Introduction As early breast cancer might relapse even after complete removal of breast and lymphnodes, the disease must persist in secondary sites. The detection of disseminated tumor cells (DTC) in the bone marrow (BM) has been described as a surrogate of residual disease. Various trials showed an impaired prognosis of DTC positive early breast cancer (EBC) patients. The PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) study is a large international pooled analysis that aimed to assess the prognostic impact of DTC detection in patients with EBC. Methods A pre-specified protocol was followed, and centers known to practice BM sampling for DTC detection were contacted for individual patient data. Patients with EBC, with available follow-up data and BM sampling before any anti-cancer treatment were eligible. BM aspirates were collected at the time of primary surgery. DTC were identified by antibody (A45-B/B3, AE1/AE3, 2E11 and E29) staining against cytokeratin. The DTC status was compared to other prognostic factors using the chi-squared test. Univariate log-rank test and multivariate cox regression were used to compare survival of DTC positive versus DTC negative patients. Results Individual data from 10,320 patients (11 centers from Europe and USA) were included with a median follow-up of 91 months. Of all patients, 2,823 (27.4 %) were DTC positive. DTC detection was associated with higher tumor grade, higher T stage, nodal positivity, ER and PR negativity, and HER2 positivity (all p<0.001). In univariate analyses, overall, breast cancer specific, disease-free and distant disease-free survival (OS, BCSS, DFS, DDFS) were significantly shorter in DTC positive patients with p-values of <0.001. Multivariate analyses showed the DTC status to be an independent prognostic marker for OS, BCSS, DFS and DDFS with hazard ratios (HR) and 95%-confidence intervals (CI) of 1.23 (95%-CI: 1.06-1.42, p=0.007), 1.38 (95%-CI: 1.11-1.72, p=0.004), 1.29 (95%-CI: 1.10-1.50, p=0.001) and 1.32 (95%-CI: 1.10-1.58, p=0.003), respectively. Conclusions Detection of DTC in the bone marrow is an independent prognostic marker in patients with non-metastatic breast cancer. Further studies should investigate the impact of DTC on metastatic cancer progression and their role for clinical decision making. Citation Format: Hartkopf AD, Brucker SY, Taran F-A, Harbeck N, von Au A, Naume B, Pierga J-Y, Hoffmann O, Beckmann MW, Rydén L, Fehm T, Aft R, Montserrat S, Walter V, Rack B, Schuetz F, Borgen E, Ta M-H, Bittner A-K, Fasching P, Fernö M, Krawczyk N, Weilbaecher K, Margelí M, Hahn M, Jueckstock J, Domschke C, Bidard F-C, Kasimir-Bauer S, Schoenfisch B, Kurt AG, Wallwiener M, Gebauer G, Wallwiener D, Janni W, Pantel K. International pooled analysis of the prognostic impact of disseminated tumor cells from the bone marrow in early breast cancer: Results from the PADDY study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-07.
Background To achieve long-term improvement in health care of transgender women, it is necessary to analyze all aspects of gender-confirming surgery, especially the relation of risks and benefits occurring in these procedures. While there are many studies presenting data on the urologic part of the surgery, there are just few data about complications and satisfaction with breast augmentation. Methods This is a retrospective study using parts of the BREAST-Q Augmentation Questionnaire and additional questions for symptoms of capsular contracture and re-operations and analyzing archived patient records of all transwomen which were operated at University Hospital Essen from 2007 to 2020. Results 99 of these 159 patients (62%) completed the questionnaire after a median time of 4 years after surgery. Breast augmentation led to re-operations due to complications in 5%. The rate of capsular contracture (Baker Grad III–IV) in this population was 3%. Most patients (75%) rated high scores of satisfaction with outcome (more than 70 points) and denied to have restrictions due to their implants in their everyday life. All patients reported an improvement in their quality of life owing to breast augmentation. Conclusion Breast augmentation by inserting silicon implants is a safe surgical procedure which takes an important part in reducing gender dysphoria.
Background: The detection and characterization of circulating tumor cells (CTCs) as one of the analytes in liquid biopsy has been considered as surrogate marker to improve treatment decisions in metastatic breast cancer (MBC). In addition, cell-free tumor DNA (ctDNA) released by tumor cells and harboring tumor-associated variants is further discussed to give additional information for therapeutic options. Thus, CTC and ctDNA analysis from the same blood tube is desired. To test usability of plasma, generated after CTC isolation from whole blood for ctDNA analysis, we analyzed ctDNA from 42 hormone receptor-positive/HER2-negative MBC patients (pts) for the detection of tumor-associated variants (plasma isolated straight from whole blood) and compared the results for similarities and differences of the detected variants in a subgroup of these pts to those, obtained from plasma generated after CTC selection (taken from a separate tube). Methods: 4 ml plasma of all MBC pts and 4 ml plasma obtained after immunomagnetic isolation of CTCs from 2x5ml blood [AdnaTest EMT-2/Stem Cell Select (n=17pts) followed by multimarker qPCR] were used for the analysis of cell-free DNA (cfDNA) applying the QIAamp MinElute ccfDNA Kit. A total of 30ng - 60ng cfDNA was applied for library construction using the QIAseq Targeted DNA Panel for Illumina with integrated unique molecular identifiers. Sequencing was executed on the NextSeq® 500 platform (Illumina, US). Data were analyzed using the QIAseq Targeted Sequencing Data Analysis Portal, the Biomedical Genomics Workbench and the Ingenuity Variant Analysis. All materials used were manufactured by QIAGEN, Germany. Results: In the total cohort of 42 pts, most variants of all analyzed genes were detected in the MUC16 gene (31.2%). ERBB2, EGFR and AR (androgen receptor) also showed high numbers of variants (11.6%, 11.0% and 8.9%, respectively) with a majority detected pathogenic variants (47.7%) in AR. 92% of all detected variants showed an allele frequency of <5% and some of the detected MUC16, ERBB2 and AR mutations significantly correlated with overall survival. Comparing the plasma results from a separate blood draw with the results from plasma samples after CTC selection in a subgroup of 17/42 pts, no significant difference was found for cfDNA concentration but variability within the cohort. Whereas the variant comparison of ctDNA isolated from both plasma sources showed great concordance, additional variants (around 15%) were exclusively found in one of the two matched samples. Interestingly, in the variant population exclusively found in ctDNA isolated after CTC isolation, the relative amount of pathogenic variants was increased compared to the variant fraction only found in ctDNA from plasma of a separate blood tube. Results obtained for frequently overexpressed CTC transcripts in this subgroup included genes involved in the PI3K signaling pathway as well as ERBB2 and ERBB3 in about 30% of the pts. Conclusion: We here present a feasible workflow for CTC and ctDNA evaluation for expression and mutation analysis from the same blood sample. These data emphasize that the use of different liquid biopsy analytes can empower treatment decisions of MBC pts in the future. Citation Format: Kasimir-Bauer S, Bittner A-K, Hoffmann O, Hauch S, Sprenger-Haussels M, Storbeck M, Benyaa K, Hahn P, Mach P, Tewes M, Kimmig R, and Keup C. The analysis of cell-free DNA and circulating tumor cells from one blood tube might empower treatment decisions in metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-01-10.
Introduction: The detection of disseminated (DTCs) and circulating (CTCs) tumor cells in patients with early stage breast cancer is a well described independent prognostic factor associated with increased risk of disease recurrence and disease-related death. We recently demonstrated that CTCs in blood of primary breast cancer patients rather than DTCs were significantly associated with reduced progression free survival (p=0.02). Using comprehensive molecular characterization, we here demonstrate that the negative prognostic impact was predominantly related to HER2-positive CTCs with stem cell character from patients with HER2-negative primary tumors. Patients and Methods: 2 x 5 ml blood from 482 primary breast cancer patients with first diagnosis between 2006 and 2010 were analyzed for CTCs with the AdnaTest BreastCancer (QIAGEN Hannover GmbH, Germany) for the detection of EpCAM, MUC-1, HER-2, and beta-Actin transcripts. The recovered c-DNA was now additionally tested for the expression of the estrogen (ER) and progesterone receptor (PR) (single-plex RT-PCR) and stem cell like CTCs (slCTCs) applying the AdnaTest TumorStemCell (single-plex RT-PCR for ALDH1) and the AdnaTest EMT (multiplex RT-PCR for TWIST, AKT2, PI3K). The analysis of PCR products was performed by capillary electrophoresis on the Agilent Bioanalyzer 2100. Results: CTCs were detected in 103/482 (21%) of the patients expressing EpCAM (27%), MUC-1 (26%), HER-2 (75%), ER (14%) and PR (8%), respectively. Notably, in 49/103 (48%) of the CTC-positive patients, HER2 was the only marker expressed. slCTCs could be analyzed in 72/103 CTC-positive patients. At least one of the EMT markers was expressed in 56/72 patients (78%), ALDH1 was present in 32/72 patients (44%) and 31/72 (44%) were positive for both, ALDH1 and EMT markers, respectively. Comparisons of expression profiles on CTCs with those on the primary tumor were only performed in CTC-positive patients. Primary tumors and CTCs displayed a concordant HER2, ER and PR status in 37% (p=0.81), 24% (p=0.257) and 27% (p=0.876) of cases, respectively. Most interestingly, in 60/75 (80%) patients with HER2-positive CTCs, primary tumors were HER2-negative. In contrast, the percentage of patients with ER- and PR-positive CTCs but negative ER/PR primary tumors was 29% and 25%, respectively. When the presence of HER2-positive CTCs was correlated with the presence of slCTCs (ALDH1-and/or EMT-positive), the concordance was 83% (p=0.0019). In detail, the concordances were HER2+ vs ALDH1+ (54%, p=0.037), HER2+ vs EMT+ (85%, p=0.0002) and HER2+ vs ALDH1+/EMT+ (80% p=0.00053), respectively. Conclusion: Our results provide evidence that a) the negative prognostic impact of CTCs in our patient cohort is related to HER2-positive CTCs with EMT and tumor stem cell characteristics which indicate therapy resistant tumor cell populations and, therefore, an inferior prognosis and b) “secondary” adjuvant treatment with HER2-targeting agents, alone or in combination, may probably be effective to eliminate these cells and thus, lead to an overall decreased relapse rate. This study further confirms that the molecular characterization of CTCs might help to stratify patients for individual treatment options. Citation Format: Kasimir-Bauer S, Bittner A-K, Aktas B, Hauch S, Kimmig R, Hoffmann O. In primary breast cancer patients with HER2-negative tumors, HER2-positive circulating tumor cells with stem cell character predict worse outcome. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-01.
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