Long-term Follow-up Data from Pivotal Studies of Adjuvant Trastuzumab in Early Breast Cancer

Targ Oncol (2016) 11:579–591 DOI 10.1007/s11523-016-0438-5 REVIEW ARTICLE Long-term Follow-up Data from Pivotal Studies of Adjuvant Trastuzumab in Early Breast Cancer Hartmut Kristeleit 1 & Marina Parton 2 & Mark Beresford 3,4 & Iain R. Macpherson 5 & Rajan Sharma 6 & Loren Lazarus 7 & Muireann Kelleher 6 Published online: 16 May 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract The addition of adjuvant trastuzumab therapy for 1 year to standard chemotherapy significantly improved disease-free survival and overall survival versus chemotherapy alone in a number of pivotal early breast cancer studies. Here we review long-term follow-up data on the efficacy, cardiac safety, and general safety of trastuzumab in these pivotal studies. We also evaluate ongoing phase II/III adjuvant trials with newer HER2-targeted agents and the efficacy and safety of the recently developed subcutaneous (SC) formulation of trastuzumab in early breast cancer. Long-term follow-up data confirm the significant survival benefit afforded by the addition of trastuzumab to chemotherapy in patients with HER2positive disease, with an acceptable safety profile. Long-term cardiac safety data suggest that the incidence of cardiac adverse events is maintained at a relatively low level with continued follow-up. At this present time, 1 year of trastuzumab treatment remains the standard of care in HER2-positive early breast cancer. Future adjuvant trastuzumab treatment strategies should focus on reducing cardiotoxicity, particularly in elderly pa- * Hartmut Kristeleit 1 Guy’s and St Thomas’ NHS Foundation Trust, London, UK 2 Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London, UK 3 Royal United Hospital, Bath, UK 4 Bath University, Bath, UK 5 Beatson West of Scotland Cancer Centre, Glasgow, UK 6 St George’s Hospital NHS Trust, London, UK 7 Roche Products Ltd, Welwyn Garden City, UK tients, by identifying potential predictive biomarkers of cardiac dysfunction. Clinicians must also decide whether to omit trastuzumab in women who would achieve little benefit from treatment to avoid cardiotoxicity. Key Points We reviewed long-term efficacy and safety data from a number of pivotal studies that reported significant survival benefits with the addition of 1 year of adjuvant trastuzumab therapy to standard chemotherapy in patients with HER2-positive early breast cancer. The significant survival benefits seen with trastuzumab were maintained with long-term follow-up, with an acceptable safety profile including a relatively low level of cardiac adverse events. Reducing cardiotoxicity should be a key factor of future adjuvant trastuzumab treatment strategies, particularly in the elderly and in those who would achieve little benefit from treatment. 1 Introduction Thirty years have passed since the discovery of the neu oncogene and subsequent identification of the human epidermal growth factor receptor 2 (HER2) transmembrane receptor tyrosine kinase that it encodes [1, 2]. Overexpression of HER2 was quickly recognized to confer poor prognosis in women with metastatic breast cancer [3]. This discovery led rapidly to the development of trastuzumab (Herceptin®, Genentech, South San Francisco, CA, USA), a humanized HER2targeting monoclonal antibody, and a clinical trials program ultimately leading to a license for the treatment of metastatic breast cancer overexpressing HER2 [4–6]. 580 The success of trastuzumab in the metastatic setting generated much optimism for this agent in the adjuvant setting. Approximately 90 % of breast cancer is diagnosed in the early stages of the disease, and it is estimated that HER2-positive tumors account for 15−20 % of invasive breast cancers [7]. Prior to the development of trastuzumab, women with HER2-positive disease faced a worse prognosis than those with HER2-negative disease, including shorter time to relapse, a higher incidence of metastasis, and reduced survival [8]. Subsequently, a number of early breast cancer studies showed that the addition of adjuvant trastuzumab therapy for 1 year to standard chemotherapy significantly improved disease-free survival (DFS) and overall survival (OS) versus chemotherapy alone, with an acceptable safety profile [9–13]. Here we review long-term follow-up data on the efficacy and safety of trastuzumab in these pivotal studies. We also evaluate ongoing adjuvant trials with newer HER2-targeted agents in early breast cancer, as well as the recently developed subcutaneous (SC) formulation of trastuzumab. 2 Adjuvant Trastuzumab: Long-term Efficacy Data Long-term follow-up data from a number of studies in the early breast cancer setting confirm the significant survival benefit afforded by the addition of trastuzumab to chemotherapy in patients with HER2-positive disease. 2.1 HERA Study The randomized, phase III HERA study (HERceptin Adjuvant) assessed the efficacy of trastuzumab in the adjuvant setting, as well as testing two durations of trastuzumab treatment. The study compared 1 or 2 years of trastuzumab with observation alone in 5102 women with HER2-positive early-stage invasive breast cancer who had completed at least four cycles of neoadjuvant or adjuvant chemotherapy. In patients receiving trastuzumab for 1 year, 127 DFS events were reported versus 220 in the observation group (hazard ratio [HR] 0.54, 95 % confidence interval [CI] 0.43−0.67; p < 0.0001) after a median follow-up of 1 year, corresponding to an 8.4 % absolute benefit in 2-year DFS rate (85.8 % vs 77.4 %, respectively) [9]. With further maturity, this DFS advantage was maintained (HR 0.76, 95 % CI 0.67−0.86; p < 0.0001) and resulted in a significant OS benefit (HR 0.76, 95 % CI 0.65−0.88; p = 0.0005) after a median follow-up of 8 years and crossover of 884 patients (52 %) from observation to trastuzumab (Fig. 1) [14]. Comparison of the efficacy of trastuzumab in patients receiving 2 years versus 1 year of treatment was assessed in a Targ Oncol (2016) 11:579–591 landmark analysis including 3105 patients who were diseasefree 12 months after randomization. At the clinical cutoff date for this analysis, 367 DFS events were recorded in both the 2-year trastuzumab group and the 1-year trastuzumab group, with no significant between-group DFS difference noted (HR 0.99, 95 % CI 0.85−1.14; p = 0.86) [14]. Thus, 2 years of trastuzumab treatment following adjuvant chemotherapy was not more effective than 1 year of treatment. Ten-year follow-up data from HERA will be published in the coming months. 2.2 NSABP B-31 and NCCTG N9831 Combined Data Two studies of adjuvant chemotherapy with or without trastuzumab in women with surgically removed HER2positive breast cancer were sponsored by The National Cancer Institute. The NSABP B-31 trial (National Surgical Adjuvant Breast and Bowel Project B-31) compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel every 3 weeks (group 1) with AC followed (...truncated)