Identification of patients at high risk of recurrent disease development by detection of HER2-positive disseminated tumor cells in bone marrow of patients with HER2-negative tumors.

Abstract

633 Background: A subpopulation of patients with HER2-negative tumors benefit from HER2 therapy. HER2 expression can be discordant between primary tumors and metastases. We have examined the bone marrow (BM) of early stage breast cancer patients for HER2-expression by disseminated tumor cells (DTCs) and the association with disease recurrence. Methods: BM was collected from clinical stage II-III breast cancer prior to treatment between 2007-2011. Gene expression of ERBB2 was determined by multiplex PCR (Fluidigm Biomark [FB]). Positive expression was defined as at least 1.4 fold above a pool of normal BM. Expression was confirmed by single gene PCR and Nanostring nCounter (NC) assays. Cox proportional model was used to estimate hazard ratios (HR). Results: BM from 74 patients was analyzed. Median follow-up was 3.4 years (range 8 months-84 months). 24% of the patients developed metastatic disease. For ERBB2 detection, there was excellent correlation between NC and the FB assays (kappa=0.87, 95% CI [0.62, 1.00]). Nine patients expressed ERBB2 in their BM. Five of the 9 patients had Her2-positive tumors and were treated with trastuzumab. One of 5 (20%) of these patients relapsed whereas 75% (3 of 4) of the patients with HER2-negative tumors but ERBB2-positive DTCs relapsed. Patients with HER2-negative tumors/ERBB2-positive BM were found to have a greater hazard of recurrence than patients with HER2-negative tumors/ERBB2-negative BM or ERBB2-positive DTCs treated with trastuzumab (p=.0069; Table). Those patients with ERBB2-positive BM who did not receive trastuzumab had a decreased disease free survival (p=.016). Conclusions: We have found discordant expression of HER2/ERBB2 in tumors and BM of stage II-III breast cancer patients. The presence of ERBB2 expressing DTCs in patients with HER2-negative tumors identifies a subset of patients at increased risk of recurrence who may benefit from targeted HER2-therapy. [Table: see text] .