Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies.

With the exception of endocrine therapy, no other systemic treatment of patients with breast cancer has reached such a magnitude of beneficial effect as trastuzumab. This targeted agent (monoclonal antibody) is associated with a significant improvement in both disease-free (DFS) and overall survival (OS) in women with HER-2 positive breast cancer when given in combination with or in sequence to adjuvant chemotherapy. This has been confirmed in a recent Cochrane meta-analysis of randomized controlled trials (RCTs), including 6 adjuvant and 2 neoadjuvant studies (NSABP B-31, NCCTG N9831, BCIRG 006, HERA, FinHer, PACS-04, Buzdar and NOAH), with data collection until February 2010. Overall, mortality is reduced by one-third and the risk of relapse by 40%. Concerns regarding cardiac dysfunction are declining, with reports indicating its reversibility in most instances, however truly long term cardiac evaluation is still lacking. Hence, the benefit of trastuzumab could be challenged by cardiac toxicity, in lower-risk patients [T1a,b node-negative (N0) tumors] or those with increased cardiovascular risk (older women and patients with previous significant heart disease/suboptimal left ventricular ejection fraction [LVEF (<55%)], all of whom were largely excluded from the aforementioned adjuvant RCTs. These patient subgroups might warrant a specific approach, such as anti-HER2 treatment combined with just a taxane (avoiding anthracyclines) or with endocrine therapy. Reasonably large phase II trials aimed at exploring these more individualized regimens are underway in the US. The optimal duration of trastuzumab therapy remains unknown since the selection of the one year duration in the pivotal trials was arbitrary. The HERA trial showed that prolonging trastuzumab administration to two years does not confer additional advantage over one year. The PHARE trial compared 6 versus 12 months of trastuzumab and failed to show non-inferiority of the shorter treatment administration. At the present time, one year of adjuvant trastuzumab remains the standard-of-care until results from SOLD, Short-HER and PERSEPHONE consolidate or negate this finding. The route of trastuzumab administration has also been recently challenged. A subcutaneous formulation is being evaluated in several studies. The HannaH phase III trial compared the subcutaneous (SC) to the intravenous (IV) formulation of trastuzumab. The former was proven non-inferior to the latter, although the incidence of serious adverse events was slightly higher in the SC arm. The authors concluded that SC trastuzumab, administered at a fixed dose of 600mg over 5min, is a valid alternative option, with the potential for human and economic savings in clinical practice.