NE Oncology Issue – April 2013

Romond EH, et al. SABCS 2012:S5-5


The initial results were reported in 2005 for the preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG) N9831 trial, both of which compared adjuvant chemotherapy with or without trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. At a general session at SABCS 2012, Romond and colleagues presented the final planned joint analysis of overall survival (OS) from these trials.1

Study design

  • Patients with HER2-positive operable breast cancer (N = 4,045) were enrolled to receive doxorubicin (A) plus cyclophosphamide (C) followed by paclitaxel (P) with or without concomitant trastuzumab (H) (ACP –/+ H) in the B-31 and N9831 trials.
  • This definitive analysis for OS was scheduled once 710 events had been reported.
  • The databases were locked on September 15, 2012, at a median follow-up of 8.4 years.
  • In these joint analyses, the control arm (ACP) was composed of patients of B-31 Arm 1 and N9831 Arm A, while patients of B-31 Arm 2 and N9831 Arm C formed the investigational arm (ACP+H).
  • The primary end point was disease-free survival (DFS) and the secondary end point was OS, both of which were analyzed by intent to treat (ITT).
  • Some patients (n = 102 [5%]) assigned to the investigational arm did not receive trastuzumab because of cardiac symptoms or a decrease in left ventricular ejection fraction that precluded initiation of the antibody. These patients were included in the trastuzumab arm in the ITT analysis.
  • In the control arm in 2005, a significant proportion of patients (n = 413 [20.4%]) who selectively crossed over to receive trastuzumab after the first interim analysis reported positive results. These patients were included in the control arm in the ITT analysis.


Key findings

  • The percentage of patients who remained disease free was significantly greater in the trastuzumab arm than in the control arm at six years (81.4% vs. 69.5%), eight years (76.8% vs. 64.9%), and 10 years (73.7% vs. 62.2%) following randomization. (Figure 1)
  • For patients with high risk HER2-positive breast cancer, the investigational regimen reduced the risk of a DFS event by 40% (HR = 0.60 [95% CI: 0.53–0.68], p <0.0001) at 10 years from randomization. (Figure 1)
  • The two most common types of DFS events in these trials — distant recurrence of disease (19.4% vs. 11.2%) and local/ regional recurrence (6.1% vs. 4.1%) — occurred more frequently in patients in the control arm, while only minor differences existed between the two arms for other DFS events. (Table 1)
  • Patients in the investigational arm had progressively greater OS rates than those in the control arm over the years following randomization: four years (93.2% vs. 90.3%), six years (89.8% vs. 84.3%), eight years (87.0% vs. 79.4%), and 10 years (84.0% vs. 75.2%). (Figure 2)
  • The addition of trastuzumab to paclitaxel following AC chemotherapy is associated with a significant and substantial improvement in OS, with a relative risk reduction of 37% (HR = 0.63 [95% CI: 0.54–0.73], p <0.0001). (Figure 2)
  • An overview of the OS events that occurred in these trials showed that a greater proportion of patients from the control arm than the investigational arm died (20.7% vs. 14.1%), primarily due to this breast cancer (16.8% vs. 10.3%) as opposed to any other cause. (Table 2)
  • Analysis of OS according to subgroups showed all patients benefited from the addition of trastuzumab, regardless of their age, hormone receptor status, tumour size, nodal status, and histologic grade. (Figure 3)

Key conclusions

  • Joint analysis data from the NSABP B-31 and NCCTG N9831 studies demonstrated a sustained and significant benefit of one year of trastuzumab, given concurrently with adjuvant chemotherapy to women with HER2-positive early breast cancer (EBC) for both OS and DFS after 10 years of follow-up.
  • Addition of trastuzumab to paclitaxel following adjuvant AC chemotherapy in patients with HER2-positive EBC was associated with a significant improvement in OS, reducing the risk of death by 37% (hazard ratio 0.63) after a median follow up of 8.4 years.
  • The OS and DFS benefit was reported in similar magnitude for virtually all subgroups of patients analyzed.
  • The statistically significant OS and DFS benefit was reached despite the 20% of patients who crossed over from the control arms.

Reference: 1. Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. SABCS Annual Meeting Abstracts 2012:S5-5.

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Canadian Perspectives


Jean-Francois Larouche, MD

Dr. Jean-Francois Larouche obtained his medical degree in 2000. Upon graduation, he trained in internal medicine, hematology, and oncology at Laval University, Quebec City. Pursuing his interest in oncology, Dr. Larouche completed a postdoctoral fellowship in 2008 in Lyon, France, on lymphoma management. His interests include lymphomas and clinical research.


Stephen Couban, MD, FRCPC

Dr. Stephen Couban is a professor of medicine at Dalhousie University and Director of the Blood and Marrow Transplant Program at Capital District Health Authority in Halifax, Nova Scotia. He is Co-Chair of the NCIC CTG Hematology Site Group and is also active with the Canadian Blood and Marrow Transplant Group. Dr. Couban is Vice President of the Canadian Hematology Society and a past-president of the Canadian Blood and Marrow Transplant Group. His research interests have focused on allografting and in particular on exploration of different types of grafts, including GCSF-stimulated allogeneic peripheral blood allografts and GCSF-stimulated bone marrow allografts. He is actively involved in a number of clinical trials for patients with leukemia and lymphoma, as well as those undergoing blood and marrow transplantation.

Investigator Commentary


Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.


Véronique Leblond, MD

Dr. Véronique Leblond is the Head of the Department of Haematology at Pitié- Salpêtrière Hospital, Paris, France. She has a long-standing research interest in the treatment of chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia (WM). Dr. Leblond has been the Principal Investigator of several multicentre trials investigating immunological therapies and novel chemotherapies. Currently, she is Chair of the French cooperative groups on CLL and WM, and is a member of the French Society of Haematology and the American Society of Haematology. Dr. Leblond has authored over 250 research articles, books, and book chapters.


Francesco Lo-Coco, MD

Dr. Francesco Lo-Coco is a full Professor of Hematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biopathology, University of Rome Tor Vergata, Rome, Italy. His main research activities include genetic characterization, monitoring, and treatment of hematologic tumours, particularly acute myeloid leukemia and acute promyelocytic leukemia (APL). He has served as President of the Italian Society of Experimental Hematology, been a board member of the Italian Foundation for Cancer Research, and a member of the Committee on Health Research at the Italian Ministry of Health. He is presently chairman of the APL subcommittee of the Italian National Cooperative Group GIMEMA, chairman of the Education Committee of the European Hematology Association, and a member of the editorial board for the journals Leukemia and Haematologica.