One of the best examples of the "bench to bedside" process is the development of trastuzumab (Herceptin) for HER2-overexpressed breast tumors. From the identification of the neu oncogene in 1984 and its subsequent cloning, to the development of a humanized monoclonal antibody targeting HER2 that improved outcome not only in the metastatic setting but also in the adjuvant setting[4-7] has been a long yet fruitful journey. In this issue of ONCOLOGY, Morris and Carey comprehensively review this journey, emphasizing the dynamic heterogeneous nature of breast tumors and its implications for the use of trastuzumab. In addition, they stress the importance of discovering newer agents such as lapatinib (Tykerb) that can overcome trastuzumab resistance. On the other hand, issues that deserve attention but were not addressed by the authors include the optimal trastuzumab regimen/combination, HER2 testing methods, and cost implications.
Trastuzumab: When, for How Long, and for Whom?
Results from five randomized adjuvant trialsthe Herceptin Adjuvant (HERA) trial, the combined North American National Surgical Adjuvant Breast and Bowel Project (NSABP)31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, the Breast Cancer International Research Group (BCIRG) 006 trial, and the Finnish trialhave established the efficacy of trastuzumab in women with early-stage HER2-positive breast cancer. Despite short follow-up, consistent results of reduction in odds of recurrence and mortality were seen across all five trials.
Although the results are remarkable, the varying designs of all five trials have resulted in a number of questions. The North American[5-7] and HERA trials used 1 year of adjuvant trastuzumab, whereas the Finnish trial used only 9 weeks of traztuzumab to achieve similar efficacy results. As the number of patients enrolled in the Finnish study was small, the result is not likely to change clinical practicebut it is food for thought. A shorter but equally efficacious trastuzumab regimen may reduce the incidence of associated cardiac morbidity, decrease the risk of developing resistance to the antibody, and would be more cost friendly.
Defining a group of patients that would receive maximum benefit from trastuzumab is difficult because of the heterogeneous nature of breast tumors. Kim et al showed that coamplification of cMyc and HER2 predicted for a superior recurrence-free survival by balancing the proapoptotic function of dysregulated cMyc with the antiapoptotic signal induced by trastuzumab. However, patients with HER2 tumors that do not have amplification of cMyc still derive a benefit, although smaller, from trastuzumab. As yet there is no way to identify a subset of patients with HER2-positive disease that would not benefit from trastuzumab.
The question of optimal timing of trastuzumab has also been an area of extensive research. The average delay in trastuzumab administration after surgery was 8 months in the HERA trial, 4 months in the NSABP-31/N9831 trials, and 1 month in the Finnish trial. The control group in the HERA trial showed that the maximum risk of relapse occurred in patients with more than four positive lymph nodes (irrespective of hormone receptor status) and in patients with hormone receptor-negative disease. The superior disease-free survival seen in the NSABP-31/N9831 trials as compared to the HERA trial suggests that concomitant administration of trastuzumab with chemotherapy may be a better approach. Both pieces of information may persuade clinicians to start trastuzumab treatment early rather than later with concomitant administration of chemotherapy at least in the high-risk cohort of patients.
Cardiac Toxicity: Are We Being Too Cautious?
Although generally safe, trastuzumab is known to be associated with cardiac toxicity. This was observed early on in studies with patients who had metastatic disease, especially those who had been treated with concomitant antrhracycline and trastuzumab. This led to subsequent adjuvant trials avoiding the concomitant use of trastuzumab and an antrhracycline. Proposed mechanisms of trastuzumab cardiac toxicity include the induction of immune-mediated destruction of cardiomyocytes, the requirement of HER2 signaling for myocyte survival and drug-drug interactions.[16-18]
With the use of stringent cardiac evaluation guidelines, the HERA trial observed a rate of 1.73% of New York Heart Association class III or IV congestive heart failure (CHF), while that observed in the NSABP-31 trial was 4.1%. The lower rate of severe CHF observed in the HERA trial may reflect the longer time allowed for the myocardium to recover from antrhracyclines before the initiation of trastuzumab. Conversely the higher rate observed in the NSABP-31 trial could be explained by the concomitant use of taxanes, which may have enhanced the trastuzumab-induced cardiac toxicity.
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