Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch^® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.

Circulating tumor cell (CTC) detection is a prognostic factor in the metastatic breast cancer (MBC) setting. Discrepancies in primary (PT) and metastatic tumor (MT) genetic profiles are also of prognostic importance. Our study aimed to compare the CTC statuses and prognoses between those with subtype stable MBCs and MBCs with specific biomarker conversions. The study enrolled 261 MBC patients, treated at the National Center for Tumor Diseases, Heidelberg, Germany in a five-year period. All underwent PT and MT biopsies and subsequent CTC enumeration before the initiation of systemic therapy. ER and HER2 statuses of the PTs and MTs were determined and progression free survivals (PFSs) and overall survivals (OSs) were recorded. We compared CTC statuses, CTC counts, PFSs and OSs between subgroups of patients with different receptor change patterns. Patients who had tumors that converted to triple negative MTs had the shortest median OSs, while HER2 expression was not associated with a shorter median OS. No significant differences in PFSs and OSs have been demonstrated by Kaplan-Meier curve comparisons in any of the subgroup analyses. CTC counts were similar in all subgroups. CTCs were comparably less frequently detected in patients with a stable HER2 expression. Similar proportions of CTC positives were observed in all other subtype change pattern subgroups, barring the aforementioned HER2 stable subgroup. The detection of CTCs was of no appreciable prognostic value in different receptor change pattern subgroups in our cohort.

The presence of circulating tumor cells (CTCs), detected as a form of liquid biopsy is associated with poor survival in both early and metastatic breast cancer. Monitoring tumor biology based on intrinsic subtypes delivers treatment-relevant information on the heterogeneity or biomarker conversion between primary and metastatic tumors. This study aimed to correlate the change of the apoptotic and intact CTC counts with mRNA-assessed intrinsic subtype change. Thirty-four breast cancer patients with available triplets of primary tumors, distant metastasis biopsies and data on intact and apoptotic CTC dynamics were included in the analysis. The intrinsic subtype was determined per RT-qPCR quantification of the gene expression ESR1, PGR, ERBB2 and MKI67. Both luminal (p = 0.038) and triple negative (p = 0.035) patients showed a significant downregulation of apoptotic CTCs. Repeated biopsies of distant metastatic sites, as well as determining a potential shift of the intrinsic subtype, combined with data on intact and apoptotic CTC dynamics from liquid biopsies might help personalize systemic therapy and generate additional surrogate markers for successful systemic therapy.

Background/Aim: To compare the microscopic, macroscopic and thermal damage inflicted to ovarian tissue by conventional monopolar and bipolar energy, argon plasma coagulation (APC) and diode laser. Materials and Methods: Bovine ovaries were used as a substitute for human tissue and subjected to the four aforementioned techniques and the inflicted damage was measured. Sixty fresh and morphologically similar cadaveric bovine ovaries were divided into five equal groups, each group was subjected to one of the following energy applications for both 1 and 5 s: Monopolar, bipolar electrocoagulation, diode laser, preciseAPC^® and forcedAPC^®. Ovarian temperatures were measured at 4 and 8 s after treatment. Formalin-fixed ovarian specimens were examined by pathologists regarding macroscopic, microscopic and thermal tissue damage. Results: None of the ovaries reached the temperature producing severe damage (40°C) after 1 s of energy transfer. Heating of adjacent ovarian tissue was least pronounced when preciseAPC^® and monopolar electrocoagulation were applied (27.2±3.3°C and 28.2±2.9°C after 5 s of application, respectively). Conversely, 41.7% of the ovaries subjected to bipolar electrocoagulation for 5 s overheated. ForcedAPC^® resulted in the most pronounced lateral tissue defects (2.8±0.3 mm after 1 s and 4.7±0.6 mm after 5 s). When the modalities were applied for 5 s, the electrosurgical instruments (mono- and bipolar) and preciseAPC^® induced similar lateral tissue damage (1.3±0.6 mm, 1.1±1.6 mm and 1.2±1.3 mm, respectively). preciseAPC^® created the shallowest defect of all the techniques (0.05±0.1 mm after 5 s of application). Conclusion: Our study hints at superior safety profiles of preciseAPC^® and monopolar electrocoagulation compared to bipolar electrocoagulation, diode laser and forcedAPC^® for ovarian laparoscopic surgery.

Background/Aim: Loss of differentiation of breast cancer cells in association with a down-regulated class I human leukocyte antigen (HLA) expression can lead to proliferation unhampered by cytotoxic T lymphocytes, which has been proven to be of prognostic relevance. The objective of this study was to determine the levels of HLA-A and HLA-B/C expression in metastatic breast cancer (MBC) cells and their usefulness for predicting 5-year survival. Materials and Methods: This prospective double-blinded cohort study analyzed patients starting a new line of therapy for MBC. RT-qPCR was used to determine the levels of HLA-A and B/C expression in MBC cells and the mRNA-based tumor intrinsic subtype. Two receiver operating characteristic curves (ROC) were constructed in order to determine whether HLA-A and HLA-B/C expression levels can be used for predicting 5-year survival. Youden J points, and sensitivity and specificity optimized cut-off points were determined for both ROC curves. Results: We enrolled 34 patients. The ROC curve for HLA-B/C had the highest AUC compared to HLA-A (0.55 vs. 0.42). High levels of HLA-A and HLA-B/C expression (40-ΔΔCT of 33.5 and 31.9, respectively) were highly specific (reaching 87.5% for HLA-A and even 100% specificity for HLA-B/C) yet insensitive for five-year survival in our study. Conclusion: High expression of certain class I HLA molecule subtypes by MBCs, in particular high HLA-A or B/C expression by MBC cells seems very specific in predicting the 5-year survival. We determined cut-off values for these HLA molecule clusters with high specificity, which might help identify patients with a favorable prognosis as prognosticators of a 5-year overall survival if their sensitivity is improved in larger prospective cohorts.

Breast cancers (BC) can mutate, allowing metastatic tumors (MT) to sometimes differ to primary tumors (PT) in gene expression. Despite contemporary metastatic breast cancer (MBC) therapy, subtype conversion seems prognostically disadvantageous. We strived to determine the influence of mRNA-assessed intrinsic subtype stability comparing PT and MT biopsies and circulating tumor cell (CTC)-based liquid biopsies on progression free survival (PFS) and overall survival (OS). Additional analyzed prognostic factors were PT subtype, MT subtype and hormone receptor loss. Kaplan-Meier curves and the log rank tests were used to compare PFSs and OSs. The proportions of luminal B and triple negative subtype MTs were increased compared to those observed in PTs. Fifteen patients were found to have tumors that underwent intrinsic subtype conversion and their OS was significantly decreased (p = 0.038). No such difference was observed when it comes to PFS. The majority of these tumors switched to a more aggressive intrinsic subtype. No significant differences in PFSs or OSs were observed between subtype converters with triple negative PTs compared to those with luminal subtype PTs. The same is true of subtype stable patients. Total CTC, iCTC and aCTC counts decreased with therapy, but there were no significant differences between subtype converters and subtype stable patients. Our data confirm a poorer overall survival of the intrinsic subtype converters and emphasize the importance of acquiring biopsies and re-biopsies of all available metastatic lesions alongside with CTC-based liquid biopsies for earlier recognition of patients with poorer prognosis and in need of altered individualized therapy regimens.