1. Lobular carcinoma in situ (LCIS)
Lobular carcinoma in situ. Presently, treatment options include close follow-up, participation in a chemoprevention trial, tamoxifen (Nolvadex), or bilateral total mastectomy with or without reconstruction. At present, the decision for a given treatment will depend upon the patient?s individual risk profile after careful counseling.
2. Ductal carcinoma in situ (DCIS)
Ductal carcinoma in situ (DCIS). Breast-conservation surgery, followed by radiation therapy to the intact breast, is now considered the standard treatment for patients with DCIS.
Axillary lymph nodes
Routine axillary lymph node evacuation is not indicated in the treatment of DCIS since the incidence of positive lymph nodes after axillary lymph node dissection for DCIS is 1%-2%.
Factors associated with an increased risk of axillary metastasis with a diagnosis of DCIS are
These factors likely are associated with unknown (nondiagnosed) invasive disease and may benefit from sentinel lymph node dissection.
A surgical margin of 1 mm has been associated with a 43% chance of having residual disease at the time of re-excision. When a surgical margin of 10 mm (which may not be practical due to cosmetic reasons) can be obtained, there is an extremely low rate of recurrence (4%), and radiotherapy to the breast may not be necessary.
Adjuvant tamoxifen therapy
Adjuvant tamoxifen therapy was shown to benefit women with DCIS in a recent NSABP trial (NSABP-24) in which the tamoxifen group had fewer breast cancer events than those in the placebo group.
Stage I & II
1. Conservative surgery
Breast-conserving surgery followed by radiation therapy to the intact breast is now considered a standard treatment for the majority of patients with stage I or II invasive breast cancer.
The extent of breast conservation is debatable. Techniques for breast conservation include: lumpectomy, segmental mastectomy, quadrantectomy & others all of which have a similar in outcome. Quadrantectomy is used by some as it has good safety margin (the radical form of conservative surgery).
A consensus statement on breast-conserving therapy issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins and that a level I-II axillary lymph node dissection be performed. The patient should subsequently be treated with adjuvant breast irradiation. This should be followed by radiation as part of the 1ry therapy.
Contraindications to conservative surgery:
Axillary lymph node surgery following breast conservation
The role of axillary lymph node surgery is controversial when breast conservation is the aim of therapy. Currently, axillary evaluation is recommended in this setting. In these cases sentinel node dissection is recommended when feasible.
The ability to identify the sentinel node can reach as high as 97% when both blue dye and Tc-99m sulfur colloid are used together.
Adjuvant radiation therapy following breast conservation
Breast conservation should be followed by radiation as part of the 1ry therapy.
For patients who undergo axillary dissection and are found to have negative nodes, regional nodal irradiation is no longer routinely employed. For patients with positive nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis.
Patients who are not candidates for breast conservation or are not interested in breast conservation are offered mastectomy.
Adjuvant radiotherapy after mastectomy
Available data suggest that in patients with the following criteria the risk of locoregional failure remains significantly high enough to consider postmastectomy radiation therapy.
Even with the use of high-dose chemotherapy, locoregional failure is a significant problem in these patients without the use of postmastectomy irradiation.
3. Adjuvant chemotherapy
Systemic therapy is indicated only for invasive (infiltrating) breast cancers larger than 1cm in size (in smaller tumors there is a very low risk of recurrence <10%).
The sequence of systemic therapy and definitive radiation therapy in women treated with breast-conserving surgery is a subject of continued clinical research. The use of concomitant chemotherapy and irradiation is not recommended due to the radiomimetic effects of chemotherapy and the potential for increased locoregional toxicity.
Delaying chemotherapy up to 8-10 weeks after surgery does not appear to have a negative impact on the development of metastasis or survival.
The role of the taxanes, ie, paclitaxel and docetaxel (Taxotere), in adjuvant therapy is being investigated in clinical trials.
4. Adjuvant hormonal therapy
Hormonal therapy with tamoxifen (20 mg PO qd for 5 years) has been shown to be of value in women ≥ 50 years of age with estrogen- and/or progesterone-receptor?positive tumors as shown in the (ATAC trial).
The most recent meta-analysis, which included information on 37,000 women in 55 trials of adjuvant tamoxifen, was published in 1998. In this analysis, the benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors.
The benefit of tamoxifen is independent of menstrual status. Long-term follow-up from the NSABP conclusively demonstrates that there is no benefit to continuing tamoxifen therapy beyond 5 years.
Stage III (Locally advanced disease)
The optimal treatment for patients with locally advanced breast
cancer has yet
Neoadjuvant therapy with cytotoxic drugs permits in vivo chemosensitivity testing, can downstage locally advanced disease and render it operable, and may allow breast-conservation surgery to be performed.
Types of neoadjuvant chemotherapy regimens
Preoperative chemotherapy regimens reported to result in high response rates (partial and complete responses) include:
Combination chemotherapy with an anthracycline-based regimen FAC or
AC is used most often. Recently published data suggest that the AT regimen of Adriamycin and docetaxel
Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response rate for women with locally advanced disease.
Patients with large lesions are more likely to have partial responses. Pathologic complete responses do occur and are more likely to be seen in patients with smaller tumors.
Radiation therapy remains an integral component of the management of patients with locally advanced breast cancer.
Operable cases: For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 5,000-6,000 cGy) is usually employed.
Inoperable cases: For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery.
Multimodality treatment plan
A multimodality approach for locally advanced breast cancer (stage IIIA and IIIB, M1 supraclavicular nodes) consists of
Benefit: This approach has been shown to result in the following benefits:
Stage IV (Metastatic disease)
Patients with metastatic cancer can be divided into two groups: those with stage IV disease at presentation and those who develop metastases after primary treatment. They can be divided into low and high risk groups based on the biologic aggressiveness of the disease.
The low-risk group includes
Hormone therapy in stage IV
First-line hormonal therapy
These drugs aim at reducing the levels of estrogen hormones in hormone receptor positive cancers. First line hormonal therapy consists of an aromatase inhibitor or tamoxifen, with careful serial assessment of clinical and disease responses. Hormone therapy may be associated with a ?flare? response, a temporary worsening of signs and symptoms of disease within the first few weeks of treatment. This response generally means clinical benefit will follow.
Second-line hormonal agents
The most commonly used second-line hormonal agents had been progestational drugs, such as megestrol acetate. Recent randomized trials have indicated that the aromatase inhibitors are equally effective for palliation of metastatic disease, have less toxicity, and may provide a survival advantage compared with megestrol acetate. Therefore, they are the drugs of choice for second-line therapy following tamoxifen administration.
Tamoxifen may also be considered as second-line therapy for patients initially treated with an aromatase inhibitor.
Hormonal therapy continues until evidence of disease progression or drug related toxicity precludes further therapy with the same agent. If a partial or complete response to the first hormonal treatment is documented at the time of disease progression, a second hormonal agent may provide further palliation of symptoms and avoid the initiation of systemic chemotherapy. However, subsequent hormonal responses tend to be of shorter duration, and, ultimately, the disease will become refractory to hormonal treatment.
Hormone-refractory disease can be treated with systemic cytotoxic therapy.
Benefits: see below.
Intermediate- or high-risk patients include
Combination chemotherapy in stage IV
Anthracycline-containing combinations are preferred for these patients.
Single agents in stage IV
Trastuzumab is a humanized monoclonal antibody to the HER-2/neu protein, has been approved for use as a single agent in second- and third-line therapy for metastatic breast cancer and in combination with paclitaxel as first-line therapy in this setting.
Pegram MD, Pienkowski T, Northfelt DW, Eiermann W, Patel R, Fumoleau P, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004;96:759?69.
Surgery for bone metastasis
If x-ray shows a metastatic lesion is in a long bone with cortical destruction, particularly the femur or humerus, pathologic fracture must be prevented if possible. Generally this will require local irradiation and internal fixation with or without systemic therapy.
If the patient presents with or develops a pathologic fracture, internal fixation followed by radiotherapy is a most effective approach, assuming the patient can undergo the operative procedure.
Spinal metastases represent a more difficult problem. Cord compression, nerve root compression, and leptomeningeal metastases can develop. Depending on the results of myelography, CT myelography, or MRI and the patient's status and short-term prognosis, decompressive laminectomy followed by radiotherapy or radiotherapy alone may be selected.
Patients with spinal cord compression who have progressive symptoms during irradiation, disease recurrence after irradiation or who require diagnosis are candidates for surgery. Patients who present with spinal instability often require internal fixation.
Radiation therapy for bone metastasis
External-beam radiotherapy has become a mainstay in the palliative treatment of metastatic bone disease.
1. Postoperative radiotherapy: Postoperative radiotherapy is used after fixation of impending and pathologic fractures and after decompression and stabilization of the spine. When surgery is planned, radiation should be delivered postoperatively to the entire surgical area.
2. Spinal metastatic disease: Indications for surgery include spinal instability, pathologic fracture with structural canal compromise, circumferential epidural tumor, occult primary tumor, and radioresistant tumors. In spinal metastatic disease, the earlier the diagnosis is made and treatment is initiated, the better the outcome. Radiotherapy should be the first-line therapy when no surgical indication is present.
Among those with spinal metastatic disease, 94% of patients who have the ability to walk maintain their ambulatory status after radiotherapy, whereas ambulation is restored in 60% with motor weakness and 11% with paraplegia at presentation.
3. Palliative radiotherapy:
Adjunctive bisphosphonate therapy
Multiple published reports have now confirmed the benefit of bisphosphonates, such as IV pamidronate disodium (Aredia) or zoledronic acid (Zometa), as an adjunct to chemotherapy and hormonal therapy for metastatic breast cancer with osteolytic disease of bone. A significant reduction in skeleton-related events, including bone pain, pathologic fracture, and the need for radiation therapy to bone, occurs in patients treated with chemotherapy and pamidronate disodium for metastatic disease.
For breast carcinoma, treatment options are determined by estrogen and progesterone receptor status. In the literature, significant tumor shrinkage with endocrine therapy is 30% to 65%.36 In one study among patients with only bone metastases who were treated with a multiagent regimen (5-fluorouracil, doxorubicin, and cyclophosphamide), complete response rate was 7% and partial response rate was 52%, and an additional 32% experienced stabilization of disease.36 Another large multicenter study evaluated the use of various endocrine agents (megestrol acetate, tamoxifen, aminoglutethimide, dexamethasone, hydrocortisone, and fluoxymesterone) in a placebo arm against pamidronate. A partial response was seen in 21% and a stabilization of disease was seen in an additional 32%.37
If bone metastases are not complicated by pathologic fracture or do not involve the spinal cord or nerve roots, treatment is dictated by symptoms, the risk of pathologic fracture, and the potential for effective systemic therapy. Breast cancer can be effectively palliated using therapies that include castration or treatment with hormones or hormone antagonists. Chemotherapy will often be effective. If the bone metastases are diffuse, palliative radiotherapy may be impractical. In such cases, use of effective oral analgesics will provide effective palliation. If there are a limited number of painful metastatic lesions, radiotherapy delivered to those sites can dramatically alleviate pain and allow the patient to function with less or no analgesics.
Lung metastases are preferentially treated with chemotherapy for tumors with a high degree of chemosensitivity. Breast cancer metastasis may respond to hormonal suppression, cytotoxic agents, and molecular targeted therapies.
Also, the lung metastasis is usually coincidental to the discovery of widespread metastatic disease. Significant prognostic factors were a complete resection and a disease-free interval of at least 36 months.
Solitary lesions can be resected with good results, but this represents fewer than 1% of all patients with metastatic breast cancer.
Breast cancer metastasis may respond to hormonal suppression, cytotoxic agents, and molecular targeted therapies.
Actuarial 5-year survival after resection of clinically isolated hepatic metastases in breast cancer patients is reported between 9% and 18%. Based on the typical systemic pattern of recurrence in patients with advanced breast cancer, this approach must be considered palliative in nature with little expectation of long-term disease control.
The median survival time for breast cancer patients with untreated brain metastases is 4 weeks, and can be increased to 4-6 months with whole-brain radiotherapy and stereotactic radiosurgery, or up to 16 months if solitary metastases can be removed surgically.
Corticosteroids and antiseizure medication should be given when indicated.
Irradiation remains an integral component of the management of metastatic breast carcinoma.
Surgery in metastatic disease
The role of surgery at this point is generally palliative.
Recurrent breast cancer
Locoregional recurrence of breast cancer can be diagnosed by surgical biopsy or FNA cytology. Whichever modality is appropriate, material should be sent for hormone-receptor studies, since there is only an 80% concordance in hormone-receptor status between the primary tumor and recurrent disease.
Recurrence after breast conservation
Most patients whose disease recurs after conservative treatment for DCIS can be treated with salvage mastectomy. The optimal treatment of a local or regional recurrence after mastectomy has yet to be defined. Locoregional recurrences are associated with initial nodal status and primary tumor size. Appropriate treatment may result in long-term control of locoregional disease.
Recurrent disease in the chest wall after mastectomy
In general, patients who develop minimal recurrent disease in the
chest wall after a long disease-free interval may be treated by excision alone,
although this approach is controversial and may not be ideal. Locoregional
control obtained by radiation therapy alone is related to the volume of residual
disease and may not be durable. When possible, disease recurring in the chest
Adjuvant systemic therapy for locoregional recurrence
These data suggest that women whose tumors recur in the ipsilateral breast / regional lymph nodes within the first few years following the original diagnosis may be considered for adjuvant systemic therapy. Given the lack of prospective, randomized data, specific treatment recommendations for these women remain highly individualized.
Adjuvant hormonal therapy in recurrence
Benefits: A recently reported randomized trial demonstrated a disease-free survival benefit with the use of adjuvant tamoxifen following radiation therapy at the time of postmastectomy recurrence of disease in the chest wall in patients with estrogen-receptor?positive tumors.
The 5-year disease-free survival rate was increased from 36% to 59%, and median disease free survival was prolonged by > 4.5 years.
Adjuvant cytotoxic chemotherapy in recurrence
Patients with estrogen-receptor?negative tumors and aggressive locoregional recurrences may also be considered for systemic cytotoxic chemotherapy, given their relatively poor prognosis and the high rate of metastasis.
During the months subsequent to therapy patient follow up is usually required every 6 months or every year depending on the risk of breast recurrence. A thorough examination is done aiming primarily at the detection of breast cancer in the opposite breast (due to a slightly increased incidence of contralateral breast cancer).
* Examination should include: bilateral breast & axillary exam in addition
to supraclavicular lymph node enlargement and liver examination for enlargement
and tenderness. A mammogram is requested annually. In cases that have
undergone conservative surgery mammographic examination is
recommended every 6 months initially then annually.
Prognosis and survival
Memory Aid for breast cancer survival:
The 50% cutoff point is at stage IIIA (50%
survive 5yrs, 40% survive 10 years).
Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 351(9114): 1451-1467, 1998.