to axillary dissection; however, the procedure is controversial because of the lack of long-term data.
Systemic Adjuvant Therapy
- Systemic adjuvant therapy is the administration of systemic therapy following surgery, radiation, or both. There is no evidence of metastatic disease but a high likelihood of recurrence because of undetectable micrometastases. The goal of such therapy is cure.
- The choice between chemotherapy and endocrine therapy, or both, as adjuvant therapy is evolving.
- Essentially all women with stage I and stage II breast cancer derive some benefit from chemotherapy, but the absolute benefit is greater in premenopausal women.
- The National Comprehensive Cancer Network (NCCN) practice guidelines reflect the trend toward the use of chemotherapy in all women regardless of menopausal status, and the addition of endocrine therapy in all women with receptor-positive disease regardless of menopausal status.
- Many combination regimens are used in the adjuvant setting (Table 59-1), which are typically derived from those that produce the highest response rate in advanced disease.
- Doxorubicin-containing regimens are popular because they are superior to cyclophosphamide, methotrexate, and fluorouracil (CMF) and require only four cycles.
- Taxanes, docetaxel and paclitaxel, are a newer class with activity against metastatic breast cancer rivaling that of anthracyclines. When used in combination regimens or given sequentially (e.g., doxorubicin and cyclophosphamide followed by paclitaxel [AC â†’ T]), taxanes increase disease-free survival in women with node-positive breast cancer. Follow-up, however, is insufficient to assess impact on the decisive endpoint, overall survival.
- Clinical trials are being conducted to evaluate newer agents (e.g., trastuzumab).
- Chemotherapy should be initiated within 3 weeks of surgical removal of the primary tumor. The optimal duration of treatment is about 12 to 24 weeks.
- Dose intensity refers to the amount of drug administered per unit of time, which can be increased by increasing dose, decreasing time, or both. Dose density is equivalent to dose intensity except that it is increased only by decreasing time. Dose intensity, but not density, is an important determinant of outcome in adjuvant therapy. Therefore, the dose of standard regimens should not be reduced unless necessitated by severe toxicity.
- The short-term toxicities of chemotherapy are generally well tolerated in the adjuvant setting, especially with the availability of serotonin-antagonist antiemetics and colony-stimulating factors.
Adjuvant Endocrine Therapy
- Tamoxifen is the gold standard for adjuvant endocrine therapy because of extensive trial experience showing decreased recurrence and mortality. Additional benefits include estrogenic effects on lipids and bone density.
- The optimal daily dose of tamoxifen is 20 mg, beginning soon after completing chemotherapy and continuing for five years.
- Tamoxifen is usually well tolerated. Symptoms of estrogen withdrawal (hot flashes and vaginal bleeding) may occur but decrease in frequency and intensity over time. Tamoxifen increases the risks of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer, especially in women older than 50 years of age.
- Other endocrine therapies show promise, but trials have insufficient follow-up to assess impact on survival. Such options included toremifene as an alternative to tamoxifen; the luteinizing hormone-releasing hormone (LHRH), goserelin, for premenopausal women; and aromatase inhibitors, either in place of or after tamoxifen, for postmenopausal women.
LOCALLY ADVANCED BREAST CANCER (STAGE III)
- Local-regional therapy with surgery, radiation, or both does not cure locally advanced breast cancer.
- Primary or neoadjuvant or chemotherapy is the initial treatment of choice. Benefits include rendering inoperable tumors resectable and increasing the rate of breast-conserving surgery.
- Combination regimens used as primary chemotherapy are similar to those used as adjuvant therapy and generally include an anthracycline and taxane.
METASTATIC BREAST CANCER (STAGE IV)
- The choice of therapy for metastatic disease is based on the site of disease involve- ment and presence or absence of certain characteristics, as described below.
- Endocrine Therapy
- Endocrine therapy is the treatment of choice for patients who have hormone receptor-positive metastases in soft tissue; bone; pleura; or, if asymptomatic, viscera. Compared with chemotherapy, endocrine therapy has an equal probability of response and a better safety profile.
- Patients are sequentially treated with endocrine therapy until they have rapidly growing metastatic disease, at which time chemotherapy can be given.
- Because most endocrine therapies are equally effective, the choice is based primarily on toxicity (Table 59-2).
- Tamoxifen is usually the agent of choice in both premenopausal and postmenopausal women whose tumors are hormone-receptor positive, unless metastases occur within a year of adjuvant tamoxifen. Maximal beneficial effects do not occur for 2 months or more. In addition to the side effects described for adjuvant therapy, tumor flare or hypercalcemia occurs in approximately 5% of patients with metastatic breast cancer. This may be a positive indication that the patient will have a response to endocrine therapy.
- New antiestrogens are being developed to maintain tamoxifen’s beneficial effects on breast cells, bone, and lipids and avoid its effects on the endometrium. The new antiestrogen, toremifene, appears to have efficacy and safety similar to that of tamoxifen, but it is not suitable for tamoxifen-refractory disease because of cross-resistance.
- Ovarian ablation (oophorectomy) is considered by some to be the endocrine therapy of choice in premenopausal women and produces similar overall response rates as tamoxifen. Medical castration with an LHRH analogue, goserelin, leuprolide, or triptorelin, is a reversible alternative to ovarian ablation.
- Aromatase inhibitors reduce circulating estrogens by blocking peripheral conversion from an androgenic precursor, the primary source of estrogens in postmenopausal women. Newer agents are more selective and better tolerated than the prototype, aminoglutethimide. As second-line therapy, anastrozole and exemestane improve overall survival and tolerability compared with progestins. As first-line therapy, anastrozole and letrozole improve time to progression and tolerability compared with tamoxifen.
- Progestins are generally reserved for third-line therapy. They cause weight gain, fluid retention, and thromboembolic events.
- Chemotherapy is preferred to endocrine therapy for women with hormone receptor-negative tumors; rapidly progressive lung, liver, or bone marrow involvement; or failure of endocrine therapy.
- The choice of treatment depends on the individual. Agents used as adjuvant therapy can be repeated unless the cancer recurred within a year. Sequential single-agent regimens are less toxic than combination regimens, but the latter are used to induce rapid response for symptomatic bulky metastases.
- Combinations produce objective responses in approximately 40% of patients previously unexposed to chemotherapy, but complete responses occur in less than 10% of patients. The median duration of response is 5 to 12 months; the median survival is 14 to 33 months.
- Single agents are associated with lower response rates, but time to progression and overall survival are similar. Single agents are better tolerated, an important consideration in the metastatic setting.
- Anthracyclines produce response rates of 50% to 60% when used as first-line therapy for metastatic breast cancer.
- Newer single agents, such as paclitaxel (50% to 60%), docetaxel (54% to 68%), capecitabine (25%), vinorelbine (30% to 50%), and gemcitabine (13% to 42%), produce impressive response rates in previously untreated patients. Although response rates are lower in previously treated patients, these agents are useful alternatives for anthracycline-refractory breast cancer. Furthermore, some of these agents are moving to first-line regimens, often in combination with anthracyclines.
- Different doses are available for single-agent therapy of metastatic breast cancer (Table 59-3). Weekly paclitaxel administration causes less myelosuppression and delayed onset of peripheral neuropathy compared with paclitaxel given every 21 days. The 100-mg/m2 dose of docetaxel is indicated for symptomatic patients requiring rapid onset of activity, whereas 60 or 75 mg/m2 is equally effective and appropriate for asymptomatic patients. Capecitabine is usually initiated at 2,000 mg/m2 daily because the 2,500-mg/m2 dose is poorly tolerated and does not improve efficacy.
- Trastuzumab, a monoclonal antibody that binds to HER-2/neu protein, produces responses rates of 15% to 20% when used as a single agent and prolongs survival when combined with chemotherapy. Trastuzumab is well tolerated, but it may increase the risk of doxorubicin-related cardiotoxicity. Non-anthracycline-containing combinations are being evaluated.
METASTATIC BREAST CANCER
- Optimizing quality of life is the therapeutic end point in the treatment of patients with metastatic breast cancer. Many valid and reliable tools are available for objective assessment of quality of life.
- The least toxic therapies are used initially, with increasingly aggressive therapies applied in a sequential manner that does not significantly compromise quality of life.
- Tumor response is measured by clinical chemistry (e.g., liver enzyme elevation in patients with hepatic metastases) or imaging techniques (e.g., bone scans or chest x-rays).
- Assessment of the clinical status and symptom control of the patient is often adequate to evaluate response to therapy.