The HER2 status of disseminated tumor cells in the bone marrow of early breast cancer patients is independent from primary tumor and predicts higher risk of relapse

Abstract

Overexpression of the HER2-receptor in early breast cancer (EBC) patients is associated with aggressive tumor behavior. However, women suffering from HER2-positive EBC benefit from trastuzumab treatment. As the HER2 status of the primary tumor may differ from that of disseminated tumor cells (DTC) in bone marrow (BM), the aim of this study was (1) to compare the HER2 status of the primary tumor (prim-HER2-status) with that of DTC (DTC-HER2-status) and (2) to analyze the influence of the DTC-HER2-status on patient survival. For this purpose, BM aspirates from 569 EBC patients were analyzed for the presence of DTC. The DTC-HER2-status was identified by a double-staining procedure against cytokeratin and the HER2-receptor. DTC were detected in 151 (27 %) patients. The concordance between the HER2 status of DTC and the primary tumor was 51 %. In patients with detectable DTC, mean disease-free survival was 77.44 (95 % CI 74.72-80.17) months for DTC-HER2-negative and 55.15 (95 % CI 48.57-61.79) months for DTC-HER2-positive patients (p = 0.044). The multivariate analysis showed that the DTC-HER2-status was an independent predictor of disease-free survival. In conclusion, the presence of HER2-positive DTC in EBC patients is associated with an increased risk of relapse. Due to the low concordance between the HER2 status of the primary tumor and DTC, only a minority (13 %) of the DTC-HER2-positive patients was treated with trastuzumab. These patients might, however, benefit from HER2-directed therapy.

Comparison of HER2 Expression in Primary Tumor and Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients

“…In this study, a clear discordance was found between primary tumor and DTCs. The acquisition of HER2 amplification in DTCs, while the primary tumor is negative, can be explained with a selective advantage conferred by HER2 to DTCs during dissemination [21,25,47,48,49,50], or with a higher tendency of the HER2-positive DTC clones to detach from the primary tumor and to spread [25,48,49,50,51,52]. We found that 23.6% of patients presented a HER2-negative primary tumor and HER2-positive DTCs.…”

“…The dissemination of tumor cells in the BM is considered responsible for the further development of the disease followed by metastasis [19,20]. Between 20 and 45% of patients with primary BC already show single tumor cells in the BM at the first diagnosis: DTCs' detection allows the identification of patients with a high risk of recurrence [17,18,21]. The percentage of patients positive for DTCs rises up to 70% in case of metastasis.…”

The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer

“…These persistent DTCs were also shown to be of negative prognostic value [25,26]. Hartkopf et al demonstrated that persistence of DTCs after systemic treatment is a strong and independent marker of reduced disease-free and overall survival [27]. Thus, presence of isolated tumor cells in BM of breast cancer patients is regarded as a surrogate marker of minimal residual disease.…”

Cellules tumorales circulantes : pierre angulaire de la médecine personnalisée

“…L'amplification d'HER2 pouvant survenir lors de l'évolution de la maladie, il est primordial de pouvoir suivre la modulation phénotypique. Ainsi, des essais cliniques évaluent le bénéfice du traitement par trastuzumab sur la base du statut HER2 des CTCs (DETECT III) [14,49,50]. Cette différence phénotypique a également été décrite pour les récepteurs hormonaux.…”