Search

As the available information about breast cancer is growing every day, the decision-making process for the therapy is getting more complex. ChatGPT as a transformer-based language model possesses the ability to write scientific articles and pass medical exams. But is it able to support the multidisciplinary tumor board (MDT) in the planning of the therapy of patients with breast cancer? We performed a pilot study on 10 consecutive cases of breast cancer patients discussed in MDT at our department in January 2023. Included were patients with a primary diagnosis of early breast cancer. The recommendation of MDT was compared with the recommendation of the ChatGPT for particular patients and the clinical score of the agreement was calculated. Results showed that ChatGPT provided mostly general answers regarding chemotherapy, breast surgery, radiation therapy, chemotherapy, and antibody therapy. It was able to identify risk factors for hereditary breast cancer and point out the elderly patient indicated for chemotherapy to evaluate the cost/benefit effect. ChatGPT wrongly identified the patient with Her2 1+ and 2+ (FISH negative) as in need of therapy with trastuzumab and called endocrine therapy “hormonal treatment”. Support of artificial intelligence by finding individualized and personalized therapy for our patients is unavoidable in this time of rapidly expanding amount of information. ChatGPT has the potential to find its spot in clinical medicine, but the current version is not able to provide specific recommendations for the therapy of patients with primary breast cancer.

Purpose:To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS).Experimental Design:A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes.Results:One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE.Conclusions:Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

PDF file, 54K, Table S1. Comparison of the LOH incidences at each marker in both fractions.

Supplementary Data from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Supplementary Table S1.

supplemental figure legend

PDF file, 44K.

Figure S1. Flow chart of the data selection process for a pooled analysis of the prognostic relevance of circulating tumor cells in early breast cancer. Patients were ineligible if no valid data on CTC presence at the time of primary diagnosis as assessed using the FDA-cleared CellSearch® System were available (e.g., because of insufficient amount of blood or test failure). * A total of 3,754 patients with early breast cancer were randomized in the SUCCESS A clinical trial; however, blood samples for the enumeration of CTCs with the CellSearch® System were only collected after written informed consent from 1,994 of those patients.

PDF file, 35K, Supplementary Figure S1. Kaplan-Meier analyses of primary breast cancer patients with positive and negative estrogen receptor (ER) status. Top curve shows patients with positive ER status, and bottom curve patients with negative ER status (see also Table 1).

Purpose: Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTC) in the peripheral blood of patients with metastatic breast cancer, less evidence is available for the prognostic relevance of CTCs at the time of primary diagnosis.Experimental Design: We conducted a pooled analysis of individual data from 3,173 patients with nonmetastatic (stage I–III) breast cancer from five breast cancer institutions. The prevalence and numbers of CTCs were assessed at the time of primary diagnosis with the FDA-cleared CellSearch System (Janssen Diagnostics, LLC). Patient outcomes were analyzed using meta-analytic procedures, univariate log-rank tests, and multivariate Cox proportional hazard regression analyses. The median follow-up duration was 62.8 months.Results: One or more CTCs were detected in 20.2% of the patients. CTC-positive patients had larger tumors, increased lymph node involvement, and a higher histologic tumor grade than did CTC-negative patients (all P < 0.002). Multivariate Cox regressions, which included tumor size, nodal status, histologic tumor grade, and hormone receptor and HER2 status, confirmed that the presence of CTCs was an independent prognostic factor for disease-free survival [HR, 1.82; 95% confidence interval (CI), 1.47–2.26], distant disease-free survival (HR, 1.89; 95% CI, 1.49–2.40), breast cancer–specific survival (HR, 2.04; 95% CI, 1.52–2.75), and overall survival (HR, 1.97; 95% CI, 1.51–2.59).Conclusions: In patients with primary breast cancer, the presence of CTCs was an independent predictor of poor disease-free, overall, breast cancer–specific, and distant disease-free survival. Clin Cancer Res; 22(10); 2583–93. ©2016 AACR.

Background: The prognostic significance of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTCs after adjuvant therapy increases the risk of subsequent relapse and death.Patients and Methods: Individual patient data from 676 women with primary diagnosis of early breast cancer stages I–III from 3 follow-up studies were pooled. During clinical follow-up, patients underwent BM aspiration (BMA) to determine the presence of DTC. Tumor cells were detected by the standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS).Results: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for DFS, distant DFS (DDFS), cancer-specific survival, and OS during the first 5 years following cancer diagnosis (log-rank test P < 0.001 values for all investigated endpoints).Conclusion: Among breast cancer patients, persistent DTCs during follow-up significantly predicted the increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials. Clin Cancer Res; 17(9); 2967–76. ©2011 AACR.

Supplementary Figure from Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

Table S1. Patients and study variables according to study center for the pooled analysis of circulating tumor cells in early breast cancer

Background Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. Methods Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. Results AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89–1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80–1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86–1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77–1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3–4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. Conclusion For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

In der Gruppe der Mammakarzinome hat das triple-negative Mammakarzinom (TNBC, „triple-negative breast cancer“) das heterogenste Outcome und die schlechteste Prognose. Durch das Fehlen von Hormonrezeptoren und des HER2/neu(„human epidermal growth factor receptor 2“)-Rezeptor bestehen in der aktuellen klinischen Routine keine Zielstrukturen fur eine spezifische Therapie. Es erfolgte eine Literaturrecherche zur aktuellen Studienlage und vielversprechenden Therapieansatzen. In der kurativen Situation finden sich neue Ansatze in der Hinzunahme von Checkpointinhibitoren zusatzlich zur Standardchemotherapie. Ebenfalls gibt es mit Capecitabin analog der CREATE-X-Studie bei non-PCR eine postneoadjuvante Therapie. In der palliativen Situation findet man neben verschiedenen Chemotherapien einen Ansatz in der Testung von Tumorgewebe und der Keimbahn. Bei PD-L1(„programmed cell death 1 ligand 1“)-Positivitat kann auf den bereits zugelassenen Checkpointinhibitor Atezolizumab zuruckgegriffen werden. Bevacizumab ist auch bei manchen Patientinnen eine Option. Weitere mogliche Antikorpertherapien umfassen in Zukunft Pembrolizumab sowie die Antikorper-drug-Konjugate Sacituzumab-Govitecan und Trastuzumab-Deruxtecan. Bei einer Aktivierung des AKT/PI3K(Phosphoinositid-3-Kinase)-Signalwegs scheinen AKT-Inhibitoren wie Capivasertib oder Ipatasertib eine Option darzustellen. Bei BRCA-Positivitat stehen PARP(Poly[ADP-ribose]-Polymerasen)-Inhibitoren zur Verfugung. Trotz Fehlens der Hormonrezeptoren und des HER2/neu-Rezeptors bestehen mittlerweile mit der PD-L1-Testung, der Keimbahnanalyse und auch der Testung auf eine Aktivierung des AKT/PI3K-Signalwegs weitere zielgerichtete Therapieoptionen fur das TNBC sowohl in der kurativen als auch in der palliativen Situation.

Background: Metastatic breast cancer (MBC) is an incurable disease and both the improvement of survival and maintenance of quality of life (QoL) are equally important aims of treatment planning. In patients with HER2-positive MBC, taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab (T) and pertuzumab (P) is the standard of care first line therapy. However, adverse events are well-known side effects of any cytostatic treatment and can seriously impact the patients’ QoL. In addition, in HER2-positive MBC activated estrogen receptor (ER) signaling is associated with primary or secondary resistance. Thus, for patients with HER2-positive and hormone-receptor (HR) positive MBC, the synergistic combination of dual HER2-targeted therapy plus endocrine therapy might offer a better treatment option compared to cytotoxic chemotherapy-based treatments. Methods: Between 9/2015 and 11/2022, the multicenter phase III DETECT V trial randomized patients with HER2-positive and HR-positive (i.e. ER positive and/or progesterone-receptor positive) MBC in the 1st-3rd line setting 1:1 to receive T and P combined with either endocrine therapy or chemotherapy followed by maintenance therapy with T, P and endocrine therapy. Chemotherapy and the endocrine agents could be chosen from a variety of available regimens according to physicians’ choice. Based on emerging data strongly suggesting an additional benefit of CDK4/6 inhibitors, an amendment came into effect in January 2019 with the addition of ribociclib to both treatment arms after 124 patients had been randomized. The primary objective of DETECT V is to compare tolerability between the chemotherapy-free and chemotherapy-containing treatment arm; secondary objectives comprise the comparison of PFS, OS and safety. Here we report results of an unplanned interim analysis with data cut off June 22th 2022. Results: The results reported here are based on 153 patients for whom end of study was documented at the time of data cut off for this interim analysis (120 patients randomized before and 33 patients randomized after the addition of ribociclib; 115 patients in the 1st line setting; 77 and 76 patients in the chemotherapy-free and chemotherapy-containing arm, respectively). Overall survival (OS) and progression-free survival (PFS) did not differ between patients receiving chemotherapy-free and chemotherapy-containing treatment (median OS not yet reached vs. 37.2 months, hazard ratio 0.87, 95% CI 0.51 – 1.50, p = 0.63; median PFS 15.6 vs. 14.9 months, hazard ratio 0.98, 95% CI 0.64 – 1.52, p = 0.93). Study treatment was terminated prematurely significantly less often in the chemotherapy-free treatment arm (43.9% vs. 72.2%, p = 0.001). Furthermore, tolerability was better for the chemotherapy-free treatment as there were less adverse events (AEs) of any grade (585 vs. 793; 70 vs. 71 patients affected), less AEs grade 3 or higher (66 vs. 90; 33 vs. 48 patients affected) and less serious adverse events (45 vs. 52; 28 vs. 29 patients affected) reported in the chemotherapy-free treatment arm as compared to the chemotherapy-containing treatment arm. Conclusion: These preliminary results suggest that chemotherapy-free treatment for patients with triple-positive MBC might be an effective and well tolerated option. Citation Format: Wolfgang Janni, Tanja Fehm, Volkmar Müller, Fabienne Schochter, Amelie De Gregorio, Thomas Decker, Andreas Hartkopf, Marianne Just, Jacqueline Sagasser, Marcus Schmidt, Pauline Wimberger, Maggie Banys-Paluchowski, Peter A. Fasching, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Natalia Krawczyk, Oliver Hoffmann, Jens-Uwe Blohmer, Dieter Niederacher, Hans Neubauer, Klaus Pantel, Thomas W. Friedl, Jens Huober. Omission of chemotherapy in the treatment of HER2-positive and hormone-receptor positive metastatic breast cancer – interim results from the randomized phase 3 DETECT V trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-07.

Background: It is well-known that tumor biology may change during the course of the disease due to clonal evolution, and such changes might have important implications for response to targeted treatments. Circulating tumor cells (CTCs) could serve as a real-time liquid biopsy to detect changes in tumor biology. It has been demonstrated that patients with HER2-negative metastatic breast cancer (MBC) may have discordant, HER2-positive CTCs in the peripheral blood. However, up to now there is no randomized clinical trial investigating whether treatment decisions based on CTC phenotype provide benefits in terms of improved outcome. The aim of the DETECT III study is to investigate whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. In addition, the significance of CTCs as an early predictive marker for response to therapy will be analyzed. Methods: The randomized phase III DETECT III trial (NCT01619111) compares lapatinib in combination with standard therapy versus standard therapy alone in patients with initially HER2-negative MBC and HER2-positive CTCs. Efficacy of lapatinib treatment is evaluated by CTC clearance rate, progression-free survival (PFS) and overall survival (OS). In addition, we investigate the association between CTC results and both PFS and OS to assess the utility of CTCs as an early predictive marker for treatment response. CTC enumeration and phenotyping was performed using the CellSearch® technology (Menarini Silicon Biosystems; Bologna, Italy). Survival data are analyzed using log rank tests, univariable and adjusted multivariable cox regressions. Results: First results on CTC clearance rates, PFS and OS of 105 prospectively randomized patients will be presented. Conclusion: This first randomized clinical trial in breast cancer patients with treatment decisions being based on the phenotype of CTCs will show whether patients with HER2 negative MBC and HER2 positive CTCs benefit from additional HER2-targeted therapy with lapatinib. This finding might be increasingly important as novel HER2-targeted drugs become available. Citation Format: Tanja Fehm, Volkmar Mueller, Maggie Banys-Paluchowski, Peter A Fasching, Thomas WP Friedl, Andreas Hartkopf, Jens Huober, Christian Loehberg, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Oliver Hoffmann, Lothar Müller, Pauline Wimberger, Eugen Ruckhaeberle, Jens Blohmer, Wolfgang Janni. Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-12.

Background: Several studies suggest clinical utility of serial circulating tumor cell (CTC) enumeration as a means of assessing response status in metastatic breast cancer (MBC). The aim of this study is to conduct a comprehensive pooled analysis comprising globally available data to further define and explore the role of CTC enumeration as a tool for early treatment monitoring in patients with MBC with a focus on the predictive power in different breast cancer subtypes and clinical settings. Methods: In a global effort, peer-reviewed published studies with data on repeated CTC assessments (CellSearch® technology; Menarini Silicon Biosystems; Bologna, Italy) in MBC patients were screened and investigators were asked to provide individual patient data for this pooled analysis. 2761 cases from 32 data sets with data on both baseline and one follow up CTC assessments were included in the analysis (median time interval between the two CTC assessments 35 days). Data were analyzed using log rank tests and Cox regressions to evaluate the association between serial CTC enumeration results and overall survival (OS) in the full patient cohort and defined subgroups. Results: 588 (21.3%) patients had no CTCs at both time points (neg/neg), 236 (8.5%) patients were CTC negative at baseline and CTC positive at follow up (neg/pos), 712 (25.8%) patients converted from CTC positive at baseline to CTC negative (pos/neg), and 1225 (44.4%) patients had at least one CTC at both time points (pos/pos). Log rank tests showed significant differences in OS between these four CTC change groups (p < 0.0001 for all pairwise comparisons except for the comparison between neg/pos and pos/neg, p = 0.015). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 34.6, and 17.6 months, respectively. Hazard ratios (HR) (reference group neg/neg) were 1.38 (95% CI 1.16 - 1.64) for the pos/neg group, 1.78 (95% CI 1.43 - 2.22) for the neg/pos group, and 3.06 (95% CI 2.63 - 3.56) for the pos/pos group. Results were similar if a cutoff of 5 CTCs was used for CTC positivity (pos/neg group: HR 1.43, 95% CI 1.25 - 1.63; neg/pos group: HR 2.39, 95% CI 1.91 - 2.99; pos/pos group: HR 3.54, 95% CI 3.12 - 4.02). In total, 2586 patients could be assigned to different tumor subtypes based on known hormone receptor (ER) and HER2 status of the primary tumor: 1513 (58.5%) patients had a luminal-like tumor (ER positive, HER2 negative), 682 (26.4%) patients had a HER2-positive tumor, and 391 (15.1%) patients had a triple-negative tumor. In patients with luminal-like tumors, the hazard ratios were 1.67 (95% CI 1.29 - 2.17), 2.01 (95% CI 1.45 - 2.77), and 3.87 (95% CI 3.09 - 4.83) for the pos/neg, neg/pos, and pos/pos group, respectively. In patients with HER2-positive tumors, the neg/pos group (HR 1.68, 95% CI 1.12 - 2.53) and the pos/pos group (HR 2.11, 95% CI 1.58 - 2.83) showed significantly worse OS compared to the neg/neg group, while in triple-negative patients, the pos/pos group had a significantly shorter OS compared to the neg/neg group (HR 2.99, 95% CI 2.11 - 4.24). The results will be up-dated by inclusion of additional large data sets (CALGB 40502, CALGB 40503, COMET, SWOG S0500, TBCRC 001) for the analysis to be presented at SABCS 2020. Conclusion: This large pooled analysis confirms that at a median of 35 days after treatment initiation, follow-up CTC assessments strongly predict overall survival. These results suggest potential clinical utility of CTC monitoring as early response marker in MBC, especially in luminal-like tumors. Citation Format: Wolfgang J Janni, Tracy C. Yab, Daniel F. Hayes, Massimo Cristofanilli, Francois-Clement Bidard, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabières, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Evi Lianidou, Mark J.M. Magbanua, Luis Manso, Dimitrios Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, José Vidal-Martínez, Rita Zamarchi, Karthik Giridhar, Thomas W.P. Friedl, Minetta C. Liu. Clinical utility of repeated circulating tumor cell (CTC) enumeration as early treatment monitoring tool in metastatic breast cancer (MBC) - a global pooled analysis with individual patient data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-08.

Simple Summary CA27.29 (MUC1) is a well described biomarker for prediction of prognosis and treatment efficacy. CA27.29 is mainly evaluated in the preoperative setting. However, testing of postoperative levels and additional assessment after chemotherapy might be more informative for analyzing the usefulness of CA27.29 in relation to the efficacy of chemotherapy. Thus, both pre- and post-chemotherapy values were assessed from patients enrolled in the breast cancer SUCCESS-A trial. Pre-chemotherapy assessment was associated with disease-free survival. It had no prognostic value in node-negative patients, but there was a clear association in node-positive patients. Furthermore, it was shown that post-chemotherapy CA27.29 assessment did not add any prognostic value, either on its own or in addition to pre-chemotherapy assessment. In conclusion, this indicates that pre- and post-chemotherapy values do not provide additional information. However, pre-chemotherapy CA27.29 could be a suitable tool to identify a group with unfavorable prognosis among node-positive patients. Abstract Soluble MUC1 has been discussed as a biomarker for predicting prognosis, treatment efficacy, and monitoring disease activity in breast cancer (BC) patients. Most studies in adjuvant settings have used preoperative assessment. This study, part of the SUCCESS-A trial (NCT02181101), assessed the prognostic value of soluble MUC1 before and after standard adjuvant chemotherapy. Patients with high-risk BC were treated within the SUCCESS-A trial with either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide followed by three cycles of docetaxel or three cycles of FEC followed by three cycles of docetaxel and gemcitabine. Cox regression analyses were performed to investigate the prognostic value of CA27.29 before and after chemotherapy relative to disease-free survival (DFS), along with established BC prognostic factors such as age, body mass index, tumor size, nodal status, estrogen receptor, progesterone receptor, HER2 status, and grading. Pre-chemotherapy and post-chemotherapy CA27.29 assessments were available for 2687 patients of 3754 randomized patients. Pre-chemotherapy CA27.29 assessment was associated with DFS in addition to established prognostic factors. It had no prognostic value in node-negative patients, but there was a clear association in node-positive patients. Post-chemotherapy CA27.29 assessment did not add any prognostic value, either on its own or in addition to pre-chemotherapy CA27.29 assessment.

Background Circulating tumor cells (CTC) in the peripheral blood in women with breast cancer has been found to be an indicator of prognosis before the start of systemic treatment. The aim of this study is the assessment of specific cytokine profiles as markers for CTC involvement that could act as independent prognostic markers in terms of survival outcome for breast cancer patients. Methods Patients selected for this study were defined as women with breast cancer of the SUCCESS study. A total of 200 patients’ sera were included in this study, 100 patients being positive for circulating tumor cells (CTC) and 100 patients being CTC negative. The matching criteria were histo-pathological grading, lymph node metastasis, hormone receptor status, TNM classification, and patient survival. Commercial ELISA with a multi cytokine/chemokine array was used to screen the sera for Interleukin 15 (IL-15) and eotaxin. Results Statistically significant concentrations were exposed for IL-15 levels regardless of the CTC-Status, lymph node involvement, or hormone receptor status. Significantly enhanced serum IL-15 concentrations were observed in those patients with worse overall survival (OS) and disease-free survival (DFS). Elevated serum concentrations of IL-15 significantly correlate with patients diagnosed with Grade 3 tumor and worse OS. In contrast, patients with a Grade 3 tumor with a favourable OS and DFS demonstrated significantly decreased IL-15 values. The CTC negative patient subgroup with a favourable OS and DFS, showed statistically significant elevated eotaxin values. Conclusion These findings suggest a potential functional interaction of increased IL-15 concentrations in the peripheral blood of patients with a worse OS and DFS, regardless of prognostic factors at primary diagnosis. The increased levels of the chemokine eotaxin in CTC negative patients and a favourable OS and DFS, on the other hand, suggest that the overexpression inhibits CTCs entering the peripheral blood, thus emphasizing a significant inhibition of circulation specific metastasis. To sum up, IL-15 could be used as an independent prognostic marker in terms of survival outcome for breast cancer patients and used as an early indicator to highlight high-risk patients and consequently the adjustment of cancer therapy strategies.

Das metastasierte Mammakarzinom gilt allgemein als nicht kurabel; dennoch hat die Lebenserwartung der betroffenen Patientinnen durch den Einsatz moderner Systemtherapien in den letzten Jahrzehnten zugenommen. Zum aktuellen Zeitpunkt stellt die primare operative Resektion des Brusttumors keine Standardtherapie dar, und ihr Effekt auf ein langeres Uberleben ist bislang nicht eindeutig geklart. In diesem Ubersichtsartikel werden Argumente pro und kontra eine primare Brustoperation beim metastasierten Mammakarzinom herausgearbeitet und validiert. Literaturrecherche retro- und prospektiver Studien in Bezug auf eine Operation bei Patientinnen mit Erstdiagnose eines Stadium-IV-Mammakarzinoms Viele retrospektive Studien legen fur Patientinnen mit metastasiertem Mammakarzinom einen Uberlebensvorteil durch die Operation des Primarius dar. Diese Untersuchungen weisen jedoch methodische Limitationen und Selektionsbias auf. Neuere prospektive Daten konnen den Uberlebensvorteil empirisch nicht bestatigen. Dennoch deuten Subgruppenanalysen auf einen Vorteil fur junge Patientinnen mit hormonrezeptorpositiver Tumorbiologie und Oligometastasierung in den Knochen hin. Ausgehend von der aktuellen Datenlage ist es nicht moglich, eine eindeutige Schlussfolgerung pro oder kontra Brustoperation in der metastasierten Erkrankungssituation zu treffen. Junge hormonrezeptorpositive Patientinnen mit Knochenmetastasen scheinen am meisten von der Resektion des Primartumors zu profitieren. Die Wertigkeit einer solchen Operation sollte allerdings immer interdisziplinar fur den Einzelfall gepruft werden.

The antiangiogenic splice variant VEGF-A165b is downregulated in a variety of cancer entities, but little is known so far about circulating plasma levels. The present analysis addresses this question and examines circulating VEGF-A/VEGF-A165b levels in a collective of female high-risk breast cancer patients over the course of treatment. Within the SUCCES-A trial 205 patients were recruited after having received primary breast surgery. Using ELISA VEGF-A/VEGF-A165b concentrations were determined and correlated to clinical characteristics (1) before adjuvant chemotherapy, (2) four weeks and (3) two years after therapy and compared to healthy controls (n = 107). VEGF165b levels were significantly elevated after completion of chemotherapy. Within the breast cancer cohort, VEGF-A165b levels increased two years after completion of chemotherapy. VEGF-A plasma concentrations were significantly elevated in the breast cancer cohort at all examined time points and decreased after treatment. VEGF-A levels two years after chemotherapy correlated with increased cancer related mortality, no such correlation could be found between VEGF-A165b and the examined clinical characteristics. Compared to controls, VEGF-A/VEGF-A165b ratios were decreased in patients before and after chemotherapy. Our data suggests that circulating VEGF-A165b is significantly reduced in women with primary breast cancer at time of diagnosis; furthermore, levels change during adjuvant treatment.

Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Purpose Discordance in human epidermal growth factor receptor 2 (HER2) status between primary tumor and metastases might have important implications for treatment response and therapy decisions. Here, we evaluate both the frequency of circulating tumor cells (CTCs) and the factors predicting HER2 discordance between primary tumor and CTCs as a potential surrogate for tumor biology and tumor heterogeneity in patients with metastatic breast cancer. Patients and Methods The number of CTCs in 7.5 mL of peripheral blood and HER2 status were evaluated in 1,123 women with HER2-negative metastatic breast cancer. HER2 discordance was defined as the presence of at least one CTC with a strong immunocytochemical HER2 staining intensity. Factors predicting discordance in HER2 phenotype were assessed using multivariable logistic regression. Results Overall, 711 (63.3%) of 1,123 screened patients were positive for CTCs (≥ one CTC). Discordance in HER2 phenotype between primary tumor and CTCs was observed in 134 patients (18.8%) and was significantly associated with histologic type (lobular v ductal; odds ratio [OR], 2.67; 95% CI, 1.63 to 4.39; P < .001), hormone receptor status (positive v negative; OR, 2.84; 95% CI, 1.15 to 7.02; P = .024), and CTC number (≥ five v one to four; OR, 7.64; 95% CI, 3.97 to 14.72; P < .001). Conclusion HER2 discordance between primary tumor and CTCs was observed in 18.8% of patients and was associated with histologic type, hormone receptor status of the primary tumor, and CTC number. The clinical utility of CTCs as liquid biopsy to assess tumor heterogeneity of metastatic disease and guide treatment decisions must be evaluated in prospective randomized trials.

Circulating tumor cells (CTCs) traverse vessels to travel from the primary tumor to distant organs where they adhere, transmigrate, and seed metastases. To cope with these challenges, CTCs have reached maximal flexibility to change their differentiation status, morphology, migratory capacity, and their responses to genotoxic stress caused by metabolic changes, hormones, the inflammatory environment, or cytostatic treatment. A significant percentage of breast cancer cells are defective in homologous recombination repair and other mechanisms that protect the integrity of the replication fork. To prevent cell death caused by broken forks, alternative, mutagenic repair, and bypass pathways are engaged but these increase genomic instability. CTCs, arising from such breast tumors, are endowed with an even larger toolbox of escape mechanisms that can be switched on and off at different stages during their journey according to the stress stimulus. Accumulating evidence suggests that DNA damage responses, DNA repair, and replication are integral parts of a regulatory network orchestrating the plasticity of stemness features and transitions between epithelial and mesenchymal states in CTCs. This review summarizes the published information on these regulatory circuits of relevance for the design of biomarkers reflecting CTC functions in real-time to monitor therapeutic responses and detect evolving chemoresistance mechanisms.

ZusammenfassungDie Streuung von Tumorzellen und Entstehung solider Metastasen findet sowohl über das Lymph- als auch das Blutsystem statt. Der Nachweis zirkulierender Tumorzellen (CTCs) und der zirkulierenden Tumor-DNA (ctDNA) im venösen Blut ist sowohl beim frühen als auch beim metastasierten Mammakarzinom möglich. Ihre prognostische Relevanz wurde bereits mehrfach bewiesen. Dabei ist die repetitive Untersuchung der CTCs bzw. ctDNA im Sinne einer regelmäßigen „liquid biopsy“ jederzeit und problemlos möglich. Durch die zusätzlichen molekularen Analysen ist es möglich, Tumorcharakteristika und ihre Heterogenität, die mit möglichen Resistenzen einhergehen, zu definieren. Dies ermöglicht den Einsatz einer personalisierten und zielgerichteten Therapie, um neben einem verlängerten Gesamtüberleben auch die Verbesserung der Lebensqualität zu erreichen.

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.

In breast cancer, large tumor size, positive nodal stage and a triple-negative tumor subtype are associated with reduced survival, but the interactions between these prognostic factors are not well understood.Here we re-evaluated the impact of tumor size, nodal stage and tumor subtype on disease-free survival (DFS), overall survival (OS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) in a retrospective analysis using data from the adjuvant SUCCESS A trial. Subgroup analyses were conducted to assess whether the effect of tumor size and nodal stage on survival depended on tumor subtype.Increasing tumor size, higher nodal stage and triple negative breast cancer (TNBC) were associated with unfavorable prognosis (all p 0.001). There was no significant interaction between tumor subtype and tumor size (p 0.5 for all four survival endpoints), but we found significant interactions between tumor subtype and nodal stage (p 0.05 for all four survival endpoints), with no differences in survival among tumor subtypes for patients with pN0 tumors (all p 0.05) and pronounced differences in survival among tumor subtypes for patients with positive nodal stage (all p 0.001).This analysis confirms tumor size, nodal stage and tumor subtype as independent prognostic factors in high-risk early breast cancer. Nodal-positive patients with TNBC had a considerably worse outcome compared to nodal-positive patients with another tumor subtype. This underlines the importance for early detection particularly for patients with TNBC.EudraCT 2005-000490-21; ClinicalTrials.gov Identifier: NCT02181101.

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.