There is little that can be done to improve on this excellent review by Emensand Davidson. In particular, the section on the preclinical pharmacology of trastuzumab (Herceptin) provides a concise summary of the multiplicity of mechanisms attributable to this fascinating compound. One of those mechanisms- its immunomodulatory effect through antibody-dependent cell-mediated cytotoxicity-has led not only to clinical trials of interleukin-2 (Pro- leukin), as cited by the authors, but to other investigative approaches as well.
Our research group participated in trials of the Coley compound CPG 7909, an oligodeoxynucleotide, plus continued trastuzumab in patients with disease progression on trastuzumab, in the hope that the resultant increase in antibody-dependent cell-mediated cytotoxicity would reverse trastuzumab resistance. These studies are now being analyzed.
Another interesting investigational approach in this regard has been the development of vaccines targeted against HER2/neu. One such vaccine, developed by Corixa and Glaxo SmithKline, is now under study by our group and others in high-risk patients with HER2/neu-positive tumors after completion of adjuvant, non- trastuzumab-containing adjuvant therapies. Dr. Emens is an expert in this particular area but wisely chose not to give the reader more than just a tantalizing hint of the future of these approaches in the manuscript's concluding paragraph, so as not to detract from the paper's major focus on trastuzumab.
In the section on cardiotoxicity, two recent abstracts from the 2003 San Antonio Breast Cancer Symposium could have been included as interesting updates to the trastuzumab cardiotoxicity story. Most of the data cited by Emens and Davidson (other than the Eastern Cooperative Oncology Group trial) involved retrospective analyses, yet at San Antonio two important abstracts bearing on this issue were presented. In the abstract by Marty et al, six trastuzumab trials prospectively incorporating cardiac monitoring were presented, encom passing a total of 377 patients, of which 259 were receiving trastuzumab. In those trials, the rate of congestive cardiac failure was only 1.7%. In addition, 4.7% were found to have a left-ventricular ejection "event" (defined as a decline from baseline of ≥ 15% coupled with an absolute value to < 50%). That rate was only 1.9% for patients without prior anthracycline exposure but 11.6% for those with prior exposure.
Another important paper was the report on cardiotoxicity in an adjuvant trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP). As cited by Emens and Davidson, considerable concern was raised about potential cardiac complications in the ongoing trastuzumab adjuvant trials. This concern was raised by the 13% rate of cardiac toxicity in the pivotal trial with paclitaxel and trastuzumab vs only 1% in patients treated with paclitaxel alone. All the patients in that trial had previously received anthracycline adjuvant therapy, with trastuzumab being initiated, on average, about 20 months after completion of the anthracycline. In the adjuvant trials, trastuzumab is often initiated within weeks after the last dose of anthracyclines.
The new NSABP data contain both good and bad news. The good news is that the 3.5% difference in the rate of congestive cardiac failure between the trastuzumab-treated and control arms did not meet the predetermined guideline to stop the study. On the other hand, this rate and the additional 11.2% who discontinued trastuzumab therapy because of an asymptomatic decrease in left-ventricular ejection fraction are certainly higher than what this author would like to see in an adjuvant setting.
Another issue concerning the adjuvant trials is worthy of comment. The authors cited the important papers bearing on laboratory variability in reporting HER2/neu overexpression in both the NSABP and Intergroup adjuvant trials. The inclusion in those trials of a significant percentage of patients whose positive HER2 status could not be confirmed by expert central review could raise significant questions about interpreting the results of those trials in future intentto- treat analyses of efficacy. A comment by the authors regarding how the NSABP and Intergroup intend to deal with this problem would have been helpful to the reader.
Finally, one minor correction is also in order. In the section dealing with HER2/neu overexpression and response to trastuzumab in the firstline trastuzumab clinical trial published by Vogel et al, the authors correctly present a 7% response rate and 10% clinical benefit rate for patients with fluorescence in situ hybridization (FISH)-negative tumors. However, subsequent retesting of samples from the three patients in that trial who derived clinical benefit from trastuzumab and yet were thought to be FISH-negative revealed that two of the three were actually FISH-positive, leaving only one patient as a true single-copy overexpressor who responded to trastuzumab. Hopefully, more information about efficacy in this very rare subset might ultimately become available from the Genentech-sponsored HER FIRST clinical trial, which has already completed accrual.
In summary, this author was very favorably impressed with the erudite review by Emens and Davidson. I recommend it strongly to my colleagues.
Financial Disclosure: The author receives research support from, is a consultant for, and/or is a member of the speakers’ bureau of Amgen, Astra-Zeneca, Aventis, BCIRG, Biomira, Bristol, Celgene, Eli Lilly, Genentech, Glaxo, Novartis, NSABP, Ortho Biotech, Pharmacia, Pierre-Fabre, and Roche.
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