NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen. 314 However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer. 315 The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects. 315 A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes. 316 Given the limited and conflicting evidence at this time, 317 the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines. 318 When prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists. Adjuvant Cytotoxic Chemotherapy Several combination chemotherapy regimens are appropriate to consider when adjuvant cytotoxic chemotherapy is utilized. All adjuvant chemotherapy regimens listed in the NCCN Guidelines have been evaluated in phase III clinical trials, and the current version of the adjuvant chemotherapy guidelines does not distinguish between options for chemotherapy regimens by ALN status. The adjuvant chemotherapy guidelines also include specific representative doses and schedules for the recommended adjuvant chemotherapy regimens. The regimens have been categorized as “preferred” or “other.”

The purpose of distinguishing the adjuvant chemotherapy regimens as preferred and other adjuvant chemotherapy regimens is to convey the sense of the panel regarding the relative efficacy and toxicity of the regimens. 319 Factors considered by the panel include the efficacy, toxicity, and treatment schedules of the regimens. Summarized below are clinical trial results focusing on treatment efficacy. Preferred Regimens Regimens listed as preferred include: dose-dense doxorubicin and cyclophosphamide (AC) with dose-dense sequential paclitaxel; dose-dense AC followed by sequential weekly paclitaxel; and docetaxel plus cyclophosphamide (TC). The results of two randomized trials comparing AC chemotherapy with or without sequential paclitaxel chemotherapy in women with axillary node-positive breast cancer suggest improved disease-free rates, and results from one of the trials showed an improvement in OS, with the addition of paclitaxel. 320,321 On retrospective analysis, the apparent advantage of the paclitaxel-containing regimen appears greater in women with ER-negative breast cancers. A randomized trial evaluated the use of concurrent versus sequential chemotherapy (doxorubicin followed by paclitaxel followed by cyclophosphamide vs. doxorubicin plus cyclophosphamide followed by paclitaxel) given either every 2 weeks with filgrastim support or every 3 weeks. The results show no significant difference between the two chemotherapy regimens, but demonstrate a 26% reduction in hazard of recurrence ( P = .01) and a 31% reduction in the hazard of death ( P = .013) for the dose-dense regimens. 322 The ECOG E1199 study was a four-arm trial that randomized 4950 women to receive AC chemotherapy followed by either paclitaxel or

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