Stages III and IV Breast Cancer
Stages III and IV Breast Cancer
This chapter addresses the diagnosis and management of locally advanced, locally recurrent, and metastatic breast cancer, that is, stages III and IV disease.
Approximately 20% to 25% of patients present with locally advanced breast cancer. Inflammatory breast cancer is a particularly aggressive form of breast cancer that falls under the heading of locally advanced disease and accounts for 1% to 3% of all breast cancers.
Locoregional recurrence of breast cancer remains a major oncologic problem. Rates of locoregional recurrence may vary from < 10% to > 50%, depending on initial disease stage and treatment.
Metastatic disease is found at presentation in 5% to 10% of patients with breast cancer. The most common sites of distant metastasis are the lungs, liver, lymph nodes, and bone.
The optimal therapy for stage III breast cancer continues to change. Neoadjuvant chemotherapy has been effective in downstaging locally advanced breast cancer prior to surgical intervention. The optimal neoadjuvant chemotherapeutic regimens continue to evolve, and studies are currently being performed to evaluate new agents and delivery methods.
In July 2012, the FDA approved the mTOR inhibitor everolimus (Afinitor) for use in postmenopausal breast cancer patients with metastatic human epidermal growth factor receptor 2 (HER2)-negative, hormone-receptor–positive disease. The drug was approved in combination with exemestane (Aromasin) in patients whose cancer has progressed following treatment with letrozole or anastrozole. The pivotal phase III trial leading to approval of everolimus for this indication, BOLERO-2, enrolled 724 patients who were treated with exemestane and randomized to receive either everolimus or placebo. Everolimus in combination with exemestane improved progression-free survival compared with exemestane alone (7.8 months vs 3.2 months; P < .001).
In June 2012, the FDA approved pertuzumab (Perjeta) for HER2-positive metastatic breast cancer patients who have not received prior systemic treatment. Pertuzumab, an anti-HER2 humanized monoclonal antibody, is believed to complement the activity of the anti-HER2 agent trastuzumab (Herceptin), as the two drugs target different regions on the HER2 receptor. Pertuzumab is approved in combination with trastuzumab and docetaxel. Its approval was based on results of CLEOPATRA, an international, phase III, randomized, double-blind, placebo-controlled trial that randomized 808 HER2-positive metastatic breast cancer patients to a trastuzumab-docetaxel regimen including either pertuzumab or placebo. Median progression-free survival was 18.5 months for patients in the pertuzumab arm compared with 12.4 months for those in the placebo arm (P < .001). Adding pertuzumab to standard treatment reduced the risk of disease progression or death by 38%.
Patients with locally advanced breast cancer do not have distant metastatic disease; they are categorized in this group based on tumor size and/or nodal status. Such patients often present with a large breast mass or axillary nodal disease that is easily palpable on physical examination. In some instances, the breast is diffusely infiltrated with disease, and no dominant mass is evident.
Patients with inflammatory breast cancer often present with erythema and edema of the skin of the breast (peau d'orange); they may not have a discrete mass within the breast. These patients often are treated with antibiotics unsuccessfully for presumed mastitis before they are diagnosed with breast cancer.
Mammography is beneficial in determining the local extent of disease in the ipsilateral breast, and in studying the contralateral breast.
Fine-needle aspiration or core biopsy
In the locally advanced setting, although breast cancer can be confirmed by either fine-needle aspiration (FNA) cytology or core biopsy, the latter is preferred. Core biopsy provides sufficient tissue to perform the wide variety of marker analyses. When there is suspicion of inflammatory breast carcinoma, a skin biopsy is also recommended to ascertain the presence of dermal lymphatic invasion. Because the diagnosis of inflammatory breast cancer is based on clinical findings, a negative skin biopsy does not preclude the diagnosis.
Search for metastasis
The presence of distant metastatic disease should be ruled out by physical examination, chest X-ray, bone scan, and contrast enhanced CT scans of the chest, abdomen, and pelvis. 18Fluorodeoxyglucose-positron emission tomography (FDG-PET) has moderate accuracy for detecting axillary metastasis. It is highly predictive of nodal involvement when multiple intense foci of tracer uptake are identified, but it fails to detect small nodal metastasis. However, addition of FDG-PET to the standard workup of patients with locally advanced breast cancer may lead to the detection of unexpected distant metastases. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.
Biopsy or FNA
Locoregional recurrence of breast cancer can be diagnosed by surgical biopsy or FNA cytology. The biopsy specimen should be sent for hormone-receptor studies, and testing for human epidermal growth factor type 2 (HER2/neu) overexpression, since these biomarkers are not always concordant between the primary tumor and recurrence. Discrepancy rates ranging from 17% to 55% have been reported. When the suspected recurrent disease is not extensive, the biopsy procedure of choice is a negative margin excisional biopsy. For an extensive recurrence, an incisional biopsy can be used if a core biopsy is not possible.
Search for distant metastasis
Prior to beginning a treatment regimen for a patient with locoregional recurrence, an evaluation for distant metastasis should be performed, since the findings may alter the treatment plan.
Metastatic breast cancer may be manifested by bone pain, shortness of breath secondary to a pleural effusion or lymphangitic spread, pleural or pulmonary nodules, or neurologic deficits secondary to spinal cord compression or brain metastases. In some instances, metastatic disease is identified after abnormalities are found on routine laboratory or radiologic studies.
Assessment of disease extent
It is important to assess the extent of disease using radiography, CT, and radionuclide scanning. Organ functional impairment may be determined by blood tests (liver/renal/hematologic) or may require cardiac and pulmonary function testing. A biopsy should be highly encouraged to confirm the diagnosis of metastatic disease; this is especially important when only a single distant lesion is identified.
Metastasis to the breasts
The most common source of metastatic disease to the breasts is a contralateral breast primary. Metastasis from a nonbreast primary is rare, representing less than 1.5% of all breast malignancies. Some malignancies that can metastasize to the breast include non-Hodgkin lymphoma, leukemias, melanoma, lung cancer (particularly small-cell lung cancer), gynecologic cancers, soft-tissue sarcomas, and gastrointestinal (GI) adenocarcinomas. Metastasis to the breasts from a nonbreast primary is more common in younger women. The average age at diagnosis ranges from the late 30s to 40s. Treatment depends on the status and location of the primary site.
Mammography in patients with metastatic disease to the breasts most commonly reveals a single lesion or multiple masses with distinct or semidiscrete borders. Less common mammographic findings include skin thickening or axillary adenopathy.
FNA or biopsy
FNA cytology has been extremely useful in establishing the diagnosis when the metastatic disease has cytologic features that are not consistent with a breast primary. When cytology is not helpful, core biopsy or even open biopsy may be necessary to distinguish primary breast cancer from metastatic disease.