Effect of cardiac dysfunction on treatment outcome in the Herceptin (trastuzumab) pivotal trial

Herceptin increases time to progression, response rate, and survival in combination with front-line chemotherapeutic agents in women with HER2-positive metastatic breast cancer. Herceptin has been associated with cardiac dysfunction (CD) reminiscent of the cardiomyopathy described with anthracycline administration. CD occurred at greatest frequency (28%) in patients simultaneously receiving an anthracycline compared with 7% in patients receiving an anthracycline alone. CD was less common and less severe in patients treated with Taxol (paclitaxel) plus Herceptin (11% vs 1% of patients receiving Taxol alone). The majority of patients with congestive heart failure (75%) improved with treatment, and 77% continued to receive Taxol for a median of 25 weeks. Methods: We performed an exploratory analysis to evaluate the effect of CD on treatment outcomes for 469 patients in the pivotal Herceptin combination chemotherapy trial. Results: If time to treatment failure is defined as the time to disease progression or CD, addition of Herceptin to chemotherapy produced an improvement of 6.5 months (95% CI, 5.8, 7.0) versus 4.6 months (4.4, 5.3) for chemotherapy alone. Similar improvements were seen in the anthracycline-cyclophosphamide (AC) and Taxol substrata-6.6 months (5.5, 7.3) for patients treated with Herceptin plus AC versus 6.0 months (4.8, 6.9) for patients treated with AC alone and 6.6 months (5.3, 7.1) for patients treated with Herceptin plus Taxol versus 2.8 months (2.0, 4.3) for patients treated with Taxol alone. Similarly, if CD-free survival is defined as the time to symptomatic congestive heart failure (New York Heart Association grade III or IV) or death, addition of Herceptin to chemotherapy produced an improvement of 22.2 months (17.7, 25.4) versus 20.0 months (16.5, 24.0) for chemotherapy alone. Similar trends were seen in both the AC and Taxol substrata-22.3 months (17.1, 26.3) for Herceptin plus AC versus 20.9 months (16.6, 25.7) for AC alone and 22.1 months (16.8, 28.6) for Herceptin plus Taxol versus 18.4 months (12.7, 24.4) for Taxol alone. Conclusion: Improvements in treatment outcomes associated with Herceptin therapy were seen despite the development of CD. These results suggest that risk/benefit considerations in the metastatic disease selling favor the use of Herceptin plus Taxol.