Staging and examination
Staging evaluation includes history and physical examination, CBC and liver function tests, chest CT, bone scan, abdominal CT or MRI, and, if possible, a biopsy of the first recurrence. Unless staging is unclear, sodium fluoride PET or PET/CT scans are generally not recommended. Evidence for the use of PET/CT scans is limited (mostly retrospective studies). Suspect site biopsies provide more accurate staging information than PET/CT scans.
FDG PET/CT is useful for suspicious sites (category 2B), and bone scan or sodium fluoride PET/CT is recommended to help identify bone metastases (category 2B), but if bone metastases have been identified by FDG PET/CT, then bone scan is not needed.
Biopsy should be performed when metastases are already present or first recurrence, which helps to determine their histology, biomarkers and choice of treatment options.
The receptor status should be repeated, especially in patients with previously unknown, negative or not overexpressed receptors. Endocrine therapy may be considered for patients with persistent positive or previously positive receptors, regardless of repeated testing or recent test results.
Genetic counseling is recommended for patients at high risk for hereditary breast cancer.
Management of localized lesions
For most patients with local recurrence after breast-conserving therapy and sentinel lymph node biopsy, the preferred surgical approach is mastectomy and level I/II axillary lymph node dissection.
The importance of individualized treatment is emphasized for patients whose recurrence is limited to a single site.
Management of stage IV or recurrent/metastatic breast cancer
Systemic treatment can prolong survival and improve quality of life, but is not curative. Therefore, the least toxic treatment should be preferred, and endocrine therapy is less toxic than cytotoxic therapy.
1.Supportive treatment for patients with bone metastases
Extensive clinical trial data have been available showing that the bisphosphonate drugs zoledronic acid or pamidronate disodium can be used to prevent and treat bone-related events (SREs) in patients with metastatic breast cancer.
Both bisphosphonate drugs and denosumab are associated with osteonecrosis of the jaw (ONJ). Dental health conditions and dental procedures are known risk factors for ONJ. Therefore, a dental examination is recommended before injecting bisphosphonate drugs or Denosemide and, if possible, dental procedures should be avoided while the drug is administered. Other risk factors include chemotherapy or corticosteroids, as well as periodontal disease and dental abscesses.
(1) Bisphosphonate drugs
Patients with bone metastases should be treated with injectable bisphosphonates (e.g., pamidronate disodium, zoledronic acid) in combination with calcium and vitamin D orally, especially in patients with osteolytic foci and/or weight-bearing bones, or who are expected to survive ≥3 months, or whose creatinine level is less than 3 mg/dl (category 1).
(2) Denosumab
Patients suitable for bisphosphonate therapy are also suitable for denosumab therapy (Class 1). This recommendation is based on the results of a randomized controlled trial of denosumab versus zoledronic acid.
2. Endocrine therapy for stage IV or recurrent/metastatic breast cancer
Patients with ER and/or PR positive recurrent or metastatic disease are suitable for endocrine therapy.
Endocrine therapy for postmenopausal women includes non-steroidal aromatase inhibitors (alatriptan and letrozole), steroidal aromatase inhibitors (exemestane), serum ER modulators (tamoxifen and toremifene), ER downregulators (fulvestrant), progestins (megestrol acetate), androgens (fluoxymesterone), and high-dose estrogens (ethinyl estradiol).
Endocrine therapy for premenopausal women includes selective ER modulators (tamoxifen and toremifene), LH-RH agonists (goserelin and leuprolide), ovariectomy, progestins (megestrol acetate), androgens (fluorometholone) and high-dose estrogens (ethinyl estradiol). For most patients after tamoxifen treatment, ovarian suppression or resection combined with endocrine therapy are appropriate.
The toxicity of endocrine therapy is low. The panel recommends that endocrine therapy be considered in hormone receptor-negative patients (lesions limited to bone or soft tissue, or without visceral organ symptoms) regardless of their HER2 status.
Aromatase inhibitors, selective ER modulators, or ER downregulators are options for postmenopausal women who have not been on anti-estrogen therapy or who have been on prior anti-estrogen therapy for more than 1 year.
For premenopausal women who have had antiestrogen therapy within 1 year, the preferred second-line treatment is oophorectomy or suppression. For premenopausal women without anti-estrogen therapy, initial treatment is selective ER modulators or ovarian suppression/removal plus endocrine therapy.
In premenopausal patients with hormone receptor-positive and HER2-positive metastatic breast cancer, a few studies have found a benefit in PFS with aromatase inhibitors plus trastuzumab or lapatinib.
Patients who experience disease progression or recurrence during treatment with nonsteroidal aromatase inhibitors may be considered for exemestane plus everolimus.
In cases of disease progression, many hormone-sensitive breast cancer patients have had success with sequential endocrine therapy.
3. Cytotoxic chemotherapy for stage IV or recurrent/metastatic breast cancer
Patients with hormone receptor-negative disease not confined to bone or soft tissue, patients with metastatic symptoms in internal organs, or patients with hormone receptor-positive disease that is not sensitive to endocrine therapy should be treated with chemotherapy.
Compared with single-agent chemotherapy, combination chemotherapy has a higher response rate and a more delayed appearance of disease deterioration; however, toxicity is increased, the effect on patient survival is not significant, and the dose of individual drugs needs to be reduced.
(1) Individual cytotoxic drugs
Classification was based on efficacy, toxicity, and treatment regimen. The panel’s preferred individual drugs include: anthracyclines, doxorubicin, epirubicin, and Pegylated liposomal doxorubicin; paclitaxel, paclitaxel, docetaxel, and albumin-bound paclitaxel; antimetabolites, capecitabine and gemcitabine; and non-paclitaxel microtubule inhibitors, eribulin and vincristine.
Eribulin is a non-paclitaxel microtubule inhibitor used in patients with metastatic breast cancer who have had at least 2 prior chemotherapeutic agents. Phase 3 clinical trials have shown that eribulin prolongs OS at one year and delays time to progression. Several trials have confirmed the efficacy of eribulin in metastatic breast cancer.
Other individual agents, the panel listed: cyclophosphamide, carboplatin, docetaxel, albumin-bound paclitaxel, cisplatin, isabepilone, and epirubicin.
Ixabepilone, an epothilone B analogue, is also used as a single agent for the treatment of recurrent or metastatic breast cancer.
(2) Combination drugs
In combination, the panel recommends FAC/CAF, FEC, AC, EC, CMF, docetaxel and capecitabine, gemcitabine and paclitaxel, gemcitabine and carboplatin, and paclitaxel and bevacizumab.
A series of trials has confirmed the role of bevacizumab in the treatment of metastatic breast cancer.
As with endocrine therapy, chemotherapy is used in a sequential fashion. Current guidelines include chemotherapy doses and regimens.3 No response to sequential chemotherapy is a guideline for palliative care.
Patients with metastatic breast cancer often have local problems; local radiation, surgery, or local chemotherapy (intrathecal methotrexate for molluscum contagiosum) may be helpful in resolving local problems.
4. HER2-targeted therapy for stage IV or recurrent metastatic breast cancer
HER2-positive patients may benefit from HER2-targeted therapy. The panel recommends selecting patients who are HER2-positive by ISH or 3+ by IHC for HER2-targeted therapy.
(1) First-line treatment options for HER2-positive patients
The NCCN panel divided the HER2-targeted therapy regimens into preferred regimens and other regimens.
Preferred first-line regimen.
The NCCN panel recommends patuximab plus trastuzumab in combination with paclitaxel as the first-line regimen for HER2-positive metastatic breast cancer. Patuximab plus trastuzumab in combination with docetaxel is an NCCN Class 1 recommendation and paclitaxel is an NCCN Class 2 recommendation.
Other first-line regimens.
Trastuzumab in combination with chemotherapy agents or as monotherapy for HER2-positive metastatic breast cancer are other available first-line options. For hormone receptor-positive, HER2-positive patients, the panel recommends initial endocrine therapy.
The NCCN panel listed trastuzumab as an alternative first-line treatment option for HER2-positive patients with the following agents: paclitaxel or plus carboplatin, docetaxel, vincristine, and capecitabine.
Trastuzumab-based treatment regimens for HER2-positive breast cancer.
The NCCN panel recommends a trastuzumab-based first-line regimen that consistently produces HER2 blockade for the treatment of HER2-positive metastatic breast cancer. This recommendation also applies to patients with HER2-positive metastatic breast cancer who have been treated with prior adjuvant trastuzumab. Several trials have demonstrated the efficacy of trastuzumab-based regimens. However, the optimal duration of continuous trastuzumab dosing has not been determined.
Representative regimens for the treatment of HER2-positive metastatic breast cancer are listed in the NCCN guidelines. However, the optimal duration of HER2-targeted therapy has not yet been determined.
The preferred trastuzumab-based regimens for the treatment of HER2-positive breast cancer are
T-DM1 (Ado-trastuzumab emtansine) is an antibody-drug coupled drug in which trastuzumab, which has HER2-targeted antitumor properties, is coupled to DM1, a cytotoxic microtubule inhibitor, through a stable linkage. Recent international multicenter phase 3 clinical trials have demonstrated the efficacy and safety of T-DM1 in patients with HER2-positive advanced and metastatic breast cancer; T-DM1 significantly improved PFS and OS compared to lapatinib in combination with capecitabine.
The NCCN panel recommends T-DM1 as the preferred regimen for patients with HER2-positive metastatic breast cancer who have been previously treated with trastuzumab-based therapy.
Other options for trastuzumab-based treatment of HER2-positive breast cancer.
Patuximab may be used in patients beyond first-line therapy.
The NCCN panel believes that trastuzumab plus patuximab (with or without cytotoxic agents such as vincristine or paclitaxel) may be considered for patients whose disease has worsened after trastuzumab-based regimens. Anti-HER2 therapy requires further determination of the ideal dosing sequence.
Capecitabine plus lapatinib is also an option for HER2-positive patients whose disease has worsened after trastuzumab-based regimens. There are also trials that have confirmed the efficacy of lapatinib in combination with letrozole and lapatinib in combination with trastuzumab.
Because of the lack of data, the panel does not recommend the combination of trastuzumab and lapatinib plus other chemotherapy agents.
Surgical treatment of stage IV or recurrent metastatic breast cancer
For patients with metastatic breast cancer and primary tumors, the primary treatment recommended by the NCCN is systemic therapy; surgery is considered after initial systemic therapy for patients who require symptomatic relief or who may develop complications (skin ulceration, bleeding, cauliflower-like lesions, pain). Surgery is usually used only when complete clearance of the tumor is possible or when disease in other areas is not immediately life-threatening. Radiotherapy may be considered as an alternative to surgical treatment.
Distant metastases requiring consideration for local treatment.
Surgery, radiotherapy, or regional chemotherapy (e.g., intrathecal methotrexate) is indicated for localized clinical lesions.
Adjuvant thermotherapy (Category 3) may be considered for radiotherapy for local recurrence/metastasis.
Surveillance of metastatic breast cancer
Surveillance for metastatic breast cancer involves performing a variety of assessments that require clinicians to gather information about the disease and determine that the effectiveness and toxicity of treatment are within acceptable limits.
It is recommended that widely accepted criteria (e.g., RECIST or WHO criteria) be used to assess disease. The same assessment methods should be used over time, e.g., chest abnormalities initially diagnosed using CT scans should be reapplied at the time of surveillance.