Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer (HERA trial)
August, 2011
Commentary by Dr Belinda Kiely
The articleGianni L, Dafni U, Gelber RD, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011;12:236–44
The reviewer
Dr Belinda Kiely is a medical oncologist and is undertaking her PhD at the NHMRC Clinical Trials Centre, University of Sydney.
SUMMARY
Abbreviations
Confidence Interval (CI); Disease-Free Survival (DFS); Herceptin Adjuvant (HERA); Hazard Ratio (HR); Left Ventricular Ejection Fraction (LVEF); Overall Survival (OS)
Study Design
The Herceptin Adjuvant (HERA) trial is a large international, multicentre, randomised, open-label, phase 3 trial. The trial randomly assigned patients with HER2-positive early breast cancer after standard neoadjuvant, adjuvant chemotherapy or both, to an observation group (n=1698), a 1-year trastuzumab group (n=1703) or a 2-year trastuzumab group (results for this group are not included in this paper). After a positive first interim analysis, event-free patients in the observation group were allowed to cross-over to receive trastuzumab.
The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS), and safety. This paper reports an intention-to-treat analysis comparing the observation and 1-year trastuzumab groups at a median follow-up of 48·4 months. The effect of the extensive crossover to trastuzumab was also assessed.
Findings
Intention-to-treat analysis
Patients in the 1-year trastuzumab group had improved DFS compared to the observation group (4-year DFS 78.6% vs. 72.2% respectively: unadjusted HR 0.76; 95% CI 0.66, 0.87; p<0.0001).
There was no OS difference between the trastuzumab and observation groups (4-year OS 89.3% vs. 87.7% respectively: unadjusted HR 0.85; 95% CI 0.70, 1.04; p=0.11).
Higher incidences of grade 3−4 (14% vs. 8%) and fatal adverse events (0.007% vs. 0.003%) were recorded on 1-year trastuzumab than in the observation group (censored at crossover). The most common grade 3 or 4 adverse events in the 1-year trastuzumab (1682 patients), and/or observation (1719 patients) safety-analysis populations, each in fewer than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache and diarrhoea.
Non-randomised crossover comparison
Overall, 885 patients (52%) of the 1698 patients randomly assigned to the observation group crossed over to receive trastuzumab.
Patients in the selective crossover cohort had improved disease-free survival compared to patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51, 0·90; p=0·0077).
Conclusion
The authors conclude that these longer-term findings confirm that adjuvant trastuzumab given sequentially to chemotherapy is associated with significant and persisting benefits, and remains an appropriate treatment modality in patients with HER2-positive early breast cancer.
COMMENTARY
What does this article add to existing clinical evidence in this area?
Without the adverse effects of chemotherapy, trastuzumab has significantly improved the outcomes for women with HER2-positive breast cancer, a type of cancer traditionally associated with a poorer prognosis.1 Longer follow-up of the large trials evaluating the benefit of adjuvant trastuzumab2-4 is awaited to determine if the promising early survival benefits will be sustained and if the trastuzumab toxicities will accumulate. The HERA trial 2-year follow-up analysis earlier reported significant benefits in both DFS (HR 0.64; 95% CI 0.54, 0.76; p<0.0001) and OS (HR 0.66; 95% CI 0.47, 0.91; p=0.0115) from 1 year of trastuzumab compared to observation.5 The 4-year follow-up results now reported of the same comparison demonstrate a persistent DFS benefit but no significant OS benefit.6
This result does not mean trastuzumab has failed to improve OS. Rather the large number of patients on the observation arm (52%) that crossed over to receive trastuzumab, and subsequently benefited from improved DFS, has likely obscured effects on overall survival. The OS benefit has persisted in the updated analyses of the other large adjuvant trastuzumab trials.7,8 These trials were different to HERA in that a smaller proportion of patients crossed over to receive trastuzumab, and the trastuzumab was commenced concurrently with chemotherapy, a means of administration that may be more effective. The question of concurrent or sequential administration is being addressed by the N9831 trial where patients were randomised to trastuzumab commencing with, or sequentially after paclitaxel.9 The first interim analysis for this trial has reported a trend for a 25% reduction in the risk of an event with the concurrent treatment relative to the sequential,9 and the final results of this comparison are awaited.
Importantly, the 4-year follow-up data reveal the overall incidence of adverse events remains low and no additional side effects have emerged. Of the 1682 women randomised to 12 months of trastuzumab, there were no cardiac deaths, 2% developed symptomatic heart failure and 4% had a significant but asymptomatic decline in left ventricular ejection fraction (LVEF).6
How adequate was the methodology used in addressing the aim of this study?
To determine the real effect of trastuzumab on survival, the ideal study design would not allow crossover of patients from observation to trastuzumab. However, after the strongly positive first interim analysis of HERA,2 the only ethically sound option was to allow all participants access to trastuzumab, and as such we may never learn its true OS effect. In an attempt to account for the large number of women crossing over, a censored analysis of the observation group with censoring at the time of crossover was also performed. This revealed significant benefits for both DFS and OS from trastuzumab however the authors appropriately caution that this analysis is biased in favour of trastuzumab. The true size of the benefit of trastuzumab likely lies between the results of the intention-to-treat and censored analyses.
What are the implications of this study for clinical practice in Australia?
Results of the adjuvant trastuzumab trials2-4 have led to HER2 testing and the addition of 12 months of trastuzumab to HER2-positive early breast cancer chemotherapy becoming routine practice in Australia. However, many questions remain unanswered. We do not understand the mechanism of trastuzumab resistance. The optimal duration of trastuzumab is unknown and most trials have only assessed 12 months. The HERA trial has randomised patients to 1 year or 2 years of trastuzumab, and these results are eagerly awaited. Because the risk of breast cancer recurrence persists for longer than 12 months from diagnosis, it is plausible that prolonged attenuation of the HER2 receptor with longer duration trastuzumab will be beneficial.
In the HERA study, trastuzumab was delivered after completion of at least 4 cycles of any approved chemotherapy and only 26% of patients received taxanes. In Australia, trastuzumab is only authorised for the initial treatment of HER2-positive early breast cancer when commenced concurrently with chemotherapy, usually taxanes, following surgery. It cannot be given as a single agent, commenced after completion of chemotherapy or given prior to surgery.
Women with node negative tumours smaller than 1 cm were not eligible for HERA2 but in Australia there is no tumour size limit for prescribing trastuzumab. The requirement to administer trastuzumab concurrently with chemotherapy probably prevents many women with very small node negative tumours receiving treatment. The risk of recurrence and optimal management for these women requires evaluation. Although trastuzumab has arguably been the most important discovery in breast cancer treatment since tamoxifen, further research is required to ensure we use it in a way that maximises its benefits.
References
1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82.
2. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–72.
3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–84.
4. Slamon D, Eiermann W, Robert N, et al. Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 7–10, 2005. Abstract 1.
5. 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 2007;369:29–36.
6. Gianni L, Dafni U, Gelber R, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011;12:236–44.
7. Slamon D, Eiermann W, Robert N, et al. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: third planned efficacy analysis. 32nd San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 9–13, 2009. Abstr 62.
8. Perez EA, Romond EH, Suman VJ, et al. 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. Proc Soc Am Clin Oncol 2007; 25(18 suppl):512.
9. Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial. 32nd San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 10–13, 2009. Abstr 80.
Editor: Dr Anne Nelson, Manager, Evidence Review, Cancer Australia
Clinical Update – Breast Cancer Editorial Committee: Mr John Collins - Surgeon, Ms Jo Keyser - Specialist Breast Nurse, Dr Warwick Lee - Radiologist, A/Prof Liz Lobb – Senior Research Fellow, Dr Sue-Anne McLachlan - Medical Oncologist, Dr Sally Meade - Breast Surgeon, Dr Sue Pendlebury - Radiation Oncologist, A/Prof Martin Stockler - Medical Oncologist.
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