• Disease-free survival [ Designated as safety issue: No ]
• Relapse-free survival [ Designated as safety issue: No ]
• Distant disease-free survival [ Designated as safety issue: No ]
• Incidence of cardiac dysfunction [ Designated as safety issue: No ]
• Safety and tolerability [ Designated as safety issue: Yes ]

• Disease-free survival
• Relapse-free survival
• Distant disease-free survival
• Incidence of cardiac dysfunction
• Safety and tolerability

• Overall survival [ Designated as safety issue: No ]
• Time to recurrence [ Designated as safety issue: No ]
• Time to distant recurrence [ Designated as safety issue: No ]

• Overall survival
• Time to recurrence
• Time to distant recurrence

RATIONALE: Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether trastuzumab is effective in treating primary breast cancer in women who have completed adjuvant chemotherapy.

PURPOSE: This randomized phase III trial is studying two different regimens of trastuzumab and observation only to compare how well they work in treating women with breast cancer.

OBJECTIVES:

Primary

• Compare the disease-free survival of women with HER2-positive primary breast cancer treated with trastuzumab (Herceptin®) for 1 year vs trastuzumab for 2 years vs standard supportive care.
• Compare the overall survival of patients treated with these regimens.
• Compare the relapse-free survival of patients treated with these regimens.
• Compare the distant disease-free survival of patients treated with these regimens.
• Compare the incidence of cardiac dysfunction in patients treated with these regimens.
• Evaluate the safety and tolerability of these regimens in these patients.

Secondary

• Compare time to recurrence in patients treated with these regimens.
• Compare time to distant recurrence in patients treated with these regimens.
• Compare outcomes, in terms of disease-free survival, overall survival, recurrence-free survival, distant disease-free survival, time to recurrence, time to distant recurrence, cardiac safety, and overall safety, in patients treated with trastuzumab for 1 year vs 2 years.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to nodal status (any nodal status and prior neoadjuvant chemotherapy vs no positive nodes and no prior neoadjuvant chemotherapy vs 1-3 positive nodes and no prior neoadjuvant chemotherapy vs 4 or more positive nodes and no prior neoadjuvant chemotherapy), prior adjuvant chemotherapy regimen (no anthracyclines or taxanes vs anthracyclines only vs anthracyclines and taxanes), receptor status and endocrine therapy (negative vs positive and no prior endocrine therapy vs positive and prior endocrine therapy), age (18 to 34 vs 35 to 49 vs 50 to 59 vs 60 and over), and participating center. Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive trastuzumab (Herceptin®) IV over 1.5 hours on day 1. Courses repeat every 3 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive trastuzumab as in arm I. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive no trastuzumab. Patients may later receive trastuzumab as in arm I or arm II.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 4,482 patients (1,494 per treatment arm) will be accrued for this study within 4 years.

• Biological: trastuzumab
• Procedure: adjuvant therapy

• Dowsett M, Procter M, McCaskill-Stevens W, de Azambuja E, Dafni U, Rueschoff J, Jordan B, Dolci S, Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart M, Leyland-Jones B. Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial. J Clin Oncol. 2009 Apr 13; [Epub ahead of print]
• Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, Cameron D, Bari M, Smith I, Leyland-Jones B, de Azambuja E, Wermuth P, Khasanov R, Feng-Yi F, Constantin C, Mayordomo JI, Su CH, Yu SY, Lluch A, Senkus-Konefka E, Price C, Haslbauer F, Suarez Sahui T, Srimuninnimit V, Colleoni M, Coates AS, Piccart-Gebhart MJ, Goldhirsch A; HERA Study Team. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol. 2008 Jun;19(6):1090-6. Epub 2008 Feb 21.
• Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36.
• Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, Perren T, Passalacqua R, Bighin C, Klijn JG, Ageev FT, Hitre E, Groetz J, Iwata H, Knap M, Gnant M, Muehlbauer S, Spence A, Gelber RD, Piccart-Gebhart MJ. Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial. J Clin Oncol. 2007 Jul 23; [Epub ahead of print]
• Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72.
• Jahanzeb M. Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer. 2008 Aug;8(4):324-33.
• Shiroiwa T, Fukuda T, Shimozuma K, Ohashi Y, Tsutani K. The model-based cost-effectiveness analysis of 1-year adjuvant trastuzumab treatment: based on 2-year follow-up HERA trial data. Breast Cancer Res Treat. 2007 Jul 28; [Epub ahead of print]

DISEASE CHARACTERISTICS:

• Histologically confirmed nonmetastatic primary invasive adenocarcinoma of the breast

  • Adequately excised
  • Axillary nodes positive or negative
  • No positive or suspicious internal mammary nodes identified by sentinel node technique that have not been irradiated
  • No supraclavicular lymph node involvement

• HER2-positive disease with one of the following:

  • 3+ overexpression by immunohistochemistry (IHC)
  • 2+ overexpression by IHC and fluorescence in situ hybridization (FISH) with c-erbB2 gene amplification
  • c-erbB2 gene amplification by FISH
• Previously treated with at least 3 months or 4 courses of approved neoadjuvant or adjuvant chemotherapy with or without radiotherapy
• No synchronous bilateral or multifocal breast cancer that is not HER2-positive
• No locally advanced or inflammatory breast cancer
• No clinical T4 primary breast tumor
• Prior curatively treated ipsilateral ductal carcinoma in situ of the breast is allowed

• Hormone receptor status:

  • Estrogen receptor and progesterone receptor status known OR
  • Estrogen receptor status known

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC at least 2,500/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000

Hepatic

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN
• Alkaline phosphatase no greater than 2.5 times ULN

Renal

• Creatinine no greater than 2 times ULN

Cardiovascular

• LVEF at least 55% by echocardiography or MUGA
• No serious cardiac illness
• No documented congestive heart failure
• No high-risk uncontrolled arrhythmias
• No angina pectoris requiring antianginal medication
• No clinically significant valvular heart disease
• No evidence of transmural infarction on EKG
• No poorly controlled hypertension (i.e., systolic greater than 180 mm Hg or diastolic greater than 100 mm Hg)

Pulmonary

• No severe pulmonary disease/illness

Other

• No other malignancy except for curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other cancer that has been curatively treated, with no evidence of disease, and has less than 15% risk of recurrence over the next 10 years
• No other concurrent serious disease that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior peripheral stem cell or bone marrow stem cell transplantation as part of prior neoadjuvant or adjuvant chemotherapy regimen
• No prior biologic therapy or immunotherapy for breast cancer
• No prior anti-HER2 therapy for any reason
• No concurrent immunotherapy for breast cancer

Chemotherapy

• See Disease Characteristics
• See Biologic therapy
• No prior cumulative dose of doxorubicin more than 360 mg/m^2 or epirubicin more than 720 mg/m^2
• No prior anthracyclines for another malignancy
• No more than 7 weeks since day 1 of last chemotherapy course
• No concurrent adjuvant chemotherapy

Endocrine therapy

• No concurrent hormonal therapy, including aromatase inhibitors, pure antiestrogens, or progestational agents, for breast cancer
• Concurrent systemic adjuvant hormonal therapy for estrogen receptor-positive patients allowed
• Concurrent tamoxifen allowed

Radiotherapy

• See Disease Characteristics
• No more than 6 weeks since completion of prior radiotherapy
• No prior mediastinal irradiation except for internal mammary node irradiation for the present breast cancer

Surgery

• See Disease Characteristics
• No more than 6 weeks since prior definitive surgery
• Concurrent ovarian ablation allowed

Other

• No other concurrent investigational therapy for breast cancer
• Concurrent bisphosphonate therapy allowed if started prior to study

• European Organization for Research and Treatment of Cancer
• NCIC Clinical Trials Group
• International Breast Cancer Study Group