Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2007

Presenter: Perez, E.A.
Presenter's Affiliation: Mayo Clinic, Jacksonville, FL.
Type of Session: Scientific


  • Up to 25% of women diagnosed with early-stage breast cancers have tumors which demonstrate overexpression of human epidermal growth factor receptor 2 (HER-2). Trastuzumab (Herceptin) is a monoclonal antibody directed against the extracellular domain of HER-2.
  • Adjuvant treatment with trastuzumab has been investigated in four major adjuvant trials, Herceptin Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006.
  • Combined analysis of the NSABP B-31 and NCCTC N9831 trials (NEJM, 2005) demonstrated a 30% reduction in mortality in patients with HER-2 positive breast cancers treated with trastuzumab after a chemotherapeutic regimen consisting of doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) when compared to those receiving chemotherapy alone.
  • Following the outcomes analysis from the combined trials, patients who had been randomized to receive AC followed by T alone were offered further treatment with trastuzumab.
  • This study represents an update of the initial combined results of these trials.

Materials and Methods

  • The NSABP trial B-31 compared AC-T alone with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of T. The NCCTC N9831 trial compared three treatment arms: AC-T alone, AC-T with trastuzumab initiated concurrently with T, and AC-T with trastuzumab after T. In the joint analysis, the lattermost group was excluded.
  • Following data analysis, patients who had been randomized to AC-T alone as part of either study, and who had completed chemotherapy within the most recent 6 months, were eligible for trastuzumab therapy.
  • Updated analysis was performed with endpoints of disease-free survival (DFS) and overall survival (OS).
  • Hazard rations were adjusted for nodal status, tumor size, hormone receptor status, age, and trial.


  • 3,969 women are included in this analysis, with a total of 619 events (compared to 394 events in the original analysis). First events have been disease recurrence in 511 patients, contralateral breast cancer in 18 patients, other second cancers in 48 patients, and death without known recurrent disease in 42 patients.
  • Patient age range was 22 - 80 years at the time of diagnosis, and median follow-up 2.9 years (range 0 - 6.4 years). At the time of this analysis, 3, 711 women were alive of the original 3,969.
  • Four-year disease free survival (DFS) was 85.9% for the trastuzumab group, and 73.1% for the AC-T alone group (HR 0.49, p < 0.0001).
  • Four-year overall survival (OS) was 92.6% for the trastuzumab group, and 89.4% for the AC-T alone group (HR 0.63, p = 0.0004).
  • For patients taking trastuzumab, rates of first event per 1000 woman-years were 26.7, 52.9, 49.6, and 23.2 for years 1-4, respectively. For patients randomized to AC-T alone, rates of first even per 1000 woman-years were 42.3, 102.3, 107.6, and 61.5 for years 1-4, respectively.

Author's Conclusions

  • With increase in median follow-up of 11 months and 222 additional events, outcomes remain substantially improved with the addition of trastuzumab to AC-T chemotherapy for patient with HER-2 positive breast cancers.
  • Improvement in OS and DFS persists despite some cross-over occurring since the initial analysis.
  • Cross-over of patients from AC-T alone to addition of trastuzumab did not appear to significantly alter the outcomes benefits from trastuzumab

Clinical/Scientific Implications

  • Treatment of early-stage breast cancer generally consists of surgical removal followed by whole breast radiation treatment and chemotherapy. Recognition of overexpression of HER-2 in a significant proportion of early-stage breast cancer patients represents an important milestone in modern cancer care. Trastuzumab is one of the most successfully utilized targeted therapies available to cancer patients.
  • This update of two previous trials demonstrates that the benefit of trastuzumab persists even with prolonged follow-up. Additionally, it indirectly demonstrates that treatment of patients with trastuzumab initiated at the time of paclitaxel initiation should remain the current standard of care; however, the addition of trastuzumab after the completion of chemotherapy still appears to procure OS and DFS benefits.
  • Further analysis of cardiac events, as described in the initial combined analysis published in 2005, would further elucidate long-term risks of trastuzumab treatment.
  • This study supports the continued use of trastuzumab in treatment of patients with early-stage, HER-2 positive, breast cancer.