Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Trastuzumab in Treating Women With Primary Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	Other, Pharmaceutical / Industry	BIG-01-01 EU-20216, ROCHE-B016348E, ROCHE-B016348C, EORTC-10011, CAN-NCIC-MA24, IBCSG-28-02, NCT00045032, MA24

Objectives

Primary

1. 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.
2. Compare the overall survival of patients treated with these regimens.
3. Compare the relapse-free survival of patients treated with these regimens.
4. Compare the distant disease-free survival of patients treated with these regimens.
5. Compare the incidence of cardiac dysfunction in patients treated with these regimens.
6. Evaluate the safety and tolerability of these regimens in these patients.

Secondary

1. Compare time to recurrence in patients treated with these regimens.
2. Compare time to distant recurrence in patients treated with these regimens.
3. 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.

Entry Criteria

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

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/m² or epirubicin more than 720 mg/m²
• 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

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/mm³
• Absolute neutrophil count at least 1,500/mm³
• 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

Expected Enrollment

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

Outcomes

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

Overall survival
Time to recurrence
Time to distant recurrence

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.

Dowsett M, Procter M, McCaskill-Stevens W, et al.: 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.[PUBMED Abstract]

Untch M, Gelber RD, Jackisch C, et al.: Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol 19 (6): 1090-6, 2008.[PUBMED Abstract]

McCaskill-Stevens W, Procter M, Goodbrand J, et al.: Disease-free survival according to local immunohistochemistry for HER2 and central fluorescence in situ hydridization for patients treated with adjuvant chemotherapy with and without trastuzumab in the HERA (BIG 01-01) trial. [Abstract] Breast Cancer Res Treat 106 (1): A-71, S18, 2007.

Smith I, Procter M, Gelber RD, et al.: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369 (9555): 29-36, 2007.[PUBMED Abstract]

Suter TM, Procter M, van Veldhuisen DJ, et al.: Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 25 (25): 3859-65, 2007.[PUBMED Abstract]

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353 (16): 1659-72, 2005.[PUBMED Abstract]

Jahanzeb M: Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer 8 (4): 324-33, 2008.[PUBMED Abstract]

Shiroiwa T, Fukuda T, Shimozuma K, et al.: 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 109 (3): 559-66, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Breast International Group

Martine Piccart-Gebhart, MD, PhD, Protocol chair		Ph: 32-2-541-3206 Email: martine.piccart@bordet.be

European Organization for Research and Treatment of Cancer

Robert Coleman, MD, FRCP, Protocol chair		Ph: 44-114-226-5213 Email: r.e.coleman@sheffield.ac.uk

NCIC-Clinical Trials Group

Karen Gelmon, MD, Protocol chair		Ph: 604-877-6000 ext. 2445; 800-663-3333 Email: kgelmon@bccancer.bc.ca
Kathleen Pritchard, MD, Protocol co-chair		Ph: 416-480-4616 Email: kathy.pritchard@sunnybrook.ca

International Breast Cancer Study Group

Olivia Pagani, MD, Protocol chair		Ph: 41-91-811-3395

Registry Information
Official Title		HERA: A Randomised Three-Arm Multi-Centre Comparison Of 1 Year And 2 Years Of Herceptin Versus No Herceptin In Women With HER2-Positive Primary Breast Cancer Who Have Completed Adjuvant Chemotherapy
Trial Start Date		2001-12-01
Registered in ClinicalTrials.gov		NCT00045032
Date Submitted to PDQ		2002-06-19
Information Last Verified		2007-01-03