ORLANDO-Interim findings from two large randomized phase III studies-a North American joint analysis and an international trial- have changed the standard of care for women with early invasive HER2- positive breast cancer. Trastuzumab(Drug information on trastuzumab) (Herceptin) plus standard adjuvant chemotherapy yielded dramatic responses, cutting the risk of locoregional and distant recurrence in half and significantly improving overall survival, with acceptable cardiac tolerability. The unprecedented findings were reported in a late-breaking scientific symposium at ASCO. US and International Trials The joint analysis combined data from 3,351 patients in two NCI-sponsored trials; NSABP (National Surgical Adjuvant Breast and Bowel Project)-B31 and NCCTG (North Central Cancer Treatment Group)- N9831; each study evaluated doxorubicin(Drug information on doxorubicin) (Adriamycin) and cyclophosphamide(Drug information on cyclophosphamide) (AC), followed by paclitaxel(Drug information on paclitaxel) (Taxol), with or without trastuzumab, using different schedules of paclitaxel. HERA (HERceptin Adjuvant), a 39-country, 5,090-patient study, assessed Herceptin vs observation following a wide range of primary chemotherapy options, and radiotherapy as applicable; it is one of the largest studies ever conducted in patients with breast cancer. Trastuzumab has shown benefit but poses a small cardiac risk, and LVEF (left ventricular ejection fraction) was monitored in both the US and international trials, with predetermined trastuzumab-stopping rules applied. Results Publicized Early Efficacy results of the NSABP-B31/ NCCTG-N9831 joint analysis and of HERA were made public in April, and both trials were stopped with about 2- year and 1-year median follow-up, respectively, because they had met their efficacy endpoints, with striking outcomes (Table 1). NSABP/NCCTG Joint Analysis NSABP-B31 and NCCTG-N9831 were led by NSABP and NCCTG, with CALGB (Cancer and Leukemia Group B), ECOG (Eastern Cooperative Oncology Group), and SWOG (Southwest Oncology Group). Because the two trial designs were so similar, the FDA agreed the data could be combined for a joint analysis. The study arm for the joint analysis was AC followed by paclitaxel plus trastuzumab, and the control arm was AC followed only by paclitaxel. The NCCTG-N9831 had three study arms, one of which included Herceptin given sequentially with paclitaxel and so was excluded from the joint analysis. NSABP study chair Edward Romond, MD, associate professor of medicine at the University of Kentucky College of Medicine, Lexington, presented the joint-analysis findings. NCCTG chair Edith Perez, MD, presented further analysis of NCCTGN9831, and in a poster presentation she discussed interim cardiac safety data from that trial (abstract 556). Dr. Perez is professor of medicine, Mayo Medical School, director, Clinical Investigations, and director of the Breast Cancer Program, in the division of hematology/oncology at the Mayo Clinic, Jacksonville, Florida. Standard-Changing Findings Trastuzumab was associated with a 52% reduction in overall risk of local recurrence at 3 years. Absolute reduction in risk of recurrence by Kaplan-Meier analysis was 12% with trastuzumab at 3 years and 18% at 4 years. Time to first distant recurrence was also assessed, as a sur- rogate for overall survival, and showed trastuzumab plus chemotherapy reduced overall probability of distant metastases by 53% at 3 years. Estimated absolute reduction in risk with trastuzumab was 9% at 3 years and 16% at 4 years. At a median overall follow-up of 2 years, trastuzumab conferred a 33% reduction in mortality. Estimated absolute reduction in risk of death with trastuzumab was 2.5% at 3 years and 4.8% at 4 years. "We have changed the standard of care," Dr. Perez told ONI. "Patients following resection should have chemotherapy plus Herceptin to minimize the risk that cancer could return." Acceptable Cardiac Risk Although chemotherapy of the type given in the NCCTG and NSABP trials carries a congestive heart failure (CHF) risk less than 1%, in the joint analysis risk of CHF in women receiving chemotherapy plus trastuzumab was increased by 3% to 4%. In the separate cardiac safety analysis of NCCTGN9831, a 2.2% greater incidence of cardiac events vs control was seen with sequential therapy and a 3.3% increased incidence was seen with concurrent therapy, but at this point in the analysis the confidence intervals overlap, Dr. Perez said. Drs. Romond and Perez emphasized the importance of cardiac monitoring in all patients if trastuzumab is to be used in this regimen in the adjuvant setting. However, in her analysis of NCCTG-N9831, Dr. Perez commented that although "adding trastuzumab to paclitaxel in the adjuvant setting resulted in an increase in cardiac toxicity, this increase remains less than the threshold of 4% [above that in the non-trastuzumab regimen], indicating acceptable cardiac tolerability." She noted that a subset of patients will be studied to evaluate the potential role of circulating biomarkers for predicting or managing adverse cardiac effects of trastuzumab. HERA Study HERA evaluated duration of trastuzumab treatment in women with early-stage HER2-positive invasive breast cancer, most of whom had received an anthracycline but not a taxane. About one-third were node-neg ative. Conducted by investigators from Roche and the Breast International Group (BIG), it evaluated adjuvant Herceptin given every 3 weeks for 12 or 24 months vs observation following standard adjuvant chemotherapy given before or after surgery. HERA accrued 5,090 women at 478 centers in 39 countries who had centrally confirmed HER2-positive invasive breast cancer and had undergone surgery with neoadjuvant chemotherapy, with or without radiotherapy. The findings were presented by lead investigator and chair of BIG Martine J. Piccart-Gebhart, MD, PhD, associate professor of oncology at the Uni- versité Libre de Bruxelles and head of the department of medicine at the Jules Bordet Institute, Brussels, Belgium. The interim analysis at 475 diseasefree survival events in 3,387 women compared Herceptin vs observation but not 12 months vs 24 months of therapy; these data are not mature but will become available later in the study. Dramatic Results Herceptin conferred a statistically significant improvement in diseasefree survival, with a 46% reduction in likelihood of recurrence (HR = 0.54, P < .0001), translating to an absolute improvement in 2-year disease-free survival of 8%. Relapse-free and distant disease-free survival results "were quite remarkable," Dr. Piccart-Gebhart reported, "with a 50% reduction in risk, translating again into an 8% 2- year reduction in risk" (P < .0001). The secondary endpoint of overall survival has not yet been reached, possibly owing to short follow-up, with 37 deaths in the observation group and 29 in the 12-month trastuzumab group. Results regarding optimal duration of therapy (ie, 12-month vs 24-month trastuzumab) will be available in 2008. Low Incidence of CHF Incidence of CHF was 0.5% in the 12-month trastuzumab group vs 0 for patients randomized to observation. The HERA study has an external independent data monitoring committee (IDMC) that regularly reviews safety data. No safety concerns were raised by the IDMC, but patients will be followed for side effects.