Adverse Obstetric Outcomes after Breast Cancer Diagnosis: An Observational Database Study in Germany.

BACKGROUND/OBJECTIVES: Breast cancer may negatively affect later pregnancy and childbirth. We aimed to analyze the impact of previous breast cancer on obstetric outcomes in postdiagnosis pregnancies. METHODS: Insurance claims data in Southern Germany were used to identify breast cancer (BC) survivors with at least one subsequent delivery after cancer diagnosis between 2010 and 2020. In total, 74 BC survivors were compared to 222 age-matched controls with frequency matching on their age at their postdiagnosis delivery. RESULTS: Endocrine therapy was associated with a significantly lower probability of birth compared to BC survivors without endocrine therapy (HR 0.36; 95% CI 0.18-0.53; p < 0.0001). The risks of preterm birth, low birth weight (LBW), gestational diabetes, hypertensive disorders, and cesarean section were not significantly increased among BC survivors compared to healthy controls. BC survivors were at an increased risk for a small-for-gestational-age (SGA) fetus (OR 3.24; 95% CI 1.17-8.97, p = 0.03). Delivery in less than 2 years after diagnosis increased the risk for SGA (OR 5.73; 95% CI 1.37-24.02, p = 0.03) and LBW (OR 4.57; 95% CI 1.32-15.87, p = 0.02). CONCLUSIONS: Our findings are encouraging regarding the risks of preterm delivery, gestational diabetes, hypertensive disorders, and cesarean section to women who consider pregnancy after BC. Delivery in less than 2 years after diagnosis was associated with an increased risk for SGA and LBW.

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2024.

Introduction: Each year the interdisciplinary AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Methods: The updated evidence-based treatment recommendations for early and metastatic breast cancer have been released in March 2024. Results and Conclusion: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.

Comparing the HER2 Status of the Primary Tumor to That of Disseminated Tumor Cells in Early Breast Cancer.

Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors (PTs) and distant metastases underscores the need to comprehensively understand metastatic pathways. This retrospective study investigated discrepancies between HER2 expression in PTs and DTCs and their implications for survival outcomes in 201 early breast cancer (EBC) patients. We found a significant association between HER2 expression in PTs and DTCs when classifying tumors as HER2-high/low/negative. Patients whose HER2 status was discordant between PTs and DTCs exhibited worse distant disease-free survival than those with concordant status. Multivariate analysis confirmed the HER2 status of DTCs as an independent prognostic factor for distant DFS. These findings emphasize the importance of assessing HER2 expression in DTCs and its potential implications for tailored therapy strategies in EBC. Furthermore, prospective trials are needed to validate these findings and explore targeted therapies based on the molecular characteristics of DTCs.

Implementation and Evaluation of a Breast Cancer Disease Model Using Real-World Claims Data in Germany from 2010 to 2020.

Breast cancer is the leading cause of cancer-related mortality among women in Germany and worldwide. This retrospective claims data analysis utilizing data from AOK Baden-Wuerttemberg, a major statutory German health insurance provider, aimed to construct and assess a real-world data breast cancer disease model. The study included 27,869 female breast cancer patients and 55,738 age-matched controls, analyzing data from 2010 to 2020. Three distinct breast cancer stages were analyzed: Stage A (early breast cancer without lymph node involvement), Stage B (early breast cancer with lymph node involvement), and Stage C (primary distant metastatic breast cancer). Tumor subtypes were estimated based on the prescription of antihormonal or HER2-targeted therapy. The study established that 77.9% of patients had HR+ breast cancer and 9.8% HER2+; HR+/HER2- was the most common subtype (70.9%). Overall survival (OS) analysis demonstrated significantly lower survival rates for stages B and C than for controls, with 5-year OS rates ranging from 79.3% for stage B to 35.4% for stage C. OS rates were further stratified by tumor subtype and stage, revealing varying prognoses. Distant recurrence-free survival (DRFS) analysis showed higher recurrence rates in stage B than in stage A, with HR-/HER2- displaying the worst DRFS. This study, the first to model breast cancer subtypes, stages, and outcomes using German claims data, provides valuable insights into real-world breast cancer epidemiology and demonstrates that this breast cancer disease model has the potential to be representative of treatment outcomes.

Characteristics, Treatment Patterns and Survival of International Federation of Gynecology and Obstetrics Stage IV Epithelial Ovarian Cancer-A Population-Based Study.

BACKGROUND: The aim of the present study was to describe an unselected population of patients with diagnosis of FIGO stage IV OC. METHODS: Data from 1183 patients were available for analysis. RESULTS: The majority of patients (962/1183, 81.3%) received cancer-directed treatment. The median follow-up time was 3.8 years, and the median overall survival duration was 1.9 years. Notably, patients >80 years had a low overall survival rate (HR of age >80 years vs. ≤50 years was 3.81, 95%-CI [2.76, 5.27], p < 0.0001). The survival rate was best in patients with HGSOC (p < 0.0001). The highest overall survival rate was observed in patients in the group with surgical intervention followed by systemic treatment, with an unadjusted HR of 0.72, 95%-CI [0.59, 0.86], p = 0.007 vs. systemic treatment only. After adjustment for age and histology, survival differences between treatment schemes were smaller (HR 0.81, 95%-CI [0.66, 1.00], p = 0.12). CONCLUSIONS: In this cohort of patients with FIGO stage IV OC, more than 80% of the patients received cancer-directed treatment. Age and high-grade serous histology were determinants for survival. The highest overall survival rate was observed in patients who underwent surgery followed by systemic treatment.

The Clinical Relevance of the NATALEE Study: Application of the NATALEE Criteria to a Real-World Cohort from Two Large German Breast Cancer Centers.

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2- early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2- breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study's inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2- eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2- breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2- eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment.

Tumor-Free Resection Margin Distance in the Surgical Treatment of Node-Negative Squamous Cell Cancer of the Vulva Has No Impact on Survival: Analysis of a Large Patient Cohort in a Tertiary Care Center.

BACKGROUND: The aim of this study was to evaluate the impact of pathological tumor-free margin distance on survival in SCC patients treated with surgery alone. METHODS: This retrospective study included 128 patients with node-negative disease that received no adjuvant treatment. Disease-free and overall survival were analyzed according to pathological tumor-free margin distance. RESULTS: The patients were subclassified into three resection margin category groups: "1 to 3 mm" (n = 42), ">3 to 8 mm" (n = 47) or ">8 mm" (n = 39). Thirty-nine of the 128 patients (30.5%) developed recurrent disease. Median follow-up for disease-free survival (DFS) was 6.49 years (95% CI 5.16 years; 7.62 years), and median follow-up for overall survival (OS) was 6.29 years (95% CI 5.45 years; 7.33 years). The 5-year DFS rate was 0.70 (95% CI: 0.62-0.79), and the 5-year OS rate was 0.79 (95% CI: 0.71-0.87). Regarding the survival outcome, there were no independent significant differences in either disease-free survival (DFS) (p = 0.300) or overall survival (p = 1.000) among patients within the three tumor-free resection margin categories. Multivariate analyses did not show any statistically significant association between tumor-free resection margin distance and recurrent disease or death, either when analyzed as a categorical variable or when analyzed as a continuous variable. CONCLUSION: The present study did not show a significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva (that did not receive adjuvant treatment) on disease-free and overall survival.

Which Patients Do We Need to Test for BRCA1/2 Mutation? Feasibility of Adjuvant Olaparib Treatment in Early Breast Cancer-Real-World Data from Two Large German Breast Centers.

BACKGROUND: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2-) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2- breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. METHODS: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women's Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. RESULTS: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2- tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2- breast cancer (TNBC). Of 2039 HER2- breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2- breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2- patients and 87 of 141 (61.7%) patients with TNBC). CONCLUSION: Approximately one in ten patients with HR+/HER2-, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies.

Comparison of Biosimilar Trastuzumab ABP 980 with Reference Trastuzumab in Neoadjuvant Therapy for HER2-positive Breast Cancer - an Analysis of a Large University Breast Cancer Centre.

Background ABP 980 is a biosimilar antibody to reference trastuzumab (RTZ). Aim of the following study is to confirm the similarity of ABP 980 and RTZ in terms of clinical efficacy and safety in patients with HER2-positive early breast cancer (EBC) undergoing neoadjuvant trastuzumab-containing chemotherapy in a clinical real-world situation that also includes patients receiving pertuzumab. Methods Patients with HER2-positive EBC, who were treated from 12/2010 to 03/2020 at the Department of Women's Health at Tuebingen University Hospital, Germany, with at least four cycles of neoadjuvant chemotherapy (+/- pertuzumab) in combination with ABP 980 or RTZ were included in a retrospective analysis. For efficacy analysis patients achieving a pathologic complete remission (pCR = no invasive tumor in breast and lymph nodes) were compared. Safety was evaluated by comparing the number of patients with a decrease in left ventricular function (LVEF) of > 10%. Results 124 patients were included of whom 46 (37.1%) have received ABP 980 and 77 (62.9%) were treated with RTZ. A pCR was found in 77 patients (62.1%). For patients treated with ABP 980 as compared to RTZ, there was no significant difference regarding efficacy (pCR-rates of 60.9% versus 62.8%, p = 0.829) or cardiac safety (LVEF decline in 6.5% versus 2.6%, p = 0.274). Conclusion Similarity of ABP 980 as compared to RTZ was confirmed in a real-world situation, including a large proportion of patients that have also received pertuzumab treatment.

Treatment and survival of patients with malignant ovarian sex cord-stromal cell tumours: An analysis of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) study group CORSETT database.

BACKGROUND: Malignant sex cord-stromal cell tumours (SCST) account for only 7% of ovarian malignancies. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) study group has established a clinicopathological database to provide an overview of the current treatment strategies and survival of SCST patients and to identify research needs. METHODS: Twenty centres provided mixed retro- and prospective data of patients with tumour specimens and second-opinion pathology review treated between 2000 and 2014. Descriptive analyses of treatment strategies, Kaplan-Meier curves and cox regression analyses were conducted. RESULTS: Two hundred and sixty-two SCST patients were included. One hundred and ninety-one Granulosa-cell tumour (GCT) and 17 Sertoli-Leydig cell tumour (SLCT) patients were stage I disease (>80%). Forty four GCT (18.7%) and two (8.3%) SLCT patients received adjuvant systemic treatment. After a median observation time of 78.2 months, 46% of all SCST patients experienced disease recurrence, treated predominantly with secondary debulking surgery (> 90%). Advanced FIGO stage, lymph node involvement and intra-operative capsule rupture were associated with disease recurrence on univariate analysis (all p < 0.05). Median OS time was not reached. DISCUSSION: In this analysis of SCST patients, adjuvant chemotherapy was unable to prevent disease recurrence. Despite high recurrence rates, overall survival rates were excellent.

Estimated Thresholds of Minimum Necessary Adherence for Effective Treatment with Direct Oral Anticoagulants - A Retrospective Cohort Study in Health Insurance Claims Data.

BACKGROUND: An essential contribution regarding the prevention of thromboembolic events in patients with (non-valvular) atrial fibrillation (AF) is good adherence to direct oral anticoagulants (DOACs). However, it is an open question what "good" adherence means for DOACs or below which threshold non-adherence is clinically relevant for AF patients. Ultimately, such a classification could prevent strokes and associated costs through adjusted treatment regimens or supportive measures. METHODS: We selected 10,092 AF patients from health insurance claims data between 2014 and 2018 who were issued a majority (at least half of the number) of maximum approved strength prescriptions of one of the following DOACs, namely rivaroxaban, apixaban, or dabigatran. Due to the limited sample size, the prescriptions of dabigatran had to be finally excluded for the cut-off analysis. DOAC adherence was calculated as the proportion of days covered (PDC) by dividing the days of theoretical use (days covered) of the drug by the duration in days of the observation interval. PDC cut-off values were derived from stroke risk as a function of continuous PDC values in time-to-event analyses and corresponding dose-response models. The influence of adherence-promoting interventions (targeted and untargeted) on the occurrence of strokes and related costs was then projected, considering intervention costs per patient. RESULTS: The population had a mean age of 74.5 years and 50% were female. The median PDC was 0.79 ± 0.28 with a median follow-up time of 1218 days, in which 2% of all DOAC patients had a stroke. The adherence cut-offs for good adherence were identified at 0.78 for rivaroxaban and 0.8 for apixaban. Targeted interventions appeared to be far more cost-effective than untargeted interventions. CONCLUSION: Clear adherence cut-offs enable healthcare professionals to identify patients with clinically relevant non-adherence. Interventions based on these cut-offs appear to be a promising means to optimize DOAC treatment.

Predicting hospital admissions from individual patient data (IPD): an applied example to explore key elements driving external validity.

OBJECTIVE: To explore factors that potentially impact external validation performance while developing and validating a prognostic model for hospital admissions (HAs) in complex older general practice patients. STUDY DESIGN AND SETTING: Using individual participant data from four cluster-randomised trials conducted in the Netherlands and Germany, we used logistic regression to develop a prognostic model to predict all-cause HAs within a 6-month follow-up period. A stratified intercept was used to account for heterogeneity in baseline risk between the studies. The model was validated both internally and by using internal-external cross-validation (IECV). RESULTS: Prior HAs, physical components of the health-related quality of life comorbidity index, and medication-related variables were used in the final model. While achieving moderate discriminatory performance, internal bootstrap validation revealed a pronounced risk of overfitting. The results of the IECV, in which calibration was highly variable even after accounting for between-study heterogeneity, agreed with this finding. Heterogeneity was equally reflected in differing baseline risk, predictor effects and absolute risk predictions. CONCLUSIONS: Predictor effect heterogeneity and differing baseline risk can explain the limited external performance of HA prediction models. With such drivers known, model adjustments in external validation settings (eg, intercept recalibration, complete updating) can be applied more purposefully. TRIAL REGISTRATION NUMBER: PROSPERO id: CRD42018088129.

Distribution of the 21-Gene Breast Recurrence Score in Patients with Primary Breast Cancer in Germany.

Background Multigene assays are being used increasingly to aid in decision-making about chemotherapy in breast cancer. Here, we present the 21-gene recurrence score (RS) of patients tested in routine clinical practice in Germany. Patients and Methods In a retrospective analysis, 4695 patients with hormone receptor-positive and HER2-negative early breast cancer (pT1 - 3, pN0 - 1, M0) were included in whom RS testing was conducted in Germany between November 2015 and July 2018. RS groups as defined in the TAILORx trial (RS result 0 - 10; 11 - 25; 26 - 100) were used. Results Of these patients, 21% were assigned to the low RS group, 63% to the midrange RS group, and 15% to the high RS group. 1772 (81%) of 2175 node-negative patients over 50 years of age were grouped either into the low RS group or the midrange RS group. The portion of patients with a low or midrange RS was 90% among node-positive patients (1284 of 1432 patients), 79% among patients with Ki-67-high (≥ 20%) tumors (1829 of 2310 patients), 86% vs. 70% among patients with G2 and G3 tumors (3244 of 3762 patients and 368 of 522 patients), respectively, 88% among patients with a tumor size of > 5 cm (140 of 159 patients), and 82% among node-negative patients at high clinical risk (1110 of 1352). Conclusions The distribution of the 21-gene RS in German patients that were tested in routine clinical practice indicates that, according to the results of the TAILORx trial, chemotherapy may not be beneficial in most of these.

Wind, waves, tides, and human error? - Influences on litter abundance and composition on German North Sea coastlines: An exploratory analysis.

Being globally and locally prevalent, beach litter has been monitored at 29 sites along the German North Sea coastline. This study offers an exploratory analysis of data from 1991 to 2016. Schleswig-Holstein exhibited lower mean litter pollution levels than Lower Saxony, possibly because the locations in Lower Saxony are situated along the main coastal current, whereas the North Frisian Islands act as a barrier for the mainland sites in Schleswig-Holstein. Locations close to the Elbe estuary had significantly larger amounts of debris, likely receiving litter from marine and riverine sources. No clear overall pattern in litter abundance or composition could be detected. Significant quantitative similarities between debris types were inconsistent. The effect of wind, tides, and exposure appeared to be marginal. Recurring data inconsistencies, gaps, and outliers were partly attributed to human error. This could be reduced through hypothesis-driven monitoring with a simpler litter classification and continuous data checking.

ClinOmicsTrailbc: a visual analytics tool for breast cancer treatment stratification.

MOTIVATION: Breast cancer is the second leading cause of cancer death among women. Tumors, even of the same histopathological subtype, exhibit a high genotypic diversity that impedes therapy stratification and that hence must be accounted for in the treatment decision-making process. RESULTS: Here, we present ClinOmicsTrailbc, a comprehensive visual analytics tool for breast cancer decision support that provides a holistic assessment of standard-of-care targeted drugs, candidates for drug repositioning and immunotherapeutic approaches. To this end, our tool analyzes and visualizes clinical markers and (epi-)genomics and transcriptomics datasets to identify and evaluate the tumor's main driver mutations, the tumor mutational burden, activity patterns of core cancer-relevant pathways, drug-specific biomarkers, the status of molecular drug targets and pharmacogenomic influences. In order to demonstrate ClinOmicsTrailbc's rich functionality, we present three case studies highlighting various ways in which ClinOmicsTrailbc can support breast cancer precision medicine. ClinOmicsTrailbc is a powerful integrated visual analytics tool for breast cancer research in general and for therapy stratification in particular, assisting oncologists to find the best possible treatment options for their breast cancer patients based on actionable, evidence-based results. AVAILABILITY AND IMPLEMENTATION: ClinOmicsTrailbc can be freely accessed at https://clinomicstrail.bioinf.uni-sb.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Comparison of Nine Instruments to Calculate Anticholinergic Load in a Large Cohort of Older Outpatients: Association with Cognitive and Functional Decline, Falls, and Use of Laxatives.

OBJECTIVE: A patient's risk for anticholinergic adverse effects is frequently estimated by instruments evaluating the drugs included in his medication profile. It remains unknown, however, which characteristics should be included in such an assessment instrument aiming to reliably predict adverse anticholinergic outcomes. DESIGN: Cross-sectional study. SETTING: ESTHER cohort (Germany). PARTICIPANTS: Home-dwelling participants (N = 2,761) aged between 60 and 87 years. MEASUREMENTS: The association between anticholinergic load calculated with nine different instruments and four anticholinergic adverse outcomes was investigated in univariate and multivariate analyses. Therefore, linear models complemented with Kendall's tau rank correlation coefficients (ԏ) were applied for continuous outcomes and generalized linear models were used to derive odds ratios (ORs) with 95% confidence intervals (CIs) for binary endpoints. RESULTS: Based on the respective identification criteria for anticholinergic drugs, the nine instruments identified between 245 (9%) and 866 (31%) anticholinergic drug users (mean age ± SD: 73 ± 6 years; Mini-Mental State Examination [MMSE] score: 28.3 ± 2.07; Barthel Index: 97.1 ± 7.5; 291 reporting falls; 29 taking laxatives [surrogate for constipation]). In the multivariate analysis, only two instruments indicated a significant association between anticholinergic load and all four outcomes. The instrument considering the prescribed dose showed the strongest association with MMSE scores (ԏ = -0.10), falls (OR: 2.30; 95% CI: 1.50-3.52), and the use of laxatives (OR: 3.11; 95% CI: 1.04-9.36). CONCLUSIONS: Instruments most reliably predicted anticholinergicadverse events if they were either based on the drugs' serum anticholinergic activity and the suggestions of clinician experts or considered the actual prescribed dose.

Efficient Verification of Holograms Using Mobile Augmented Reality.

Paper documents such as passports, visas and banknotes are frequently checked by inspection of security elements. In particular, optically variable devices such as holograms are important, but difficult to inspect. Augmented Reality can provide all relevant information on standard mobile devices. However, hologram verification on mobiles still takes long and provides lower accuracy than inspection by human individuals using appropriate reference information. We aim to address these drawbacks by automatic matching combined with a special parametrization of an efficient goal-oriented user interface which supports constrained navigation. We first evaluate a series of similarity measures for matching hologram patches to provide a sound basis for automatic decisions. Then a re-parametrized user interface is proposed based on observations of typical user behavior during document capture. These measures help to reduce capture time to approximately 15 s with better decisions regarding the evaluated samples than what can be achieved by untrained users.

The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients.

BACKGROUND: In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time "liquid biopsy" approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC. METHODS: CTC-positive (five or more CTCs/7.5 mL blood; CellSearch®, Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch®). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan-Meier plots. RESULTS: One hundred seven patients (median age (range) 57 (33-81) years) were included. 100/107 (93%) patients were followed-up for a median [95% confidence interval (CI)] of 28.5 [25.1-40.1] months. Of 37/107 (35%) CTC-HER2-positive patients only 10 (27%) were PRIM-HER2-positive. 6/46 (13%) patients were MET-HER2-positive; only 2/10 (20%) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69% and 74%, respectively. Kaplan-Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95% CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7-13.7] versus 4.34 [3.5-5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7-30.0] versus 8.7 [5.9-15.3] months; p = 0.287). CONCLUSIONS: HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform "liquid biopsy" to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed.

Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients.

BACKGROUND: To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC). METHODS: CTCBL and CTC1C status was determined as negative (-) or positive (+) for < 5 or ≥ 5 CTCs/7.5 ml blood using CellSearch™ (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2-3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS. RESULTS: 133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5-3.2) and 2.9 (0.5-4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7-6.1] vs. 7.8 [6.4-9.2]; OS 10.4 [7.9-15.0] vs. 27.2 [22.3-29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6-6.0] vs. 8.5 [6.6-10.4]; OS 7.7 [6.4-13.9] vs. 30.6 [22.6-not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, ≥ 3rd-line therapy, and triple-negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, ≥ 3rd-line therapy, and triple-negative receptor status). CONCLUSIONS: CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC. TRIAL REGISTRATION: Not applicable.