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Adjuvant trastuzumab in breast cancer: more questions than answers?
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The FDA recently approved trastuzumab, a humanized monoclonal antibody targeted against the HER2 receptor, as part of a treatment regimen containing doxorubicin, cyclophosphamide and paclitaxel for the adjuvant treatment of patients with HER2–overexpressing, node-positive breast cancer. Despite the data supporting this indication, many questions remain regarding the adjuvant use of trastuzumab in patients with breast cancer.
Five major clinical trials have evaluated trastuzumab (Herceptin, Genentech) use in the adjuvant setting for breast cancer. Important similarities exist within these trials. All of these studies included treatment of both node-positive patients as well as high-risk node-negative patients, albeit the numbers of patients in each trial differs. Also, these trials have demonstrated statistically superior disease-free survival with trastuzumab compared with regimens without trastuzumab. All of the trials, with the exception of the Finland Herceptin (FinHer) study, have also shown statistically improved overall survival, but also more cardiotoxicity in patients receiving trastuzumab.
The differences between these trials spotlight what is unclear regarding the use of trastuzumab in this setting. Currently, the optimal schedule for adjuvant trastuzumab therapy for early stage breast cancer is unknown. In the Herceptin Adjuvant (HERA) trial, trastuzumab was given after the administration of chemotherapy. In the North Central Cancer Treatment Group (NCCTG) N9831 trial, there were three arms that were compared: two with trastuzumab and one without. In one of the trastuzumab arms the biologic agents was administered concurrently with paclitaxel, and in the other arm the agent was administered sequentially after chemotherapy was completed.
Although the sequential arm of this study was not included in the published manuscript, the data relating to this arm were presented at the 41st Annual Meeting of the American Society of Clinical Oncology in 2005 and are available for comparison. The unpublished analysis suggests that trastuzumab administered after chemotherapy may be less effective than trastuzumab administered with chemotherapy. In the remainder of the adjuvant trials, trastuzumab was administered concomitantly with at least some of the chemotherapy. More research is needed at this time to fully determine the optimal timing of administration.
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Different regimens
The regimens used in each of the trials also differed. The patients in the B-31/N9831 studies received four cycles of doxorubicin plus cyclophosphamide (AC) followed by 12 weeks of paclitaxel (given either weekly or every 3 weeks) with or without trastuzumab. Patients in the BCIRG 006 study received four cycles of AC followed by four cycles of docetaxel (Taxotere, Sanofi Aventis), with or without trastuzumab. In these three trials, the trastuzumab was continued for 52 weeks.
The BCIRG 006 study also included a third arm in which patients received docetaxel, carboplatin and trastuzumab for six cycles. Although this nonanthracycline arm had an improved disease-free survival and overall survival and similar cardiotoxicity compared with the control arm, this regimen is considered controversial and further follow-up is needed to determine its place in the adjuvant treatment of HER2–positive breast cancer.
Patients in the FinHer study were assigned nine weeks of trastuzumab during chemotherapy, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide. This study was controversial for many reasons, including the fact that the half-life of trastuzumab is long (28.5 days after repeated dosing) and substantial plasma concentrations of trastuzumab remain during the epirubicin portion of the regimen, predisposing patients to a higher risk for cardiotoxicity. Nonetheless, the benefits of trastuzumab demonstrated in this trial are similar to that seen in the other trials, and there were no cases of cardiac events or decreases in left ventricular ejection fraction in the trastuzumab arms of the FinHer study to date with a median follow-up of more than three years.
The optimal duration of adjuvant trastuzumab therapy is also unknown. One year of trastuzumab therapy (either during or after chemotherapy) is currently supported by the HERA trial, BCIRG 006, as well as the combined analysis of the B-31/N9831 trials. Results from a third arm of the HERA trial are expected to be released in 2008, and will also include patients treated with a total of two years of trastuzumab. Interestingly, data from the FinHer study showed improved disease-free survival with only nine weeks of trastuzumab therapy and another neoadjuvant trastuzumab trial with six months of therapy has also demonstrated benefit compared with a nontrastuzumab regimen. Other ongoing trials are investigating this question and the results from these analyses are eagerly awaited.
Some debate exists regarding trastuzumab use in patients with node-negative breast cancer. The FDA’s recent approval of trastuzumab for adjuvant therapy includes only patients with node-positive disease due to the fact that the trials used to support this indication included only 5.7% of patients with node-negative disease (B-31/N9831). Despite this indication, there are sufficient data to support clinical benefit in the node-negative population when considering the HERA, FinHer and BCIRG studies. Although the magnitude of benefit may be smaller in this group than in the node-positive group, the risks for recurrence and death and the impact of trastuzumab therapy should be considered for each individual patient.
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The addition of trastuzumab to these adjuvant regimens is not without risks. Throughout most of these trials, there were consistently higher rates of cardiac events, predominately manifested as heart failure. Interestingly, patients in the FinHer study did not have an increased rate of heart failure. This may be due to a number of different factors, possibly including a lower cumulative dose of anthracycline and a shorter duration of therapy. Many of the cases of heart failure experienced in the metastatic setting related to trastuzumab are reversible with appropriate medical management despite continued exposure to trastuzumab. Obviously, longer follow-up is required to determine the overall nature of the cardiotoxicity experienced with the addition of trastuzumab to these adjuvant regimens, but the overall rates are acceptable in light of the overwhelming benefits.
Technological advances such as this come with significant upfront costs. However, the cost-avoidance that may be experienced with preventing a case of metastatic disease must be considered and weighed against the initial costs of therapy. Pharmacoeconomic analyses encompassing these types of issues are beginning to be published, and appear to indicate a relatively acceptable “cost” of adding trastuzumab compared with other benchmarks in the field. The methodology by which these analyses are accomplished is controversial and fraught with bias. However, in all countries, including those with and without nationalized health care, this discussion is relevant as health care resources are ultimately limited and difficult choices will eventually have to be made.
Other sources of debate exist regarding the use of trastuzumab in early stage breast cancer, including the optimal method to determine HER2 status, sequence of administration both with the anthracycline and/or chemotherapy, and the use of trastuzumab with chemotherapy for primary treatment (neoadjuvant) of early stage or locally advanced breast cancers. Although some information is available to begin to address these questions, results from ongoing studies and further follow-up of the adjuvant trials are required to accurately determine trastuzumab’s benefits. The sequelae of cardiac events, together with the dramatic benefits seen in these adjuvant trials, need to be appropriately analyzed when considering the most clinically appropriate and cost-effective regimen in a world with finite medical resources.
For more information:
- Chad M. Barnett, PharmD, BCOP, is an Oncologist Clinical Pharmacy Specialist and Laura Boehnke Michaud, PharmD, BCOP, is Manager of Clinical Pharmacy Services at The University of Texas MD Anderson Cancer Center.
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