Introduction Molecular Fluorescence Guided Surgery (MFGS) might be used for intraoperative detection of positive resection margins in breast conserving surgery (BCS) for the treatment of breast cancer. Currently, the presence of tumor positive resection margins can only be assessed ex vivo by histopathological analysis of the excised tissue, which takes up to 5 working days. The current study defined the optimal dose of the near-infrared (NIR) optical imaging tracer bevacizumab-800CW to enable intraoperative detection and image-guided pathology of tumor positive resection margins in breast cancer patients. Methods Molecular Fluorescence Guided Surgery during BCS was performed in subjects treated for primary breast cancer. The NIR optical imaging tracer bevacizumab-800CW targeting vascular endothelial growth factor A was administered intravenously three days prior to surgery in four escalating dose groups (4.5mg, 10mg, 25mg and 50mg). NIR fluorescent signals were detected real-time using an intraoperative fluorescence camera system (SurgVision BV). Standardized ex vivo analyses of tumor-to-normal ratios (TNR) were performed to define the optimal tracer dose using a BlackBox imaging system (SurgVision BV) for imaging fresh bread loaf slices, a NIR fluorescence flatbed scanner (Odyssey, Li-Cor) for imaging 10µm slices of formalin-fixed paraffin-embedded (FFPE) blocks, NIR Confocal Laser Endomicroscopy (CLE, Mauna Kea Technologies) and multi-diameter single fiber reflectance and single fiber fluorescence (MDSFR/SFF) spectroscopy quantification to enable correction for the influence of tissue optical properties on fluorescence in tumor and normal breast tissue. Results Currently, 12 subjects have been included and analyzed in four dosing groups. All tumors showed specific tracer uptake at macroscopic and microscopic level during ex vivo analyses, confirmed by histopathology. Quantification of NIR fluorescent signals showed higher TNRs by increasing doses up to 25mg. No further increase in TNR was seen in the 50mg dose group. CLE showed the feasibility of visualization of the tracer accumulation in tumor tissue compared to normal tissue at a microscopic level. MDSFR/SFF spectroscopy objectively confirmed the dose dependency up to 25mg. Conclusion and future perspective Intravenous administration of bevacizumab-800CW in doses up to 50mg is safe and highly tumor specific, showing a plateau of TNR at 25mg and 50mg. Further expansion of the dosing cohorts of 10mg and 25mg with additional seven patients per group will be performed to establish the optimal dose for MFGS during BCS for an upcoming phase III multicenter randomized controlled trial. By enabling MFGS during BCS the surgical treatment of primary breast cancer patients might be optimized by a reduced need for re-excision surgery and thereby reducing the risk of co-morbidity, psychological burden, poor cosmesis and healthcare costs. Citation Format: van Dam GM, Koller M, Qiu SQ, Linssen MD, de Vries J, Jansen L, Kelder W, de Jong JS, Jorritsma-Smit A, van der Vegt B, Robinson DJ, Nagengast WB. Phase II in-human dose escalation study of the optical molecular imaging tracer bevacizumab-800cw for molecular fluorescence guided surgery in primary breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-01.
Background: In the era of precision medicine, the surgical management of axillary lymph nodes (ALN) should be patient-tailored. Omission of sentinel lymph node biopsy (SLNB) is possible in patients with early breast cancer and very low or very high probability of ALN metastasis. Recently, we developed a nomogram to predict the probability of ALN metastasis in breast cancer patients based on clinicopathological parameters including ultrasound using a Chinese patient dataset1. In this study the nomogram performance was validated in an independent Dutch population from one hospital. Methods: Data of 170 Dutch patients with a successful SLNB or axillary lymph node dissection were collected. A lymph node containing either micro- or macrometastatic disease was considered as a positive lymph node. Performance of the nomogram was assessed by calculating the area under the receiver-operator characteristic (ROC) curve (AUC). False-negative rates (FNRs) and false-positive rates (FPRs) at several different predictive cut-off points were calculated. Results: There were 69 (40.6%) patients having a positive ALN. The AUC for the nomogram was 0.84 (95% confidence interval 0.78-0.90) compared with 0.86 in the Chinese validation population, showing excellent discrimination of the model. The FNR and FPR of the model were 10.2% and 0% for the predicted probability cut-off points of 14.5% and 90%, respectively. Table 1 False-negative rates (FNRs) and false-positive rates (FPRs) of the nomogram at different predictive cut-off pointsPredicted rishPatient number and percentage (%)Number of patients with positive ALNFNR (%)< 14.5%59 (34.7)610.2< 20%79 (46.5)1113.9 Number of patients with negative ALNFPR (%)> 70%27 (15.9)13.7> 90%18 (10.6)00ALN: axillary lymph node This means that omission of SLNB is possible for patients with a predictive probability of less than 14.5% or higher than 90%, which accounts for 45.3% of all patients in this study. Conclusions and future perspectives: In this study, the Chinese nomogram showed excellent performance in predicting the probability of ALN metastasis in an independent Dutch population. A multicentre validation of this nomogram in large Dutch patient population (>2500 patients) is ongoing. Reference 1.Qiu S-Q, Zeng H-C, Zhang F, et al. A nomogram to predict the probability of axillary lymph node metastasis in early breast cancer patients with positive axillary ultrasound. Sci Rep 2016; 6: 21196. Citation Format: Qiu S-Q, Aarnink M, van Maaren MC, Dorrius M, Koffijberg H, van Dam GM, Siesling S. Validation of a Chinese nomogram with a Dutch breast cancer population: Excellent prediction of the probability of axillary lymph node metastasis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-26.
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