HERA (BIG 1-01)

Intro text: 

Herceptin® (trastuzumab) in treating women with human epidermal growth factor receptor (HER) 2-positive primary breast cancer

HERA (HERceptin Adjuvant) is a randomised three-arm multicentre comparison of one year and two years of trastuzumab (Herceptin®) versus no trastuzumab in women with HER2-positive primary breast cancer who have completed (neo)adjuvant chemotherapy.

In HER2-positive breast cancer, increased quantities of a protein known as HER2 that promotes cell growth are present on the surface of the tumour cells. This represents approximately 15-20% of patients with breast cancer. HER2-positive breast cancer is a particularly aggressive form of the disease that previously meant poor survival rates.

Trastuzumab is an antibody designed to target and block the function of the HER2 protein. The way the drug works is unique in that it activates the body’s immune system and suppresses HER2 signalling to target and destroy the tumour.
The main objective of HERA was to compare the clinical benefits and the effects of giving one and two years of the anti-HER2 drug trastuzumab in addition to standard treatment versus standard treatment alone for patients with HER2-positive early breast cancer.

HERA’s results indicated that one year of treatment with trastuzumab had a significant and sustained benefit in preventing cancer recurrence and improving overall survival among patients with HER2-positive breast cancer. Two years of the drug was not found to have a significant benefit in comparison to one year of treatment.

HERA contributed to setting a new standard of treatment for patients with early stage HER2-positive breast cancer. It helped accelerate the approval of a drug called trastuzumab (Herceptin®) that has decreased relapse rates by 50% and is now the standard treatment for this aggressive cancer type. To date, more than 1.2 million people worldwide have been treated with trastuzumab.

The final analysis of HERA was published in The Lancet in April 2017. As noted in the paper, to our knowledge, this 11-year follow-up of the trial provides the longest survival data of any trial that assessed the addition of anti-HER2 therapy to standard treatment for HER2-positive early breast cancer.

Women diagnosed with early-stage HER2-positive breast cancer who had already received chemotherapy before or after their breast cancer surgery and radiotherapy (if applicable).
Overall recruitment (completed): 5,102 patients

Coordinating partners: The Institut Jules Bordet / Clinical Trials Support Unit - IJB-CTSU (formerly BrEAST), Frontier Science Scotland and the Breast International Group (BIG).

Pharmaceutical partner and sponsor: Roche

The trial compared two different durations of adjuvant (post-surgery) trastuzumab treatment versus the standard of care for enrolled patients:

• Observation (standard of care when the study started)
• One year of trastuzumab
• Two years of trastuzumab

Patients were followed up over a period of 8 years to monitor cancer recurrence and overall survival, and continued to be followed for a mean duration of 11 years to enable the analyses of long-term benefits (disease-free survival) and side effects. When the first results were made public in 2005, patients on the observation arm were given the option to switch to treatment with trastuzumab.

• Recruitment of 5,102 patients occurred from December 2001 to June 2005.
• The primary results on disease-free survival were reported in 2005, enabling accelerated approval of the drug as standard treatment.
• The final database lock occurred in September 2015. The final Clinical Study Report (CSR) was officially published and signed off on 26 April 2016. The main results have been published in prestigious journals such as the New England Journal of Medicine and The Lancet. Exploratory analyses continue.

480 hospitals in 39 countries participated in this trial through 27 BIG member groups.

• Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, McFadden E, Leyland-Jones B, Bell R, Dowsett M, Jackisch C; Herceptin Adjuvant (HERA) Trial Study Team. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389:1195-1205, 2017

• Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: the HERA trial experience. Metzger-Filho O, de Azambuja E, Procter M, Krieguer M, Smith I, Baselga J, Cameron D, Untch M, Jackisch C, Bell R, Gianni L, Goldhirsch A, Piccart M, Gelber RD for the HERA Study Team. Breast Cancer Res Treat 155:127-132, 2016.

• Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial. Loi S, Dafni U, Karlis D, Polydoropoulou V, Young BM, Willis S, Long B, de Azambuja E, Sotiriou C, Viale G, Rüschoff J0, Piccart MJ, Dowsett M, Michiels S, Leyland-Jones B. JAMA Oncol. 2016 Apr 21. doi: 10.1001/jamaoncol.2016.0339. [Epub ahead of print]

• Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors ≤ 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. O'Sullivan CC, Bradbury I, Campbell C, Spielmann M, Perez EA, Joensuu H, Costantino JP, Delaloge S, Rastogi P, Zardavas D, Ballman KV, Holmes E, de Azambuja E, Piccart-Gebhart M, Zujewski JA, Gelber RD. J Clin Oncol. 2015 Aug 20;33(24):2600-8. doi: 10.1200/JCO.2015.60.8620. Epub 2015 Jun 22.

• Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, Untch M, Smith IE, Gianni L, Baselga J, Jackisch C, Cameron DA, Bell R, Leyland-Jones B, Dowsett M, Gelber RD, Piccart-Gebhart MJ, Suter TM. J Clin Oncol. 2014 Jul 10;32(20):2159-65. doi: 10.1200/JCO.2013.53.9288. Epub 2014 Jun 9.

• Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. Piccart-Gebhart MJ1, 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, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. N Engl J Med. 2005 Oct 20;353(16):1659-72.

The study was sponsored and funded by Roche but run according to BIG’s research principles.

ClinicalTrials.gov Identifier: NCT00045032