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Originally published as JCO Early Release 10.1200/JCO.2009.23.8873 on August 17 2009 © 2009 American Society of Clinical Oncology.
Trastuzumab Beyond Disease Progression: Case Closed?University Medical School of Turin, Turin, Italy
Division of Medical Oncology, Institute for Cancer Research and Treatment, Candiolo, Italy Von Minckwitz et al1 reported in Journal of Clinical Oncology the first and only, to our knowledge, partially successful attempt at studying prospectively the value of continuing trastuzumab in addition to chemotherapy in patients with human epidermal growth factor receptor 2 (HER2) –positive advanced breast cancer in whom a previous trastuzumab-containing line of treatment had failed. First of all, we would like to congratulate the authors on enrolling a sufficient number of patients to draw statistically significant conclusions about this controversial topic in breast oncology, a field in which others had previously failed to do so. However, we believe that the results reported by von Minckwitz et al leave open two main questions. First, were the 156 patients enrolled onto this trial representative of the population of patients in whom a trastuzumab-based regimen has failed and for whom we have to choose the most appropriate salvage treatment in our daily practice? Second, how will these results fit into the current scenario regarding management of HER2-positive disease? With respect to the first question, we must consider that the GBG (German Breast Group) 26 study was conducted within the framework of a diffuse belief that the best option for a patient in whom disease had progressed during initial trastuzumab-based therapy was the addition of a different cytostatic agent to this monoclonal antibody.2–5 Was this a possible reason for the slow accrual rate in the study by von Minckwitz et al1 (156 patients over 45 months at 64 participating institutions) before the randomized phase III study with lapatinib6 inflicted a coup the grace on the hope of enrolling the planned number of 482 patients? An average of 3.5 patients per month is a figure that was likely greatly surpassed by the number of patients seen at the participating institutions with progressive disease after an initial trastuzumab-based regimen during those 45 months who were not enrolled onto the trial. Difficulties in patient accrual and premature closure determined an imbalance in the median age of patients; those in the capecitabine-alone arm were 6.5 years older than those in the experimental arm. This issue must be taken into account when interpreting the encouraging trend toward improved overall survival. Furthermore, with regard to the above mentioned framework, lack of centralized review of tumor responses and lack of a clear indication of timing of response assessments suggest two possible biases in the observed results. One is the overestimation of tumor responses in patients in the experimental arm. The other is that patients receiving capecitabine alone, who were also older than patients in the experimental arm, might have been observed more closely for tumor progression by investigators because of a concern that these patients were receiving suboptimal treatment. This might have resulted in an artificially shorter time to progression in the capecitabine-alone arm. With respect to the second question, when the GBG 26 study was conceived, the full clinical exploitation of the only active anti-HER2 agent available was a reasonable and biologically justified approach,7 but it was also a contingency in the absence of alternative targeting agents. The scenario is now rapidly changing, with the availability of newer compounds that are active against HER2-positive cancer cells, either untreated or resistant to trastuzumab.8 An expanding body of knowledge suggests that several molecular mediators of resistance to anti-HER2 agents are present in tumors and, in the next future, could be routinely identified with prospectively validated tests.9–11 In conclusion, we believe that the results of this study are encouraging because they suggest that there may be a subset of patients with HER2-positive advanced breast cancer for whom trastuzumab can still be exploited beyond disease progression. However, because of methodologic limitations and the changing scenario of the management of HER2-positive disease, we argue that this policy should be adopted across the board in clinical practice on the basis of the GBG 26 study results. In an era in which the therapeutic arsenal to target HER2 is expanding considerably, we should intensify our efforts to establish, by well-designed clinical trials, a rationale for using each specific agent or combination in molecularly defined subsets of patients. AUTHORS'; DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Massimo Aglietta, GlaxoSmithKline Expert Testimony: None Other Remuneration: None REFERENCES
1. von Minckwitz G, du Bois A, Schimdt M, et al: Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: A German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 27:1999–2006, 2009. 2. Tanchiu E, Kaufman PA, Paik S, et al: registHER: A prospective, longitudinal cohort study of women with HER2 positive metastatic breast cancer. J Clin Oncol 23:46s; 2005 (suppl) abstr 670. 3. Tripathy D, Slamon DJ, Cobleigh M, et al: Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22:1063–1070, 2004. 4. Fountzilas G, Razis E, Tsavdaridis D, et al: Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: A retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin Breast Cancer 4:120–125, 2003.[Medline] 5. Gelmon KA, Mackey J, Verma S, et al: Use of trastuzumab beyond disease progression: Observations from a retrospective review of case histories. Clin Breast Cancer 5:52–58, 2004.[Medline] 6. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743, 2006. 7. Pegram MD, Konecny GE, O'Callaghan C, et al: Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 96:739–749, 2004. 8. Ross JS, Slodkowska EA, Symmans WF, et al: The HER-2 receptor and breast cancer: Ten years of targeted anti–HER-2 therapy and personalized medicine. Oncologist 14:320–368, 2009. 9. Valabrega G, Montemurro F, Aglietta M: Trastuzumab: Mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 18:977–984, 2007. 10. Nagata Y, Lan KH, Zhou X, et al: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127, 2004.[CrossRef][Medline] 11. Scaltriti M, Rojo F, Ocana A, et al: Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99:628–638, 2007.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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