Women with an aggressive type of early-stage breast cancer (HER2-positive disease) given trastuzumab (Herceptin) for one year following standard chemotherapy are at significantly less risk of the cancer returning, and the effect is long lasting, according to the long-term results of the landmark HERA trial published Online First in The Lancet Oncology.
Around 20% of women with breast cancer have HER2-positive cancer and are at high risk of cancer recurrence and of dying from the disease. Trastuzumab is a monoclonal antibody developed to block the cancer-causing activity of the HER2 protein and has been shown to prolong survival in patients with advanced breast cancer.
The HERA trial was designed to establish whether trastuzumab could increase disease-free survival (DFS) and overall survival (OS) in women with early HER2-positive breast cancer when given after standard chemotherapy. Between December 2001 and June 2005, over 5000 women from 39 countries were enrolled and randomly assigned to observation only, trastuzumab for 1 year, or trastuzumab for 2 years.
In 2005, initial results (median follow-up 1 year) showed that 1 year of adjuvant trastuzumab significantly reduced the risk of disease recurrence by 46%. On the basis of these results, a protocol amendment allowed patients in the observation group who were disease free and had normal heart function to receive trastuzumab. A second analysis published in 2007 (median follow-up 2 years) confirmed the significant improvement in DFS after 1 year of trastuzumab and also showed a significant improvement in OS.
In this study, Luca Gianni from Fondazione San Raffaele, Milan, Italy and international colleagues report the long-term outcomes (median 4 years) of women from the HERA trial treated with trastuzumab for 1 year and examine the outcome of patients who crossed over to trastuzumab treatment.
After 4 years, trastuzumab was associated with significantly better DFS compared with chemotherapy alone (78.6% vs 72.2%), reducing the likelihood of cancer coming back by 24%. However, there was no significant difference in risk of death between the trastuzumab and observation groups (89.3% vs 87.7%), which was most likely the result of the cross-over impact.
Over half (52%) of patients from the observation group crossed over to receive trastuzumab treatment a median of 23 months after randomisation. These patients had fewer recurrences than patients remaining on observation.
Trastuzumab was generally well tolerated, although more serious side-effects were recorded in the trastuzumab group than in the observation group. However, the rate of congestive heart failure remained low during the longer follow-up.
The authors say: "These findings confirm that adjuvant trastuzumab [Herceptin] given sequentially to chemotherapy is associated with significant and persisting benefits, and remains an appropriate treatment modality in patients with HER-2 positive early breast cancer…The optimal duration of trastuzumab therapy is the subject of ongoing studies."
In an accompanying Comment, Heikki Joensuu from Helsinki University Central Hospital, Helsinki, Finland points out that: "When the HERA trial was designed, the preference was to give trastuzumab [Herceptin] in the same manner as endocrine therapy—ie, as a single drug after chemotherapy and for a long period. Yet, mounting evidence suggests that the optimum way to give trastuzumab differs from that of endocrine therapy, and that concomitant administration of trastuzumab with chemotherapy might be more effective compared with trastuzumab given after chemotherapy."
In a second Comment, Evandro de Azambuja from the Institut Jules Bordet and Universite Libre de Bruxelles, Brussels, Belgium and colleagues discuss the best way to combine trastuzumab and chemotherapy and argue that there is insufficient evidence to safely promote the concurrent [at the same time] use of trastuzumab and anthracyclines in patients with primary HER2-positive breast cancer.
Indeed, their combined analysis of the cardiac events observed in published neoadjuvant studies finds that: "The concurrent use of trastuzumab and anthracycline-based chemotherapy significantly increases the risk of cardiac toxicity, even if administered for brief periods in the neoadjuvant setting."
They conclude: "We strongly discourage the concurrent use of trastuzumab and anthracycline-based regimens in clinical practice outside the context of a clinical trial…To validate this treatment approach in the clinical setting, a properly powered, randomised phase 3 clinical trial…[of] sequential versus concomitant administration of trastuzumab and anthracycline-based chemotherapy…is needed."
Professor Luca Gianni, Fondazione San Raffaele, Milan, Italy. T) +39 02 2643 6529 E) gianni.luca@hsr.it
Professor Heikki Joensuu, Helsinki University Central Hospital, Helsinki, Finland. T) +358 (0)9 471 3200 or +358 (0)40 72 10 438 (mobile) E) heikki.joensuu@hus.fi
Dr Evandro de Azambuja, Institut Jules Bordet and Universite Libre de Bruxelles, Brussels, Belgium. T) + 32 2 541 72 44 E) evandro.azambuja@bordet.be
For full Article and both Comments, see: http://press.thelancet.com/tlohercep.pdf
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Journal
The Lancet Oncology