The clinical development of trastuzumab (Herceptin) for the treatment of HER2-overexpressing breast cancer has been perhaps the most important recent advance in the management of metastatic breast cancer. In their rigorous and comprehensive review, Emens and Davidson highlight the important trials that resulted in the US Food and Drug Administration (FDA) approval of trastuzumab, discuss combination chemotherapy options with trastuzumab, and preview promising future strategies for combining trastuzumab with other targeted biologic agents.
With many agents demonstrating potentially additive or synergistic antitumor activity with trastuzumab, clinicians and patients now have several options for combination regimens. The pivotal trial demonstrating the superiority of a trastuzumab/chemotherapy combination over chemotherapy alone involved trastuzumab in combination with paclitaxel. Since then, a variety of other cytotoxic agents have proven effective in combination with trastuzumab. In multiple phase II trials, useful trastuzumab/chemotherapy doublets have included those with vinorelbine (Navelbine) and gemcitabine (Gemzar).[2-4]
A recently reported randomized trial comparing docetaxel (Taxotere) alone to the combination of docetaxel and trastuzumab again demonstrated the superiority of the doublet. In this trial, the median survival in the trastuzumab/docetaxel arm was 27 months compared to 18 months in the docetaxel-alone arm. This result is consistent with the advantage gained by the addition of trastuzumab to paclitaxel. The results of this trial and the recently reported Tax 311 trial (which demonstrated a survival benefit with docetaxel over paclitaxel in the firstline treatment of metastatic breast cancer), suggest that docetaxel/ trastuzumab is perhaps superior to the FDA-approved standard of paclitaxel/ trastuzumab. However, the recently completed Cancer and Leukemia Group B (CALGB) 9840 study comparing weekly vs every-3-week scheduling of paclitaxel with trastuzumab for HER2 overexpressors provides additional information on the optimal scheduling of paclitaxel/trastuzumab.
More recently, clinical studies have exploited the preclinical observation of the synergistic effects of platinum salts with trastuzumab. The authors describe the recently reported results of the phase III trial by Robert et al comparing the triplet combination of carboplatin (Paraplatin), paclitaxel, and trastuzumab to paclitaxel/trastuzumab.[ 7] The triplet was associated with an improved overall response rate and time to progression. This advantage was particularly striking in patients with tumors that were 3+ on immunohistochemistry. As with paclitaxel/ trastuzumab, the combination of carboplatin, paclitaxel, and trastuzumab may be more efficacious and less toxic if given weekly rather than every 3 weeks.
An important study by Rowland et al was reported at the American Society of Clinical Oncology meeting in 2003. In this randomized phase II trial comparing the safety and tolerability of paclitaxel, carboplatin, and trastuzumab administered every 3 weeks vs every week, a significant reduction in both hematologic and nonhematologic toxicity was seen with the weekly schedule. The substitution of paclitaxel for its novel nanoparticle formulation Abraxane used in combination with carboplatin and trastuzumab is currently under investigation at our institution.
Toxicity and Treatment Duration
Emens and Davidson succinctly review the cardiac toxicity associated with trastuzumab. In the pivotal trial of trastuzumab in combination with chemotherapy, patients treated with concurrent anthracyclines and trastuzumab experienced cardiac dysfunction at a rate of 27% compared with a rate of 8% in patients treated with the anthracycline combination alone. A modestly increased incidence of cardiac dysfunction was also seen in patients treated with paclitaxel plus trastuzumab vs those treated with paclitaxel alone (13% vs 1%). The significant cardiac toxicity associated with anthracycline/trastuzumab combinations precludes the use of such combinations in clinical practice. Substituting liposomal doxorubicin (Doxil) or epirubicin (Ellence) for standard doxorubicin are promising experimental approaches.[10,11]
The duration of trastuzumab therapy for metastatic disease remains controversial. All of the registration trials of combination chemotherapy with trastuzumab continued the drug as monotherapy until disease progression. However, there are few data guiding oncologists as to what to do at the time of disease progression. Indeed, most oncologists continue trastuzumab, adding a different cytotoxic agent at the time of disease progression. The prolonged use of trastuzumab has been demonstrated to be safe and well tolerated. However, the efficacy of this approach remains to be proven in a controlled study. An ongoing trial at M. D. Anderson Cancer Center with the Southwest Oncology Group, randomizing patients who progress on taxane/trastuzumab combinations to vinorelbine alone or vinorelbine plus trastuzumab, should help clarify this issue. An additional trial in development by the US Oncology group will address the same question but will utilize gemcitabine instead of vinorelbine.
The marked improvement in survival associated with the addition of trastuzumab to cytotoxic agents in HER2-overexpressing metastatic breast cancer, has motivated several studies investigating the role of trastuzumab in the adjuvant setting. Emens and Davidson include a table that clearly summarizes these ongoing trials.
It is important to note that almost all of these adjuvant trials use conventional 3-weekly dosing of doxorubicin/ cyclophosphamide (Cytoxan, Neosar). With the results of CALGB 9741 demonstrating a significant survival advantage using dose-dense 2-weekly treatment (with growth factor support) over standard 3-weekly treatment, many of our patients are reluctant to enroll in these protocols, because they do not wish to forgo the potential survival benefit afforded by dose-dense therapy. Consideration should be given to amending these protocols so that patients choosing a dose-dense strategy may be included.
Targeting the HER-2 transmembrane glycoprotein receptor has been a highly successful strategy in the treatment of metastatic breast cancer. As the complex molecular pathways driving breast cancer oncogenesis are further elucidated, additional targets continue to be realized. Preclinical data showing the synergistic inhibitory effect of gefitinib (Iressa) and trastuzumab has resulted in the development of an Eastern Cooperative Oncology Group phase II trial testing this combination. Pan-erbB inhibition with CI-1033 is another promising approach.
The antivascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin), in combination with irinotecan (Camptosar)-based chemotherapy, has recently been shown to improve survival in patients with metastatic colorectal cancer. This agent will soon be FDA-approved for the treatment of metastatic colorectal cancer. As VEGF expression is increased in HER2-overexpressing breast cancer cells, trials exploring dual therapy with trastuzumab and bevacizumab are anticipated.
The continued discovery of therapies targeted toward HER2-signaling pathways promises to improve the lives of these patients. Combinations of these agents used in a rational manner may herald a bright future for the treatment of HER2-overexpressing breast cancer.
Financial Disclosure: Dr. Seidman receives research support from Pfizer, and is a consultant for and member of the speakers’ bureaus of Eli Lilly, Aventis, Bristol-Myers Squibb, and Genentech.
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