title: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials.
abstract: BACKGROUND
  Results from three National Surgical Adjuvant Breast and Bowel Project sequentially conducted randomized trials of postoperative chemotherapy in women with estrogen receptor-negative tumors and negative axillary lymph nodes have demonstrated that a combination of methotrexate and 5-fluorouracil (MF) is more effective than surgery alone, that cyclophosphamide with MF (CMF) is more effective than MF, and that CMF and doxorubicin (Adriamycin) with cyclophosphamide (AC) are equally beneficial. This report presents updated findings from those trials, relates the results to age and menopausal status, and estimates the extent of progress made in treating such patients.
  
  
  METHODS
  Patients were randomly assigned as follows: in B-13, 760 patients were assigned to surgery only or to MF; in B-19, 1095 patients were assigned to MF or CMF; in B-23, 2008 patients were assigned to CMF or AC. Recurrence-free survival (RFS) and overall survival (OS) were estimated according to age and menopausal status. Smoothed recurrence rates were used to evaluate patterns of recurrence as a continuous function of age. The Cox proportional hazards model was used to test for interactions between treatment and covariates and to estimate hazard ratios (HRs) for pairwise group comparisons.
  
  
  RESULTS
  In B-13, through 16 years of follow-up, an overall benefit was seen with MF relative to surgery alone (RFS: HR = 0.59, 95% confidence interval [CI] = 0.44 to 0.78, P<0.001; OS: HR = 0.75, 95% CI = 0.58 to 0.98, P = 0.03). In B-19, through 13 years of follow-up, an overall benefit was seen for CMF relative to MF (RFS: HR = 0.59, 95% CI = 0.45 to 0.77, P<0.001; OS: HR = 0.71; 95% CI = 0.55 to 0.92; P = 0.01). In both trials, all age and menopausal groups demonstrated an RFS benefit, and most demonstrated an OS benefit. In B-23, through 8 years of follow-up, there were no statistically significant differences between the CMF and AC groups (RFS: HR = 1.00, 95% CI = 0.79 to 1.27, P = 0.97; OS, HR = 0.92, 95% CI = 0.73 to 1.17; P = 0.51). When women in the CMF or AC groups (B-19, B-23) were compared with those who were in the surgery-alone group (B-13), through 8 years of follow-up there was a 58% reduction in recurrence and a 40% reduction in mortality as a result of the chemotherapy.
  
  
  CONCLUSIONS
  Outcomes in CMF- or AC-treated women with estrogen receptor-negative tumors and negative axillary lymph nodes were similar in all age groups. The decreased benefit from chemotherapy observed with increasing age was a result of a better outcome associated with advancing age in women who underwent surgery alone rather than a poorer outcome resulting from the use of chemotherapy.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project, Operations Center, USA. bernard.fisher@nsabp.org
authors.forename: Bernard
authors.initials: B
authors.lastname: Fisher
authors.forename: Jong-Hyeon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Stewart
authors.initials: S
authors.lastname: Anderson
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008593:Menopause; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000032:analysis; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D011960:Receptors, Estrogen; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate