Protection of adjuvant trastuzumab in sites of early relapses.

Abstract

619 Background: About 50% of patients with HER2-positive breast tumors benefit from adjuvant trastuzumab therapy, but the highest benefit, as indicated by the HERA trial results, is restricted to the first 18 months from the start of treatment. Methods: The GHEA Italian multicentric observational study of 1021 patients treated with adjuvant trastuzumab according to HERA protocol between 2006 and 2008 registered 121 (11.8) events including distant, local, contralateral and second tumors according to anatomical sites in the first 18 months from the start of treatment (early relapses) and thereafter (late relapses). Based on an expected 50% reduction of early metastases at any site, the number of metastases per site was calculated and compared with the observed data to yield a percent trastuzumab protection value at each single site. Results: Early relapses comprised 49 (4.8%) events and late relapses represented 72 (7%) events. The frequency of late metastases in the different sites was similar to that observed for HER2-positive tumors before the trastuzumab era, while the frequency of early relapses followed a different pattern, i.e., liver, lung and lymph node relapses were less frequent in early than in late relapses (10.5% vs 18.6%, 10.5% vs 23.2% and 2.6% vs 9.3%, respectively), while bone and CNS metastatic disease was more frequent in early than in late relapses (36.9% vs 18.6% and 23.7% vs 14%, respectively). No changes in frequency of multiple metastases was observed (15.8% vs 16.3%). Trastuzumab did not protect against bone and CNS metastases (0% and 10% respectively), whereas a protection of 71.4% for liver, 75% for lung, 85.6% for lymph nodes was observed. Conclusions: In addition to the well-known CNS relapses due to the failure of the antibody to pass the blood-brain barrier, also bone relapses were found to be resistant. This may be due to a bone microenvironment inadequate for antibody activity or escape of bone metastases from HER2 targeting. Excluding the two “resistant” sites, the protection by trastuzumab was more than 70% in all other distant metastases. Supported by AIRC and Roche.