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Background: Preoperative evaluation of axillary lymph node status is crucial for the selection of both systemic and surgical treatment in early breast cancer. This study assessed the particular role of additional shear wave elastography (SWE) in axillary staging in patients undergoing initial breast cancer diagnostics. Methods: One hundred patients undergoing axillary lymph node biopsy due to a sonographically suspicious axillary lymph node were prospectively evaluated with SWE using virtual touch tissue imaging quantification (VTIQ). Mean values of tissue stiffness for axillary tissue and lymph node tissue were measured prior to core-cut biopsy of the lymph node. All lymph nodes were clip-marked during the biopsy. Cut-off values to differentiate between malignant and benign lymph nodes were defined using Youden's index. Results: Lymph nodes with evidence of malignant tumor cells in the final pathological examination showed a significantly higher velocity as measured by SWE, with a mean velocity of 3.48 ± 1.58 m/s compared to 2.33 ± 0.62 m/s of benign lymph nodes (p < 0.0001). The statistically optimal cutoff to differentiate between malignant and benign lymph nodes was 2.66 m/s with a sensitivity of 69.8% and a specificity of 87.5%. Conclusions: Lymph node metastases assessed with SWE showed significantly higher elasticity values compared to benign lymph nodes. Thus, SWE provides an additional useful and quantifiable parameter for the sonographic assessment of suspicious axillary lymph nodes in the context of pre-therapeutic axillary staging in order to differentiate between benign and metastatic processes and support the guidance of definitive biopsy work-up. Critical relevance statement: Shear-wave elastography provides an additional useful and quantifiable parameter for the assessment of suspicious axillary lymph nodes in the context of pre-therapeutic axillary staging in order to differentiate between benign and metastatic processes and support guiding the definitive biopsy work-up. Key Points: SWE is a quantifiable ultrasound parameter in breast cancer diagnosis. SWE shows a significantly higher velocity in malignant lymph nodes. SWE is useful in improving the sensitivity and specificity of axillary staging. [ABSTRACT FROM AUTHOR]

Purpose: Individuals with cancer predisposition syndromes (CPS) inherit elevated cancer risks. Medical supply gaps for people at risk of CPS cause insufficient outreach and miss potential benefits of individualized care strategies. Increased awareness of CPS and progress in the eHealth sector are untapped sources of health care improvement for affected individuals. Methods and results: This study addressed German–speaking medical students with an online questionnaire in respect to their knowledge of CPS, their medical education, and perspectives. The study population (n = 404) reported interest in and knowledge of CPS, supported by a satisfactory and sustainable education for their prospective patient care. The next generation of doctors would implement eHealth to improve medical services. Skepticism about digitization was claimed by students. They were especially concerned about deterioration in the physician–patient relationship, data abuse, dependence on technology, and incorrect diagnoses. Conclusion: Due to increasing diagnosing of CPS and deeper knowledge, this topic is essential for the curriculum in medical schools. In particular, care providers need know-how on identifying patients at risk for a CPS, certain diagnostic and therapeutic steps, surveillance and prophylactic strategies to improve patients' outcomes. Education in medical school as well as implemented eHealth seems to have potential to meet this demand in an upcoming era of personalized medicine. What does this study add to the clinical work. Medical teaching on cancer predisposition syndromes should be expanded to improve knowledge and individualized and personalized healthcare. [ABSTRACT FROM AUTHOR]

Objectives: Response assessment to neoadjuvant systemic treatment (NAST) to guide individualized treatment in breast cancer is a clinical research priority. We aimed to develop an intelligent algorithm using multi-modal pretreatment ultrasound and tomosynthesis radiomics features in addition to clinical variables to predict pathologic complete response (pCR) prior to the initiation of therapy. Methods: We used retrospective data on patients who underwent ultrasound and tomosynthesis before starting NAST. We developed a support vector machine algorithm using pretreatment ultrasound and tomosynthesis radiomics features in addition to patient and tumor variables to predict pCR status (ypT0 and ypN0). Findings were compared to the histopathologic evaluation of the surgical specimen. The main outcome measures were area under the curve (AUC) and false-negative rate (FNR). Results: We included 720 patients, 504 in the development set and 216 in the validation set. Median age was 51.6 years and 33.6% (242 of 720) achieved pCR. The addition of radiomics features significantly improved the performance of the algorithm (AUC 0.72 to 0.81; p = 0.007). The FNR of the multi-modal radiomics and clinical algorithm was 6.7% (10 of 150 with missed residual cancer). Surface/volume ratio at tomosynthesis and peritumoral entropy characteristics at ultrasound were the most relevant radiomics. Hormonal receptors and HER-2 status were the most important clinical predictors. Conclusion: A multi-modal machine learning algorithm with pretreatment clinical, ultrasound, and tomosynthesis radiomics features may aid in predicting residual cancer after NAST. Pending prospective validation, this may facilitate individually tailored NAST regimens. Clinical relevance statement: Multi-modal radiomics using pretreatment ultrasound and tomosynthesis showed significant improvement in assessing response to NAST compared to an algorithm using clinical variables only. Further prospective validation of our findings seems warranted to enable individualized predictions of NAST outcomes. Key Points: • We proposed a multi-modal machine learning algorithm with pretreatment clinical, ultrasound, and tomosynthesis radiomics features to predict response to neoadjuvant breast cancer treatment. • Compared with the clinical algorithm, the AUC of this integrative algorithm is significantly higher. • Used prior to the initiative of therapy, our algorithm can identify patients who will experience pathologic complete response following neoadjuvant therapy with a high negative predictive value. [ABSTRACT FROM AUTHOR]

Purpose: A previous study in our breast unit showed that the diagnostic accuracy of intraoperative specimen radiography and its potential to reduce second surgeries in a cohort of patients treated with neoadjuvant chemotherapy were low, which questions the routine use of Conventional specimen radiography (CSR) in this patient group. This is a follow-up study in a larger cohort to further evaluate these findings. Methods: This retrospective study included 376 cases receiving breast-conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) of primary breast cancer. CSR was performed to assess potential margin infiltration and recommend an intraoperative re-excision of any radiologically positive margin. The histological workup of the specimen served as gold standard for the evaluation of the accuracy of CSR and the potential reduction of second surgeries by CSR-guided re-excisions. Results: 362 patients with 2172 margins were assessed. The prevalence of positive margins was 102/2172 (4.7%). CSR had a sensitivity of 37.3%, a specificity of 85.6%, a positive predictive value (PPV) of 11.3%, and a negative predictive value (NPV) of 96.5%. The rate of secondary procedures was reduced from 75 to 37 with a number needed to treat (NNT) of CSR-guided intraoperative re-excisions of 10. In the subgroup of patients with clinical complete response (cCR), the prevalence of positive margins was 38/1002 (3.8%), PPV was 6.5% and the NNT was 34. Conclusion: This study confirms our previous finding that the rate of secondary surgeries cannot be significantly reduced by CSR-guided intraoperative re-excisions in cases with cCR after NACT. The routine use CSR after NACT is questionable, and alternative tools of intraoperative margin assessment should be evaluated. [ABSTRACT FROM AUTHOR]

Purpose: Metabolites are in the spotlight of attention as promising novel breast cancer biomarkers. However, no study has been conducted concerning changes in the metabolomics profile of metastatic breast cancer patients according to previous therapy. Methods: We performed a retrospective, single-center, nonrandomized, partially blinded, treatment-based study. Metastatic breast cancer (MBC) patients were enrolled between 03/2010 and 09/2016 at the beginning of a new systemic therapy. The endogenous metabolites in the plasma samples were analyzed using the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences AG, Innsbruck) a targeted, quality and quantitative-controlled metabolomics approach. The statistical analysis was performed using R package, version 3.3.1. ANOVA was used to statistically assess age differences within groups. Furthermore, we analyzed the CTC status of the patients using the CellSearch™ assay. Results: We included 178 patients in our study. Upon dividing the study population according to therapy before study inclusion, we found the following: 4 patients had received no therapy, 165 chemotherapy, and 135 anti-hormonal therapy, 30 with anti-Her2 therapy and 38 had received treatment with bevacizumab. Two metabolites were found to be significantly different, depending on the further therapy of the patients: methionine and serine. Whereas methionine levels were higher in the blood of patients who received an anti-Her2-therapy, serine was lower in patients with endocrine therapy only. Conclusion: We identified two metabolites for which concentrations differed significantly depending on previous therapies, which could help to choose the next therapy in patients who have already received numerous different treatments. [ABSTRACT FROM AUTHOR]

Purpose: Endometrial carcinoma is the second most common gynecological malignancy. Until today lacking a screening tool. A blood-based biomarker could help address this need. Methods: The expression levels of 30 acylcarnitines, 18 amino acids, 6 miRNAs, and 7 DNA methylation sites were measured in blood samples from 331 women (20 EC, 14 benign uterine lesions (benign), 140 breast cancers (BC), 157 controls). Areas under the ROC curves (AUC), sensitivity (sens.) and specificity (spec.) were computed to identify the variables best distinguishing. Results: The best top ten markers for the four comparisons (cancer vs. cancer-free; EC vs. BC, EC vs. controls; EC vs. benign), were identified via AUC. Malonylcarnitine distinguished best patients with EC from controls (AUC: 0.827, sens. 80%, spec. 73.1%) or BC (AUC: 0.819, sens. 84.3%, spec. 80%) being most notable. Tryptophan best differentiated benign from EC (AUC: 0.846, sens. 70%, spec. 92.9%). Conclusions: The levels of the analyzed blood markers yielded promising results in the detection of EC and warrant further evaluation. [ABSTRACT FROM AUTHOR]

Objectives: AI-based algorithms for medical image analysis showed comparable performance to human image readers. However, in practice, diagnoses are made using multiple imaging modalities alongside other data sources. We determined the importance of this multi-modal information and compared the diagnostic performance of routine breast cancer diagnosis to breast ultrasound interpretations by humans or AI-based algorithms.Methods: Patients were recruited as part of a multicenter trial (NCT02638935). The trial enrolled 1288 women undergoing routine breast cancer diagnosis (multi-modal imaging, demographic, and clinical information). Three physicians specialized in ultrasound diagnosis performed a second read of all ultrasound images. We used data from 11 of 12 study sites to develop two machine learning (ML) algorithms using unimodal information (ultrasound features generated by the ultrasound experts) to classify breast masses which were validated on the remaining study site. The same ML algorithms were subsequently developed and validated on multi-modal information (clinical and demographic information plus ultrasound features). We assessed performance using area under the curve (AUC).Results: Of 1288 breast masses, 368 (28.6%) were histopathologically malignant. In the external validation set (n = 373), the performance of the two unimodal ultrasound ML algorithms (AUC 0.83 and 0.82) was commensurate with performance of the human ultrasound experts (AUC 0.82 to 0.84; p for all comparisons > 0.05). The multi-modal ultrasound ML algorithms performed significantly better (AUC 0.90 and 0.89) but were statistically inferior to routine breast cancer diagnosis (AUC 0.95, p for all comparisons ≤ 0.05).Conclusions: The performance of humans and AI-based algorithms improves with multi-modal information.Key Points: • The performance of humans and AI-based algorithms improves with multi-modal information. • Multimodal AI-based algorithms do not necessarily outperform expert humans. • Unimodal AI-based algorithms do not represent optimal performance to classify breast masses. [ABSTRACT FROM AUTHOR]

Purpose: This is the first study to systematically evaluate the diagnostic accuracy of intraoperative specimen radiography on margin level and its potential to reduce second surgeries in patients treated with neoadjuvant chemotherapy. Methods: This retrospective study included 174 cases receiving breast conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) of primary breast cancer. Conventional specimen radiography (CSR) was performed to assess potential margin infiltration and recommend an intraoperative re-excision of any radiologically positive margin. The histological workup of the specimen served as gold standard for the evaluation of the accuracy of CSR and the potential reduction of second surgeries by CSR-guided re-excisions. Results: 1044 margins were assessed. Of 47 (4.5%) histopathological positive margins, CSR identified 9 correctly (true positive). 38 infiltrated margins were missed (false negative). This resulted in a sensitivity of 19.2%, a specificity of 89.2%, a positive predictive value (PPV) of 7.7%, and a negative predictive value (NPV) of 95.9%. The rate of secondary procedures was reduced from 23 to 16 with a number needed to treat (NNT) of CSR-guided intraoperative re-excisions of 25. In the subgroup of patients with cCR, the prevalence of positive margins was 10/510 (2.0%), PPV was 1.9%, and the NNT was 85. Conclusion: Positive margins after NACT are rare and CSR has only a low sensitivity to detect them. Thus, the rate of secondary surgeries cannot be significantly reduced by recommending targeted re-excisions, especially in cases with cCR. In summary, CSR after NACT is inadequate for intraoperative margin assessment but remains useful to document removal of the biopsy site clip. [ABSTRACT FROM AUTHOR]

Objective: The FUSION-X-US-II prototype was developed to combine 3D automated breast ultrasound (ABUS) and digital breast tomosynthesis in a single device. We evaluated the performance of ABUS and tomosynthesis in a single examination in a clinical setting. Methods: In this prospective feasibility study, digital breast tomosynthesis and ABUS were performed using the FUSION-X-US-II prototype without any change of the breast position in patients referred for clarification of breast lesions with an indication for tomosynthesis. The tomosynthesis and ABUS images of the prototype were interpreted independently from the clinical standard by a breast diagnostics specialist. Any detected lesion was classified using BI-RADS® scores, and results of the standard clinical routine workup (gold standard) were compared to the result of the separate evaluation of the prototype images. Image quality was rated subjectively and coverage of the breast was measured. Results: One hundred one patients received both ABUS and tomosynthesis using the prototype. The duration of the additional ABUS acquisition was 40 to 60 s. Breast coverage by ABUS was approximately 80.0%. ABUS image quality was rated as diagnostically useful in 86 of 101 cases (85.1%). Thirty-three of 34 malignant breast lesions (97.1%) were identified using the prototype. Conclusion: The FUSION-X-US-II prototype allows a fast ABUS scan in combination with digital breast tomosynthesis in a single device integrated in the clinical workflow. Malignant breast lesions can be localized accurately with direct correlation of ABUS and tomosynthesis images. The FUSION system shows the potential to improve breast cancer screening in the future after further technical improvements. Key Points: • The FUSION-X-US-II prototype allows the combination of automated breast ultrasound and digital breast tomosynthesis in a single device without decompression of the breast. • Image quality and coverage of ABUS are sufficient to accurately detect malignant breast lesions. • If tomosynthesis and ABUS should become part of breast cancer screening, the combination of both techniques in one device could offer practical and logistic advantages. To evaluate a potential benefit of a combination of ABUS and tomosynthesis in screening-like settings, further studies are needed. [ABSTRACT FROM AUTHOR]

Purpose: Psychosocial and biological factors influence the perception of physical changes during pregnancy. Some pregnant women present to the obstetric emergency department (ED) with diverse symptoms not requiring urgent medical action. These visits result in over-consultation, tying up resources and inflating health care expenses. This study outlines factors associated with multiple ED visits during pregnancy, measures the prevalence of anxiety and depression, and explores the choice of maternity clinic for delivery aiming to elucidate options for care strategies. Methods: This prospective, cross-sectional, questionnaire-based bicentric study was performed in the obstetric outpatient departments of two university hospitals in Germany and recruited pregnant women between 12/2016 and 11/2017. The questionnaire included socio-demographics, obstetric history, anxiety (GAD-7), depression (PHQ-9), and health status (WHO-5, SF-12). Results: This analysis included 496 women and showed that women with numerous ED visits were significantly younger (p < 0.0001), less educated (p = 0.0002), and more likely to be unemployed and single. Different prevalences for anxiety and depression were detected correlating with the number of ED visits although each showing only low effect sizes (0.024 resp. 0.015). Conclusions: Pregnant women attending the ED more often might benefit from health education, psychosomatic interventions, and social support to overcome their depression and anxiety to avoid non-urgent ED consultations. Further prospective studies are needed to support these findings. [ABSTRACT FROM AUTHOR]

Background: The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses are frequently discordant between the primary tumor and metastatic lesions in metastatic breast cancer. This can have important therapeutic implications. Patients and methods: In all, 541 patients with available receptor statuses from both primary tumor and metastatic lesion treated at Heidelberg and Tuebingen University Hospitals between 1982 and 2018 were included. Results: Statistically significant discordance rates of 14% and 32% were found for ER and PR. HER2 status was statistically insignificantly discordant in 15% of patients. Gain in HER2 positivity was associated with an improved overall survival, whereas loss of HR positivity was associated with worse overall survival. Antiendocrine treatment differed in 20% of cases before and after biopsy and HER2-directed treatment in 14% of cases. Conclusions: Receptor statuses are discordant between primary tumor and metastasis in a considerable fraction of patients with metastatic breast cancer. Next to a highly presumed predictive value with respect to efficacy of endocrine and HER2-targeted therapy, discordance seems to provide prognostically relevant information. Where feasible, metastatic lesions should be biopsied in accordance with current guidelines. [ABSTRACT FROM AUTHOR]

Purpose: As an independent, negative-prognostic biomarker for progression-free survival (PFS) and overall survival (OS), circulating tumor cells (CTCs) constitute a promising component for developing a liquid biopsy for patients with metastatic breast cancer (MBC). The effects of HER2-targeted therapy such as trastuzumab, pertuzumab, T-DM1, and lapatinib on CTC status and longitudinal enumeration were assessed in this trial. Methods: CTC status of 264 patients with MBC was analyzed prior to and after 4 weeks of a new line of palliative systemic therapy. CTCs were assessed using CellSearch®. Three groups were compared: patients with HER2-positive MBC receiving ongoing HER2-targeted therapy (n = 28), patients with de novo HER2-positive MBC and no HER2-targeted therapy in the last 12 months prior to enrollment and start of HER2-targeted therapy (n = 15), and patients with HER2-nonamplified disease and no HER2-targeted therapy (n = 212). Results: Positive CTC status (≥ 5 CTC/7.5 ml blood) at enrollment was observed in the 3 groups for 17.9, 46.7, and 46.2% (p = 0.02) of patients, respectively. At least one CTC/7.5 ml was seen in 28.6, 53.3, and 67.0% (p < 0.001) of these patients. Furthermore, 3.6, 40.0, and 3.3% (p < 0.001) of the patients had at least one HER2-positive CTC. After 4 weeks of therapy 7.1, 0.0, and 31.1% (p = 0.001) of patients had still a positive CTC status (≥ 5 CTC/7.5 ml blood). At least one CTC/7.5 ml was still observed in 25.0, 20.0, and 50.5% (p = 0.004) of the patients. Furthermore, 7.1, 0.0, and 1.9% (p = 0.187) had at least one HER2-positive CTC. After 3 months of therapy, 35.7, 20.0, and 28.3% (p = 0.536) showed disease progression. Conclusions: HER2-targeted therapy seems to reduce the overall CTC count in patients with MBC. This should be taken into account when CTC status is used as an indicator for aggressive or indolent metastatic tumor disease. [ABSTRACT FROM AUTHOR]

Purpose: Serial longitudinal enumeration of circulating tumor cells (CTCs) has shown its prognostic value on progression-free survival and overall survival (OS) in patients with stage IV breast cancer. This study prospectively evaluated the role of CTCs as a prognostic marker during further progression of metastatic breast cancer (MBC).Methods: Among 476 MBC patients recruited between 2010 and 2015, the 103 patients with a known CTC status at baseline (CTCBL) and within 4 weeks of tumor progression (CTCPD) were included. Progressive disease (PD) was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Using the CellSearch method, < 5 and ≥ 5 CTCs per 7.5 ml blood were determined as negative and positive, respectively. A shift in CTC status from baseline to progression (CTCBL+ to CTCPD- and vice versa) was considered as alternating KineticsBL-PD.Results: Median follow-up was 29.9 [21.2, 40.0] months. CTCPD positivity (37%, n = 38) was associated with a significantly shorter OS than CTCPD negativity (8.0 [5.1, 10.9] vs 22.6 [15.3, 39.8] months; P < 0.001). Alternating KineticsBL-PD was observed in 24% of the patients. This significantly changed the OS prediction of CTCBL+ patients (CTCBL+CTCPD- vs CTCBL+CTCPD+, 11.4 [9.7, not available (NA)] vs. 7.6 [4.4, 11.5] months; P = 0.044) and CTCBL- patients (CTCBL-CTCPD+ vs. CTCBL-CTCPD-, 8.4 [4.0, NA] vs. 22.6 [18.9, NA] months, respectively; P < 0.001).Prediction of survival was significantly improved (P = 0.002) by adding CTCPD status to clinicopathological characteristics and CTCBL status.Conclusions: CTC status upon further disease progression is a prognostic factor that could significantly improve well-established models. Thus, it represents a potential additional instrument supporting treatment decision. [ABSTRACT FROM AUTHOR]

Purpose: Reduction of maternal morbidity and mortality is a major worldwide objective anchored in the millennium goals of the United Nations. To improve fetal and maternal care, a constant attempt to discover groundbreaking technologies is ongoing. One approach is the enhancement of non-invasive fetal ECG devices. Most importantly, acceptance of new technologies by pregnant women is a prerequisite for successful implementation.Methods: This questionnaire-based study conducted at the University Hospital Heidelberg, Germany between May and June 2017 evaluates pregnant women's attitudes towards a new device for fetal ECG monitoring and its potential home usage. The study population was questioned after exposure to the Parides/Atlantis prototype (Nemo Healthcare, Veldhoven, The Netherlands), whereas the maternal and gestational age-matched control group was left to envision telemedical topics.Results: The prototype and its potential usage in a clinical and telemedical setting was highly accepted, and its comfort and appearance satisfied participants. Its use caused significantly improved telemedical understanding as envision increased (p = 0.0015). Implementation and integration of telemedical devices into antenatal care was significantly preferred by the study group (p = 0.0011), though participants desire more specific features for their personal use. Optional home-based self-monitoring to reduce scheduled doctoral visits (p = 0.0004) as well as self-assessment prior to self-initiated, unscheduled consultation (p < 0.0001) could be affected positively by such a device. Furthermore, it could reduce face-to-face interaction with the care provider (p = 0.0163).Conclusions: The positive feedback on remote self-monitoring might open options for a more "patient as partners" oriented prenatal care in the future. Safety and reliability remain a major issue. More comprehensive studies with new technologies are needed to diligently ensure quality of care. Finally, results for new technologies must be communicated to pregnant women for their acceptance and usage of new devices. [ABSTRACT FROM AUTHOR]

Purpose: While intact circulating tumor cells (iCTC) have independent negative prognostic impact on patients with metastatic breast cancer (MBC), the prognostic relevance of apoptotic CTC (aCTC) has not been validated in larger patient cohorts. This study assessed aCTC and iCTC statuses at baseline (CTC) and CTC kinetics (CTC) as changes from CTC to one completed treatment cycle for their utility in predicting response, progression-free survival (PFS), and overall survival (OS) in MBC. Methods: Status of iCTC and aCTC was prospectively assessed in 442 patients using the CellSearch™ system. Different cutoffs were analyzed both for iCTC and aCTC (≥5, ≥10, ≥25 and ≥50 CTC/7.5 ml). CTC were characterized by ≥25 % changes in CTC counts. Results: Numbers of iCTC and aCTC at baseline correlated strongly ( r = 0.7). For iCTC positive patients, additional detection of aCTC had a significant prognostic impact on OS (aCTC positive 10.3 vs. aCTC negative 16.4 months, p = 0.012). Worst prognosis for OS was observed in patients with ≥50 iCTC/7.5 ml and simultaneously detected aCTC. Determination of aCTC showed stronger discriminating power than iCTC, with higher PFS and OS for the group with decreasing CTCs (PFS 7.7 vs. 6.1; OS 22.2 vs. 16.4). Conclusions: Intact and aCTC are predictive of outcome in MBC. Apoptotic CTC counts ≥ 5/7.5 ml in conjunction with iCTC at baseline have an independent unfavorable prognostic impact on OS. Decreasing aCTC at ≥ 5/7.5 ml in serial enumeration is associated with favorable outcome. Therefore, separate enumeration of iCTC and aCTC is useful in tailoring systemic treatment. [ABSTRACT FROM AUTHOR]

Metastasis is the main cause of death in breast cancer patients. The development of reliable and cost-effective biomarker to evaluate the prognosis of metastatic breast cancer (MBC) patients is of great importance. S100P is a member of S100 family and has been proved to be associated with metastasis establishment. Methods: We investigated the plasma S100P levels in 60 healthy controls, 48 primary and 273 metastatic breast cancer patients. The MBC patients were followed-up for disease progression and death up to 3.5 years after recruitment. Radiographic response of MBC patients were also analyzed for investigation on treatment monitoring value of plasma S100P level. We found a robust association between high plasma S100P level (>7 ng/mL) and poor prognosis of metastatic breast cancer (MBC) patients (median progression-free survival time: 5.0 vs. 8.7 months, log-rank test p < 0.001; median overall survival time: 22.5 vs. 31.6 months, log-rank test p < 0.001). The plasma S100P level added additional prognostic relevance to the conventional prognostication model with clinicopathological factors and CTC enumeration. The plasma S100P level decreased significantly after treatment, while the reduction correlated with the radiographic response of the MBC patients. This finding indicates the value of plasma S100P in dynamic evaluation of treatment outcome. We hereby suggest plasma S100P level as a simple and cost-effective marker for the prognosis of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Circulating or cell-free DNA (cfDNA) has been evaluated as a biomarker in many cancers including breast cancer. In particular, integrity of cfDNA has been shown to be altered in cancers. We have estimated the biomarker potential of cfDNA in primary (PBC) and metastatic breast cancer (MBC). cfDNA integrity (cfDI) and concentration were determined in plasma of 383 individuals, including 82 PBC and 201 MBC cases, as well as 100 healthy controls, by measuring ALU and LINE1 repetitive DNA elements using quantitative PCR. The MBC patient group was further sub-divided into patients with detectable circulating tumour cells (CTCpos-MBC, n = 100) and those without (CTCneg-MBC, n = 101). A hierarchical decrease in cfDI and increase in cfDNA concentration from healthy controls to PBC and further onto MBC patients were observed. Investigation of cfDNA in media of cell lines was in concordance with these results. Combination of cfDI and cfDNA concentration could differentiate PBC cases from controls (area under the curve, AUC = 0.75), MBC cases from controls (AUC = 0.81 for CTCneg-MBC, AUC = 0.93 for CTCpos-MBC), and CTCneg-MBC from CTCpos-MBC cases (AUC = 0.83). cfDI additionally demonstrated a positive correlation to progression-free (HR of 0.46 for ALU, P = 0.0025) and overall survival (HR of 0.15 for ALU and 0.20 for LINE1, P < 0.0001) in MBC, and had lower prediction error than CTC status. Our findings show that reduced cfDI and increased cfDNA concentration can serve as diagnostic markers for PBC and MBC, and cfDI as a prognostic marker for MBC, thereby making them attractive candidates for blood-based multi-marker assays. [ABSTRACT FROM AUTHOR]