Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.
586 Background: In recent years CTCs have been extensively studied in different neoplasms. However, in PC CTCs are still emerging as a potential prognostic tool and the significance in different stages of the disease and the correlation with tumor markers are poorly understood. Methods: We conducted an observational, prospective, cohort study in two Spanish centers. Isolation was carried out with Isoflux technology (Fluxion Biosciences, Inc. San Francisco, CA, USA), that is combining cell separation by immunomagnetic particles (positive selection) with a microfluidic system. Before isolation, it was performed a first cell enrichment step using the density gradient cell separation technique (Ficoll). Four different markers were used, including two mesenchymal markers, EpCAM and EGFR (EMT Enrichment Kit:EpCAM/EGFR/Mesenchymal). The count of CTCs was done in a confocal microscope using the iMSRC (intelligent Matrix Screen Remote Control). A high throughput system was performed over the entire area, using a 20x objective, increasing to a 60x objective. Primary endpoint was the prognostic significance of CTCs, correlating the number of CTCs at diagnosis with overall survival. Secondary endpoints: Correlation between number of CTCs with Ca19.9/CEA values, and the difference in the median value of CTCs in metastatic compared to locally advanced disease. CTCs were analyzed at day 0 (CTC-0), just before first chemotherapy cycle was administered. Results: Thirty-four patients were analyzed. Clinical characteristics: Table 1. Median follow up 12.0 months. Median value of CTC-0 was 347 (range 104 - 3273) for metastatic and 436 (81 - 1082) for locally advanced patients (p = 0.942). Correlation coefficient for Ca 19.9 0.006 (p = 0.97); CEA correlation coefficient 0.191 (p = 0.303). For a cutoff of 500 CTCs, we found an AUC of 0.8 for mortality. Kaplan-Meier analysis showed an estimated median overall survival for patients with ≥500 CTCs of 8.6 months (95% confident interval [95% CI] 5.3 – 12) vs not reached for patients with < 500 CTCs (p = 0.007). HR for mortality 3.3 (95% CI 1.3 – 8.4; p = 0.011) for patients with ≥ 500 CTCs. Conclusions: Our data suggest 500 CTCs might be a potential cutoff for prognostic assessment. The absence of differences of CTC-0 between metastatic and locally advanced patients supports the idea of a systemic disease irrespective of the presence of metastases at diagnosis. CTC-0 seems not to correlate with tumor markers at diagnosis.[Table: see text]
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