Comparative analysis between the HER2 status in primary breast cancer tissue and the detection of isolated tumor cells in the bone marrow

The presence of isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients is an independent prognostic parameter, indicating hematogenous tumor cell dissemination. While the HER2 status of breast cancer tissue has predictive value for the efficacy of different therapies, its prognostic relevance is controversial. To investigate the relationship between HER2 and ITC-BM, we retrospectively analyzed tumor tissues of 327 patients who underwent bone marrow aspiration at primary diagnosis or during the disease-free interval. Screening for ITC-BM was performed immunocytochemically, using the anti-cytokeratin antibody A45 B/B3. HER2 was determined by immunohistochemistry (IHC) with the antibody CB 11 (n=277) and by fluorescence in situ hybridization (FISH, PathVision, Vysis, n=206). ITC-BM were found in 83 of 327 patients (25.4%), with a median of 2.0 per 2x10(6) mononuclear cells. HER2 positivity (2+/3+) was demonstrated in 18.8% of the tumors, amplification by FISH in 56 of 206 cases (27.2%). Established pathological parameters, such as tumor size (p=0.15), lymph node status (p=0.93) and HER2 did not predict the presence of ITC-BM. After a median follow-up of 49 months (1-255), the presence of ITC-BM was a significant prognostic factor for distant disease free and overall survival, as well in univariate (log-rank- test, p=0.024) as in multivariate analysis (cox-regression, p=0.033). This also was confirmed in subgroups of patients by adjuvant treatment. Only patients with IHC 3+ tumors had a shortened overall survival, whereas 2+/3+ results predicted reduced disease free survival (p=0.013) and local recurrence (p=0.003). The detection of ITC-BM is superior in predicting overall survival, compared to the HER2 status of the primary tumor. The direct identification of HER2 on ITC-BM is the aim of ongoing research, potentially synergizing the prognostic relevance of ITC-BM and the predictive value of the HER2 status.