BackgroundHER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy.MethodsThe number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining.Results258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1–1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC.ConclusionThis study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.

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IntroductionNeoadjuvant systemic therapy of primary breast cancer (PBC) patients offers the possibility to monitor treatment response. However, patients might have metastatic relapse despite achieving a pathologic complete response (pCR). This indicates that local response to therapy must not be representative for systemic treatment efficacy. Therefore, the aim of this study was to compare local response with systemic tumor cell dissemination by determining the presence of disseminated tumor cells (DTCs), including apoptotic tumor cells, in the bone marrow (BM) of PBC patients after neoadjuvant chemotherapy (NACT).MethodsDTCs were detected by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology (DTC status). The presence of apoptotic tumor cells was determined by using the M30 antibody (M30 status). This antibody detects a neo-epitope that is expressed only during early apoptosis.ResultsBM aspirates from 400 PBC patients that had completed NACT were eligible for this study. Of these, 167 (42%) patients were DTC positive (DTC status). The M30 status was investigated in 308 patients. Apoptotic (M30-positive) tumor cells were detected in 89 (29%) of these. Whereas the DTC status was not correlated (P = 0.557) to local treatment response (that is, pCR or a clinical complete/partial response), the presence of M30-positive tumor cells was significantly higher in patients that responded to therapy (P = 0.026). Additionally, DTC-positive patients were at an increased risk for disease relapse (hazard ratio, 1.87; 95% CI, 1.11 to 3.15; P = 0.019).ConclusionThe presence of DTC is independent of therapy response of the primary tumor. As patients that are DTC positive after NACT have an unfavorable outcome, they might benefit from additional systemic treatment.

!Classification -expansion with molecular genetic subtypes Breast cancer is being classified, as previously, using the TNM classification system, which is supplemented by the histological grading (G), the involvement of lymph vessels (L) and blood vessels (V), as well as by the hormone receptor status (ER and PR) and the HER2/neu status. Most recently, researchers have been using a molecular classification system of mRNA expression profiles into four types. This classification has the potential to differentiate among future patients who will actually benefit from chemotherapy and those for whom chemotherapy would represent excessive treatment (cf. l " Table 1). The proliferation marker Ki-67The Ki-67 protein is expressed in human cells throughout the entire cell division cycle. Its abAbstract ! Advances in research have a highly influential role to play in the strategy of early detection, treatment and aftercare of breast cancer and therefore everyday clinical practice. Newly-defined prognosis factors and a new form of molecular subtype classification, for example, are intended to help identify patients who will actually benefit from chemotherapy. In the field of neoadjuvant chemotherapy, the inclusion of the angiogenesis inhibitor Bevacizumab and dual antiHER2 therapy is being discussed. Whatʼs more, where defined criteria are met, even with positive sentinel lymph nodes, axillary dissection is not performed; besides bisphosphonates RANKL antibody Denosumab is now an option in the treatment of bone metastases.