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Sandra M. Swain, Gong Tang, Charles E. Geyer Jr, Priya Rastogi, James N. Atkins, Paul P. Donnellan, Louis Fehrenbacher, Catherine A. Azar, Andr ́e Robidoux, Jonathan A. Polikoff, Adam M. Brufsky, David D. Biggs, Edward A. Levine, John L. Zapas, Louise Provencher, Donald W. Northfelt, Soonmyung Paik, Joseph P. Costantino, Eleftherios P. Mamounas, and Norman Wolmark Journal of Clinical Oncology VOL 31 NUM 26 SEPTEMBER 10 2013 Adjuvant anthracycline- and taxane- based chemotherapy provides substantial benefits for women diagnosed with node-positive, early-stage breast caner However, a significant proportion of women treated with adjuvant chemotherapy still develop disease recurrence, which necessitates additional studies that evaluate alternative treatment strategies. Doxorubicin(A) and cyclophosphamide(C) followed by paclitaxel(P) on a dose-dense schedule(DD AC→P) is considered an optimal Paclitaxelbased adjuvant regimen for node-positive primary breast cancer. The addition of Gemcitabine(G) to paclitaxel has shown improved outcomes in women with metastatic breast cancer. Therefore in NSABP B-38 trial they chose to test whether the addition of a fourth agent, Gemcitabine, to DD AC→P would provide a disease-free survival benefit in the adjuvant setting. Because docetaxel(T), A, and C (TAC) is also considered an optimal docetaxel-based adjuvant regimen, They designed this trial to also compare TAC with the investigational dose-dense AC→PG regimen. Gemcitabine Patients ◦ Women with histologically proven node-positive invasive breast cancer who had undergone primary surgery with a total mastectomy or lumpectomy with clear margins of resection. ◦ Primary tumor stage pT1, pT2, or pT3 ◦ Ipsilateral lymph node stage pN1, pN2a, pN3a, or pN3b ◦ Exclusive criteria Contralateral breast cancer, a prior history of breast cancer ductal carcinoma in situ Cardiac disease that precluded the use of anthracyclines, grade 2 or greater peripheral neuropathy and pregnant HER-2-positive tumor Study design ◦ Patients were stratified according to the number of positive lymph node(1 to 3, 4 to 9, or ≥ 10) ◦ Hormone receptor status(ER- and PR-, ER+ and/or PR+) ◦ Type of surgery and planned radiotherapy ◦ After stratification, patients were randomly assigned by using a biased-coin minimization algorithm ◦ Three treatment regimens DD AC→P : four cycles of A 60 mg/m2 plus C 600 mg/m2 every 2 weeks followed by four cycles of P 175 mg/m2 every 2 weeks DD AC→PG : four cycles of A 60 mg/m2 plus C 600 mg/m2 every 2 weeks followed by four cycles of P 175 mg/m2 plus G 2,000 mg/m2 every 2 weeks TAC : six cycles of concurrently administered A 50 mg/m2 plus C 500 mg/m2 plus docetaxel 75 mg/m2 every 3 weeks Statistical Analysis ◦ The primary end point Disease-free survival Local, regional, or distant breast cancer recurrence, second primary cancer Death as a result of any cause that occurred before these other events ◦ Secondary end point Overall survival Death as a result of any cause; recurrence-free interval Time to first local, regional, or distant recurrence; distant recurrence-free interval Time to distant disease recurrence only Toxicities of the drug regimens Patients ◦ November 3 2004~ May 3 2007 ◦ 4894 women were randomly assigned TAC : 1630 DD AC→P : 1634 DD AC→PG : 1630 ◦ 4859 had follow-up ◦ Baseline charateristics Efficacy ◦ After median follow-up of 64months 941 DFS events had been reported TAC : 327, DD AC→P : 294, DD AC→PG : 320 ◦ At the time of this analysis, 540 of the 4859 patients had died TAC : 185, DD AC→P : 188, DD AC→PG : 188 ◦ Results from multiple Cox proportional hazards models, adjusting age at study entry, number of positive lymph nodes, estrogen receptor status, and radiation therapy and type of surgery did not show significant differences in DFS or OS among the three treatment arms Safety ◦ Toxicity from protocol therapy was acceptable for the adjuvant setting and typical for the regimens used. ◦ There were 25 deaths on treatment: 13 in the TAC arm, five in the DD AC→P arm, and seven in the DD AC→PG arm (P=0.2) Use of ESA ◦ Among 4,841 patients with follow-up data, 2,149 (44.4%) received an ESA (epoetin alfa or darbepoetin alfa) ◦ Patients who received ESAs had similar incidences of second primary cancer compared with those who did not receive ESA support (4.3% v 3.8%; P=0.35). ◦ ESA use showed no association with risk of DFS events after adjusting for treatment, age, tumor size, number of positive nodes, and surgery type Anthracyclines and taxanes are among the most active and commonly used chemotherapeutic agents for the treatment of early-stage breast cancer On the basis of the findings of the Cancer and Leukemia Group B 9741 trial, which demonstrated significantly improved DFS and OS with dosedense regimens over conventionally scheduled regimens ‘DD AC→P’ is considered to be one of the most effective P-based adjuvant chemotherapy regimens In this study, the addition of G to DD AC→P did not improve outcomes and no significant differences in efficacy end points were identified between the investigational arm DD AC→PG and TAC The future lies in studies that will help us determine appropriate treatments based on tumor biology(gene expression, hormonal therapy, endocrine therapy).