The National Comprehensive Cancer Network (NCCN), which consists of a panel of experts in various fields from 25 cancer centers across the United States, publishes annual clinical practice guidelines for various malignancies, which are recognized and followed by clinicians worldwide. The NCCN does not have independent clinical guidelines for stage IV, metastatic recurrent breast cancer, and on 2015-03-11, the NCCN published the 2nd edition of the 2015 breast cancer guidelines, which are described and interpreted in this article. Stage IV, metastatic recurrent breast cancer is advanced breast cancer, which is incurable disease. The goal of treatment is to prolong survival, control tumor load, reduce tumor-related symptoms and complications, and improve quality of life. Obviously, because of the presence of distant metastasis, the main treatment strategy for stage IV breast cancer should be systemic combination therapy, supplemented by local treatment. Comprehensive treatment of metastatic recurrent breast cancer The new guidelines state that comprehensive treatment of stage IV, metastatic recurrent breast cancer can prolong survival and improve quality of life, but is not curable. Therefore, treatment with minimal toxicity should be preferred. According to this principle, the use of endocrine therapy with low toxicity is preferred over cytotoxic therapy. The new guidelines suggest that when considering comprehensive treatment for stage IV, metastatic recurrent breast cancer, they should first be classified according to the presence of bone metastases, and then these two subgroups should be further classified according to tumor hormone receptor and human epidermal growth factor receptor 2 (HER2) status again. The therapeutic value of osteoclast activity is to prevent fractures in patients with bone metastases; radiotherapy is needed to treat bone pain and spinal cord compression; and to manage skeletal related events (SREs) such as hypercalcemia. The bisphosphonates zoledronic acid or disodium pamidronate have been used for this purpose and both have been extensively supported by clinical trials for the prevention of SREs. Bisphosphonate use is based on chemotherapy or endocrine therapy; zoledronic acid may be superior to pamidronate disodium for resolving bone metastases. Current clinical trial results support the use of bisphosphonates for up to 2 years. The randomized controlled trial by Stopeck et al. in metastatic breast cancer showed a bisphosphonate equivalence and temporal advantage of denosumab for the prevention of SREs, and denosumab is a modulator of osteoclast function compared with zoledronic acid. However, no studies have demonstrated an effect of bisphosphonates or denosumab on OS in patients with metastatic breast cancer. Bisphosphonates and denosemide have been associated with the development of osteonecrosis of the jaw (ONJ). Therefore, an oral examination prior to intravenous bisphosphonate or denosemide therapy is recommended and should be avoided during dental surgical treatment whenever possible. Other risk factors for the development of ONJ include the use of chemotherapy or hormones, poor oral hygiene habits, and periodontal disease and dental abscesses. 2, endocrine therapy The new guidelines recommend that estrogen receptor (ER) or progesterone receptor (PR) positive patients are an appropriate population for initial endocrine therapy; after second-line endocrine therapy, there is no high level of evidence to help choose the best sequence of endocrine therapy. Endocrine therapy in postmenopausal women includes nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); serum estrogen receptor modulators (tamoxifen or toremifene), ER downregulators (fulvestrant), progestins (megestrol acetate), androgens (fluoxymesterone), and high-dose estrogens (ethinyl estradiol). Endocrine therapy for premenopausal women includes selective estrogen receptor modulators (tamoxifen or toremifene); luteinizing hormone-releasing hormone (LH) receptor agonists (goserelin and leuprolide acetate); surgical or radiation oophorectomy; progestins (progesterone); androgens (mesterolone); and high-dose estrogens (ethinyl estradiol). For most premenopausal patients, a combination of tamoxifen, ovarian suppression, or ablative therapy is appropriate. Endocrine therapy may be effective in patients with negative ER and PR measurements, especially in patients with negative primary tumors and predominantly soft tissue and/or bone metastases; given the relatively low toxicity of endocrine therapy and the inconsistency between primary and metastatic sites, further determination of primary and metastatic ER and PR status is necessary. The new guidelines suggest that endocrine therapy may be considered in patients with hormone receptor-negative disease limited to local bone or soft tissue metastases or asymptomatic visceral metastases, regardless of HER2 receptor status. For postmenopausal women who have failed anti-estrogen therapy or have been on anti-estrogen therapy for more than 1 year, options include aromatase inhibitors, or selective estrogen receptor modulators, or ER modulators. Some studies suggest that aromatase inhibitors may have better benefit than tamoxifen, but the difference is not significant. In postmenopausal patients with prior anti-estrogen therapy or with anti-estrogen therapy within one year, the evidence supports the selective use of aromatase inhibitors as the first-line treatment of choice for recurrent disease. In premenopausal women with prior anti-estrogen therapy or recurrent anti-estrogen therapy within 1 year, the preferred second-line treatment is oophorectomy or ovarian function suppression followed by endocrine therapy as in postmenopausal patients. In premenopausal patients without a history of anti-estrogen therapy, initial treatment can be with selective estrogen receptor modulators or ovarian suppression or ablation alone, followed by endocrine therapy as in postmenopausal patients. In postmenopausal hormone receptor-positive metastatic breast cancer with HER2 positivity, there is limited evidence of a PFS advantage with aromatase inhibitors plus trastuzumab or lapatinib. Resistance to endocrine therapy occurs in hormone receptor-positive patients. One mechanism of resistance is activation of the mammalian target of rapamycin (mTOR) signal transduction pathway. Several randomized controlled clinical trials are investigating the use of inhibitors of the mTOR signaling pathway in combination with aromatase inhibitors. A phase II RCT evaluated the efficacy of tamoxifen alone versus tamoxifen in combination with everolimus, and after a median follow-up of 13 months, an intention-to-treat analysis showed that an improved median time to progression was seen with everolimus in combination with tamoxifen versus tamoxifen alone (8.5 months vs. 4.5 months); results have not been formally published. In another phase III clinical trial in late postmenopause with hormone receptor-positive breast cancer not previously treated with endocrine therapy, subjects were randomized to letrozole with or without the mTOR inhibitor temsirolimus, and the results showed no statistically significant difference in progression-free survival (PFS). The results of this trial were completely different from those of the BOLERO-2 clinical trial. However, the reason for the difference in results between these two randomized phase III studies is uncertain and may be related to patient selection and the extent of prior endocrine therapy. The final results of the Phase III clinical trial (BOLERO-2) in postmenopausal hormone receptor-positive advanced progressive or recurrent breast cancer with exemestane plus or without the mTOR inhibitor everolimus showed significantly longer median PFS with everolimus in combination with exemestane compared to exemestane alone at 11.0 months and 4.1 months, respectively. The new version of the guideline states that the evidence for BOLERO-2 is compelling enough to consider the addition of everolimus to exemestane patients who meet the BOLERO-2 enrollment criteria. Many patients with pre- and postmenopausal hormone-sensitive breast cancer benefit from sequential endocrine therapy as their disease progresses. Therefore, patients with breast cancer whose tumors have previously shrunk or remained stable for a long time on endocrine therapy should continue endocrine therapy as their disease progresses. Two clinical trials have yielded different results regarding combination endocrine therapy in hormone receptor-positive postmenopausal patients. In one study (FACT), combination endocrine therapy was not superior to single agent anastrozole (time to disease progression HR=0.99; 95% CI: 0.81 to 1.20; P=0.91). The results of another study (S0226) showed that the combination of both anastrozole and flovisetron was superior to monotherapy. Subgroup analysis showed that those treated without tamoxifen adjuvant therapy benefited more. 3. Cytotoxic chemotherapy The new guidelines state that chemotherapy should be given to those who are hormone receptor negative, whose tumors are not limited to bone or soft tissue, and who have symptomatic visceral metastases, or despite the ineffectiveness of endocrine therapy for hormone receptor-positive tumors. Combination chemotherapy usually provides higher treatment response rates and longer time to disease progression than single-agent chemotherapy, which significantly increases toxicity [22]; however, the new edition of the guidelines states that there is currently no convincing evidence that combination chemotherapy is superior to single-agent sequences. The standard clinical treatment is to continue first-line chemotherapy until disease progression. Side effects may require discontinuation of chemotherapy by dose reduction or prior to disease progression. Limited data suggest that sequential chemotherapy is more likely to achieve PFS than shorter courses of chemotherapy, and due to the lack of overall survival benefit, there is a trade-off between efficacy and overall quality of life for sequential chemotherapy or shorter courses of chemotherapy. The panel’s recommendations for single-agent cytotoxic agents and combination chemotherapy regimens for patients with metastatic breast cancer are listed in the NCCN guidelines. (1) Single agent chemotherapy The preferred single agent selection is based on efficacy, toxicity, and timing of drug administration. Among the preferred single agents are anthracyclines, adriamycin, epi-adriamycin, polyethylene glycol liposomal adriamycin, paclitaxel, paclitaxel, docetaxel, albumin-bound paclitaxel, antimetabolites, capecitabine and gemcitabine, non-paclitaxel microtubule inhibitors, eribulin, and vincristine. eribulin is a non-paclitaxel microtubule inhibitor for patients with metastatic breast cancer who have received at least two previous chemotherapy regimens. Prior therapy should include an anthracycline paclitaxel, either adjuvant or relief therapy. In a phase III clinical trial, 762 patients with metastatic breast cancer were randomized 2:1 to eribulin or physician’s choice. eribulin treatment group had an OS of 53.9% vs. 43.7% in the control group, with a median OS of 13.1 months vs. 10.7 months, significantly reducing the risk of death by 19% (p=0.041); time to disease progression was 3.7 months vs. 2.2 months (P=0.14). (2) Combination chemotherapy regimens The regimens recommended by the panel included FAC/CAF, FEC, AC, EC, CMF, doxorubicin, gemcitabine, paclitaxel, capecitabine, carboplatin and paclitaxel, and bevacizumab. A series of clinical trials sought to determine the role of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in the treatment of metastatic breast cancer. The E2100 randomized clinical trial, which included 722 cases of recurrent or metastatic breast cancer, showed that bevacizumab combined with paclitaxel compared with paclitaxel alone; PFS was significantly longer (11.8 months vs. 5.9 months, HR=0.60, p<0.001). A similar RCT enrolling 736 patients randomized to docetaxel combined with bevacizumab versus docetaxel and placebo treatment demonstrated a PFS survival benefit in the bevacizumab-containing group (10.1 months vs. 8.2 months, HR=0.77, P=0.006). Results from another clinical trial showed a significant increase in PFS with bevacizumab in combination with capecitabine (8.6 months vs. 5.7 months, HR=0.69, P<0.001). The new version of the guidelines states that a sequential treatment effect is observed when combined with endocrine therapy, whether monotherapy or combination is used. Local lesion progression after chemotherapy does not necessarily mean treatment failure. Patients with metastatic breast cancer frequently present with many localized lesions at anatomic sites, and these patients can often benefit from local irradiation, surgery, or regional chemotherapy. (3) HER2-targeted therapy Patients with HER2-positive breast cancer may benefit from HER2-targeted therapy. The new guidelines recommend HER2-targeted therapy if the tumor is HER2-positive or IHC3-positive by FISH. Tumors with 0 or 1+ immunohistochemistry and no amplification by FISH or ISH have a very low response rate to HER2-targeted therapy. Standardization of immunohistochemical assays and the use of in situ hybridization for HER2 detection in clinical practice is an issue of concern, and data suggest that false-positive assays are common. A randomized, double-blind phase III RCT compared the safety and efficacy of pertuzumab in combination with docetaxel and trastuzumab versus trastuzumab in combination with docetaxel for the first-line treatment of HER2-positive metastatic breast cancer. The primary endpoint of the study was PFS; secondary endpoints were PFS investigator assessment, objective response rate, OS, and safety. A total of 808 patients were enrolled in the trial. The addition of pertuzumab in the group showed a statistically significant increase in median PFS of 6.1 months compared to the trastuzumab-docetaxel group. After a median follow-up of 30 months, there was also a significant improvement in OS and a 34% reduction in the risk of death in the group including pertuzumab. Therefore, the new guideline recommends patuximab in combination with trastuzumab plus paclitaxel as the first-line treatment of choice for patients with HER2-positive metastatic breast cancer. Advanced tumor treatment previously treated with trastuzumab. The new guidelines recommend that HER2 activity should be consistently blocked, even in patients with HER2-positive metastatic breast cancer treated with trastuzumab-containing regimens in the first line. This is because several clinical trials have demonstrated the continuation benefit of trastuzumab therapy even in the presence of prior progression of trastuzumab-containing treated disease base; moreover, the optimal timing of trastuzumab use for long-term disease control is currently unknown. The preferred regimen for prior use of trastuzumab is an antibody-drug coupled drug, trastuzumab-Ado-emtansine (T-DM1). In an international multicenter randomized clinical phase III study (EMILIA) evaluating its efficacy and safety, T-DM1 demonstrated significant benefits in PFS and OS compared to lapatinib in combination with capecitabine for locally advanced breast cancer or metastatic breast cancer. Therefore, the new guideline suggests that T-DM1 may be the preferred option for patients with HER2-positive metastatic breast cancer who have been treated with trastuzumab. For options in other situations, the new version of the guideline states: (1) For patients who have progressed after trastuzumab treatment and have not used pertuzumab, first-line therapy should be considered to include trastuzumab combined with pertuzumab with or without cytotoxic agents (vincristine, paclitaxel). (2) Capecitabine in combination with lapatinib is also an option for HER2-positive patients who have progressed on trastuzumab-containing therapy. (3) The panel does not recommend trastuzumab in combination with lapatinib concurrently with chemotherapy.