Update 1: Denosumab for prevention of bone-related events Denosumab (Denosumab) is a fully humanized monoclonal antibody targeting the receptor activator of nuclear factor κB (RANK) ligand. a randomized group clinical trial by Stopeck et al. published in the American Journal of Clinical Oncology (JCO) in 2010 compared denosumab and zoledronic acid in delaying or preventing A randomized group clinical trial published in the American Journal of Clinical Oncology in 2010 compared denosumab and zoledronic acid in delaying or preventing bone-related events (SREs) in patients with bone metastases from breast cancer. Patients enrolled in the study were randomized to treatment with denosumab 120 mg subcutaneously and placebo intravenously (1026 patients) or zoledronic acid 4 mg intravenously (dose adjusted for creatinine clearance) and placebo subcutaneously (1020 patients) once every 4 weeks. The primary study endpoint was time to first SRE (defined as pathological fracture, bone radiotherapy or bone surgery, or spinal cord compression). The results showed that time to first SRE and time to first and subsequent (multiple) SRE were significantly better in the denosumab group than in the zoledronic acid group. Bone turnover markers decreased more significantly in the denosumab group. Overall survival (OS), time to disease progression, incidence of adverse events (AEs), and incidence of serious AEs were similar in both groups. The incidence of nephrotoxicity-related AEs and acute phase reactions was higher in the zoledronic acid group; the incidence of hypocalcemia was higher and the incidence of osteonecrosis of the jaw was lower in the denosumab group (2.0% in the denosumab group vs. 1.4% in the zoledronic acid group, P=0.39). In patients with bone metastases from breast cancer, denosumab was superior to zoledronic acid in delaying or preventing SREs and was well tolerated. Because of the convenience of subcutaneous injection and the absence of monitoring of renal function during treatment, denosumab offers a new treatment option for patients with bone metastases. Based on these findings, the new guideline recommends the use of denosumab, zoledronic acid, or pamidronate for the prevention of SRE in patients with bone metastases from breast cancer. Update 2: Eribulin for the treatment of advanced breast cancer Eribulin Mesylate, a synthetic analogue of Ota soft spongiin, blocks the formation of microtubulin multimers. The results of the EMBRACE study were reported at the 2010 ASCO Annual Meeting. The study enrolled 762 patients with locally advanced or metastatic breast cancer who had previously failed multiple courses of treatment and were randomized in a 2:1 ratio to either the eribulin group (508 patients) or the treatment group of the physician’s choice (TPC group, 254 patients). The results showed that the efficiency rate was 12% and 5% (P = 0.002), clinical benefit rate was 23% and 17%, median PFS was 3.7 months and 2.2 months (HR = 0.87, P = 0.14), median OS was 13.12 months and 10.65 months (HR = 0.81, P = 0.041) in the eribulin and TPC groups, respectively, and 1 year OS rates of 53.9% versus 43.7%, respectively. Accordingly, on November 15, 2010, the FDA approved the marketing of eribulin for the treatment of patients with metastatic breast cancer who have been treated with at least two prior chemotherapy regimens for metastatic tumors. The 2011 edition of the NCCN guidelines also includes it as a single agent for the treatment of advanced breast cancer. Update 3: Can CYP2D6 predict TAM efficacy or toxicity? Tamoxifen (TAM) is metabolized by the cytochrome P4502D6 enzyme (CYP2D6) to the active product 4-hydroxy-N-desmethyltamoxifen (Endoxifen). exploratory studies such as the Big-198 trial attempted to answer the question of whether alterations in the extent of TAM metabolism due to CYP2D6 gene polymorphisms affect the efficacy or toxicity of TAM, however, the results of existing studies are conflicting and it is unclear whether this genotype predicts the efficacy or toxicity of TAM; therefore, the new version of the guideline is silent on this issue and does not recommend routine testing for CYP2D6. Update 4: Metastases ER, PR, HER2 re-testing Previous The results of several studies suggest that ER, PR and HER2 can be altered in breast cancer metastases, with the rate of conversion from positive to negative ER ranging from 21% to 31%, from negative to positive ER ranging from 8% to 60%, and from 3% to 8% for altered HER2. Therefore, the new version of the guidelines recommends that tumors with unknown ER/PR and HER2 status and negative or no overexpression at the primary site need to be considered for confirmation by re-biopsy. Update 5: Some SLND-positive breast cancers may not be ALND The ACOSOGZ0011 trial is a randomized group clinical trial comparing further axillary lymph node dissection (ALND) with no further surgical management in patients with clinical stage T1 to 2N0M0 breast cancer with positive sentinel lymph node biopsy (SLND). The results at a median follow-up of 6.3 years showed that the tumor locoregional recurrence rates were 4.1% and 2.8% in the ALND group (420 patients) and SLND group (436 patients), respectively (P=0.11). There were no significant differences in the rates of local area recurrence-free survival, disease-free survival and OS. Regarding whether SLND-negative should be followed by further ALND, there is only one randomized group clinical trial mentioned above, which suggested that in patients with clinically negative LN, T1 to T2 lesions, <3 number of anterior lymph node metastases, and those who underwent breast-conserving surgery and total breast irradiation, total axillary lymph node dissection was associated with increased complications compared with anterior lymph node biopsy alone, but did not reduce the local-regional recurrence rate, and there was no significant difference in OS. Based on the results of this study, the new guideline adds the recommendation that "ALND may not be necessary for selected patients with SLND-positive breast cancer". Other Updates Bevacizumab Treatment Recommendations for Advanced Patients: Although the FDA withdrew the indication for bevacizumab in advanced breast cancer, the NCCN guideline panel recommended retaining bevacizumab in combination with paclitaxel as a treatment option for advanced breast cancer based on the primary study endpoint of the E2100 trial and its long-term follow-up results. Adjuvant therapy for small HER2-positive tumors (0.6-1.0 cm): The 2011 edition of the NCCN guidelines recommended adjuvant trastuzumab for patients with tumors ≥1 cm in diameter. The new edition of the guidelines recommends considering adjuvant trastuzumab for patients with tumors 0.6-1.0 cm in diameter, based on the results of several retrospective studies. Radiotherapy: In the recommendation to consider partial breast irradiation (PBI) for selective patients, the scope of radiotherapy is increased to include the "subclavian region" in addition to the supraclavicular region. That is, ≥4 positive axillary lymph nodes → chemotherapy followed by chest wall (category 1) + subclavian and supraclavicular radiotherapy. Internal breast lymph node radiotherapy (category 3) can be considered; 1~3 positive axillary lymph nodes → strongly consider chest wall + subclavian and supraclavian area radiotherapy after chemotherapy; if radiotherapy is to be performed, internal breast lymph node radiotherapy (category 3) can be considered; negative axillary lymph nodes but tumor >5cm or positive cut margin → consider chest wall ± subclavian and supraclavian lymph node radiotherapy. Internal breast lymph node radiotherapy (category 3) can be considered.