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3. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study (vol 30, pg 1279, 2019)

Author

Loibl, S., Untch, M., Burchardi, N., Huober, J., Sinn, B. V., Blohmer, J. -U., Grischke, E. -M., Furlanetto, J., Tesch, H., Hanusch, C., Engels, K., Rezai, M., Jackisch, C., Schmitt, W. D., von Minckwitz, G., Thomalla, J., Kuemmel, S., Rautenberg, B., Fasching, P. A., Weber, K., Rhiem, K., Denkert, C., Schneeweiss, A., Loibl, S., Untch, M., Burchardi, N., Huober, J., Sinn, B. V., Blohmer, J. -U., Grischke, E. -M., Furlanetto, J., Tesch, H., Hanusch, C., Engels, K., Rezai, M., Jackisch, C., Schmitt, W. D., von Minckwitz, G., Thomalla, J., Kuemmel, S., Rautenberg, B., Fasching, P. A., Weber, K., Rhiem, K., Denkert, C., and Schneeweiss, A.

Published
2022

7. 28P EVI1 expression in early-stage breast cancer patients treated with neoadjuvant chemotherapy

Author

Leichsenring, J., primary, Vladimirova, V., additional, Solbach, C., additional, Karn, T., additional, Ataseven, B., additional, Sinn, B., additional, Barinoff, J., additional, Mueller, V., additional, Blohmer, J-U., additional, Schem, C., additional, Engels, K., additional, Marmé, F., additional, Fissler-Eckhoff, A., additional, Fasching, P.A., additional, Stickeler, E., additional, van Mackelenbergh, M., additional, Denkert, C., additional, Stenzinger, A., additional, Loibl, S., additional, and Gröschel, S., additional

Published
2021
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8. 17P Impact of body mass index (BMI) on prognostic and predictive value of stromal tumour-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC): A pooled analysis of six neoadjuvant trials

Author

Furlanetto, J., primary, Denkert, C., additional, Untch, M., additional, Sinn, B., additional, Lederer, B., additional, Schneeweiss, A., additional, Mueller, V., additional, van Mackelenbergh, M., additional, Stickeler, E., additional, Fasching, P.A., additional, Schem, C., additional, Karn, T., additional, Marmé, F., additional, Nekljudova, V., additional, and Loibl, S., additional

Published
2021
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9. 21P BACH1 and HIF1α predict response to neoadjuvant nab-paclitaxel (nP) treatment in early breast cancer (BC)

Author

Vladimirova, V., primary, Schneeweiss, A., additional, Jackisch, C., additional, Weber, K.E., additional, Denkert, C., additional, Schmatloch, S., additional, Karn, T., additional, Fasching, P.A., additional, Braun, S., additional, Szeto, C., additional, Sinn, B., additional, van Mackelenbergh, M., additional, Schem, C., additional, Stickeler, E., additional, Soon-Shiong, P., additional, Marmé, F., additional, Mueller, V., additional, Untch, M., additional, Nekljudova, V., additional, and Loibl, S., additional

Published
2021
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18. GeparX: Denosumab (Dmab) as add-on to different regimen of nab-paclitaxel (nP)-anthracycline based neoadjuvant chemotherapy (NACT) in early breast cancer (BC): Subgroup analyses by RANK expression and HR status

Author

Link, T., Blohmer, J-U., Just, M., Untch, M., Stoetzer, O., Fasching, P. A., Schneeweiss, A., Wimberger, P., Seiler, S., Huober, J., Schmitt, W. D., Jackisch, C., Rhiem, K. E., Hanusch, C., Denkert, C., Sinn, B. V., Engels, K., Nekljudova, V., Loibl, S., Link, T., Blohmer, J-U., Just, M., Untch, M., Stoetzer, O., Fasching, P. A., Schneeweiss, A., Wimberger, P., Seiler, S., Huober, J., Schmitt, W. D., Jackisch, C., Rhiem, K. E., Hanusch, C., Denkert, C., Sinn, B. V., Engels, K., Nekljudova, V., and Loibl, S.

Published
2020

19. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

Author

Loibl, S., Untch, M., Burchardi, N., Huober, J., Sinn, B., V, Blohmer, J-U, Grischke, E-M, Furlanetto, J., Tesch, H., Hanusch, C., Engels, K., Rezai, M., Jackisch, C., Schmitt, W. D., von Minckwitz, G., Thomalla, J., Kuemmel, S., Rautenberg, B., Fasching, P. A., Weber, K., Rhiem, K., Denkert, C., Schneeweiss, A., Loibl, S., Untch, M., Burchardi, N., Huober, J., Sinn, B., V, Blohmer, J-U, Grischke, E-M, Furlanetto, J., Tesch, H., Hanusch, C., Engels, K., Rezai, M., Jackisch, C., Schmitt, W. D., von Minckwitz, G., Thomalla, J., Kuemmel, S., Rautenberg, B., Fasching, P. A., Weber, K., Rhiem, K., Denkert, C., and Schneeweiss, A.

Abstract

Background: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. Patients and methods: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). Results: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage >= IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected chi(2) P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P< 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. Conclusions: Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patien

Published
2019

21. Abstract P1-17-07: Cancer management and outcome of very young non-pregnant patients with breast cancer diagnosed at 40 years or younger– GBG 29

Author

Seiler, S, primary, Schmatloch, S, additional, Reinisch, M, additional, Neunhöffer, T, additional, Schmidt, M, additional, Bechtner, C, additional, Marmé, F, additional, Wagner, M, additional, Möbus, V, additional, Reimer, T, additional, Kleine-Tebbe, A, additional, Sinn, B, additional, Stickeler, E, additional, Untch, M, additional, Janni, W, additional, Seither, F, additional, and Loibl, S, additional

Published
2019
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22. Abstract P2-08-10: Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials

Author

Villegas, SL, primary, Lederer, B, additional, Untch, M, additional, Holms, F, additional, Ulmer, H-U, additional, Diebold, K, additional, Fasching, PA, additional, Weber, K, additional, Schmitt, WD, additional, Tesch, H, additional, Rezai, M, additional, Marmé, F, additional, Sinn, B, additional, Hackmann, J, additional, Schneeweiss, A, additional, Tannapfel, A, additional, Nekljudova, V, additional, Denkert, C, additional, and Loibl, S, additional

Published
2019
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23. Final analysis of the Male-GBG54 study: A prospective, randomised multi-centre phase II study evaluating endocrine treatment with either tamoxifen +/- gonadotropin releasing hormone analogue (GnRHa) or an aromatase inhibitor + GnRHa in male breast cancer patients

Author

Reinisch, M., primary, Seiler, S., additional, Hauzenberger, T., additional, Schmatloch, S., additional, Strittmatter, H.-J., additional, Zahm, D.-M., additional, Thode, C., additional, Jackisch, C., additional, Strik, D., additional, Moebus, V., additional, Reimer, T., additional, Sinn, B., additional, Stickeler, E., additional, Marme, F., additional, Janni, W., additional, Kamischke, A., additional, Rudlowski, C., additional, Nekljudova, V., additional, von Minckwitz, G., additional, and Loibl, S., additional

Published
2018
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26. Abstract P5-20-09: Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study

Author

Möbus, V, primary, Mahlberg, R, additional, Janni, W, additional, Tomé, O, additional, Marmé, F, additional, Forstbauer, H, additional, Reimer, T, additional, von der Assen, A, additional, Reinisch, M, additional, Lorenz, R, additional, Schmatloch, S, additional, Schmidt, M, additional, Sinn, B, additional, Klutinus, N, additional, Stickeler, E, additional, Untch, M, additional, Seiler, S, additional, Burchardi, N, additional, von Minckwitz, G, additional, and Loibl, S, additional

Published
2018
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27. Abstract P2-09-02: Blinded molecular subtyping analysis from RNA-Seq of FFPE samples in the GeparQuinto trial reveals predictive value of VEGFA metagene for bevacizumab treatment

Author

Karn, T, primary, Meissner, T, additional, Weber, K, additional, Sinn, B, additional, Denkert, C, additional, Budczies, J, additional, Nekljudova, V, additional, Fasching, PA, additional, Holtrich, U, additional, Schem, C, additional, Solbach, C, additional, Hartmann, A, additional, Röcken, C, additional, Untch, M, additional, Young, BM, additional, Willis, S, additional, Leyland-Jones, B, additional, von Minckwitz, G, additional, and Loibl, S, additional

Published
2018
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28. TP53 mutation predicts sensitivity to adjuvant gemcitabine in pancreatic cancer: Results from the CONKO-001 study

Author

Sinn, M., primary, Budczies, J., additional, Damm, F., additional, Lohneis, P., additional, Schmuck, R., additional, Treue, D., additional, Striefler, J.K., additional, Bahra, M., additional, Pelzer, U., additional, Jühling, A., additional, Bläker, H., additional, Bischoff, S., additional, Oettle, H., additional, Denkert, C., additional, Riess, H., additional, and Sinn, B., additional

Published
2017
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29. A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with anthracycline-based neoadjuvant chemotherapy

Author

Criscitiello, C., primary, Bayar, M.A., additional, Curigliano, G., additional, Symmans, F., additional, Desmedt, C., additional, Bonnefoi, H., additional, Sinn, B., additional, Pruneri, G., additional, Vicier, C., additional, Pierga, J-Y., additional, Denkert, C., additional, Loibl, S., additional, Sotiriou, C., additional, Michiels, S., additional, and André, F., additional

Published
2017
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30. A gene signature to predict high tumour-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple negative breast cancer.

Author

Criscitiello, Carmen, Bayar, M.A., Curigliano, Giuseppe, Symmans, Fraser, Desmedt, Christine, Bonnefoi, Herve, Sinn, B, Pruneri, Giancarlo, Vicier, C, Pierga, Jean-Yves, Denkert, Carsten, Loibl, Sibylle, Sotiriou, Christos, Michiels, Stefan, Andre, Fabrice, Criscitiello, Carmen, Bayar, M.A., Curigliano, Giuseppe, Symmans, Fraser, Desmedt, Christine, Bonnefoi, Herve, Sinn, B, Pruneri, Giancarlo, Vicier, C, Pierga, Jean-Yves, Denkert, Carsten, Loibl, Sibylle, Sotiriou, Christos, Michiels, Stefan, and Andre, Fabrice

Abstract

In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival., info:eu-repo/semantics/published

Published
2017

31. Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

Author

Darb-Esfahani, S, Denkert, C, Stenzinger, A, Salat, C, Sinn, B, Schem, C, Endris, V, Klare, P, Schmitt, W, Blohmera, J-U, Weichert', W, Moebs, M, Teschl, H, Kuemmeln, S, Sinn, P, Jackisch, C, Dietel, M, Reimer', T, Loi, S, Untch, M, von Minckwitz, G, Nekljudoval, V, Loibl, S, Darb-Esfahani, S, Denkert, C, Stenzinger, A, Salat, C, Sinn, B, Schem, C, Endris, V, Klare, P, Schmitt, W, Blohmera, J-U, Weichert', W, Moebs, M, Teschl, H, Kuemmeln, S, Sinn, P, Jackisch, C, Dietel, M, Reimer', T, Loi, S, Untch, M, von Minckwitz, G, Nekljudoval, V, and Loibl, S

Abstract

BACKGROUND: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. METHODS: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. RESULTS: Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019). CONCLUSIONS: Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.

Published
2016

32. 273PD_PR - Final analysis of the Male-GBG54 study: A prospective, randomised multi-centre phase II study evaluating endocrine treatment with either tamoxifen +/- gonadotropin releasing hormone analogue (GnRHa) or an aromatase inhibitor + GnRHa in male breast cancer patients

Author

Reinisch, M., Seiler, S., Hauzenberger, T., Schmatloch, S., Strittmatter, H.-J., Zahm, D.-M., Thode, C., Jackisch, C., Strik, D., Moebus, V., Reimer, T., Sinn, B., Stickeler, E., Marme, F., Janni, W., Kamischke, A., Rudlowski, C., Nekljudova, V., von Minckwitz, G., and Loibl, S.

Published
2018
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37. Decentral gene expression analysis for ER+/Her2- breast cancer: results of a proficiency testing program for the EndoPredict assay

Author

Denkert, C, Kronenwett, R, Schlake, W, Bohmann, K, Penzel, R, Weber, K E, Höfler, H, Lehmann, U, Schirmacher, P, Specht, K, Rudas, M, Kreipe, H H, Schraml, P, Schlake, G, Bago-Horvath, Z, Tiecke, F, Varga, Z, Moch, H, Schmidt, M, Prinzler, J, Kerjaschki, D, Sinn, B V, Müller, B M, Filipits, M, Petry, C, Dietel, M, Denkert, C, Kronenwett, R, Schlake, W, Bohmann, K, Penzel, R, Weber, K E, Höfler, H, Lehmann, U, Schirmacher, P, Specht, K, Rudas, M, Kreipe, H H, Schraml, P, Schlake, G, Bago-Horvath, Z, Tiecke, F, Varga, Z, Moch, H, Schmidt, M, Prinzler, J, Kerjaschki, D, Sinn, B V, Müller, B M, Filipits, M, Petry, C, and Dietel, M

Abstract

Gene expression profiles provide important information about the biology of breast tumors and can be used to develop prognostic tests. However, the implementation of quantitative RNA-based testing in routine molecular pathology has not been accomplished, so far. The EndoPredict assay has recently been described as a quantitative RT-PCR-based multigene expression test to identify a subgroup of hormone-receptor-positive tumors that have an excellent prognosis with endocrine therapy only. To transfer this test from bench to bedside, it is essential to evaluate the test-performance in a multicenter setting in different molecular pathology laboratories. In this study, we have evaluated the EndoPredict (EP) assay in seven different molecular pathology laboratories in Germany, Austria, and Switzerland. A set of ten formalin-fixed paraffin-embedded tumors was tested in the different labs, and the variance and accuracy of the EndoPredict assays were determined using predefined reference values. Extraction of a sufficient amount of RNA and generation of a valid EP score was possible for all 70 study samples (100%). The EP scores measured by the individual participants showed an excellent correlation with the reference values, respectively, as reflected by Pearson correlation coefficients ranging from 0.987 to 0.999. The Pearson correlation coefficient of all values compared to the reference value was 0.994. All laboratories determined EP scores for all samples differing not more than 1.0 score units from the pre-defined references. All samples were assigned to the correct EP risk group, resulting in a sensitivity and specificity of 100%, a concordance of 100%, and a kappa of 1.0. Taken together, the EndoPredict test could be successfully implemented in all seven participating laboratories and is feasible for reliable decentralized assessment of gene expression in luminal breast cancer.

Published
2012

47. [NF-kappaB subunit p65/RelA expression in ovarian carcinoma: prognostic impact and link to COX-2 overexpression]

Author

Niesporek S, Weichert W, Sinn B, Röske A, Noske A, Ac, Buckendahl, Wirtz R, Sehouli J, Koensgen D, Dietel M, and Carsten Denkert

Subjects
Ovarian Neoplasms, Receptors, Estrogen, Cyclooxygenase 2, Transcription Factor RelA, Humans, Antineoplastic Agents, Female, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53, Promoter Regions, Genetic, Immunohistochemistry, Survival Analysis, Polymorphism, Single-Stranded Conformational
Abstract

NF-kappaB has been demonstrated to activate proliferative, inflammatory, and angiogenic processes in ovarian cancer cells in vitro. To add translational information on the situation in vivo, we determined the expression pattern of p65, an important subunit of the classic NF-kappaB pathway, in ovarian carcinoma tissue, and investigated in vivo and in vitro whether this pathway is implicated in the known overexpression of cyclooxygenase-2 (COX-2).p65 siRNA, chemiluminescent NF-kappaB transcription factor assay, Taqman PCR, as well as immunoblotting were performed with OVCAR-3 ovarian cancer cells. 83 primary ovarian cancinomas as well as 17 cases of benign ovarian tissue were analyzed by p65 and COX-2 immunohistochemistry using a tissue microarray.DNA-binding avtivity as well as COX-2 mRNA and protein expression were strongly inducible by IL-1beta treatment in OVCAR-3 cells, while p65 siRNA inhibited IL-1beta-dependent p65 activity (p = 0.037) as well as COX-2 expression on the mRNA (p0.03) and on the protein level. In human tumor tissue, p65 protein expression was significantly associated with COX-2 expression (p = 0.002) as well as tumor grading (p = 0.005). Furthermore, p65 expression was a significant prognostic indicator of a reduced patient survival both in univariate (p = 0.038) and in multivariate analysis (p = 0.014).Our study indicates a deregulation of the classical NF-kappaB pathway in ovarian cancer, which results in the overexpression of the NF-kappaB target gene COX-2. Components of this pathway might constitute novel attractive targets for a specific therapy of advanced ovarian cancer.

48. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.

Author

Loibl, S, Untch, M, Burchardi, N, Huober, J, Sinn, B V, Blohmer, J -U, Grischke, E -M, Furlanetto, J, Tesch, H, Hanusch, C, Engels, K, Rezai, M, Jackisch, C, Schmitt, W D, Minckwitz, G von, Thomalla, J, Kümmel, S, Rautenberg, B, Fasching, P A, and Weber, K

Subjects
*TRIPLE-negative breast cancer, *METASTATIC breast cancer
Abstract

Background Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. Patients and methods GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). Results A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23–76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ 2 P  =   0.287), corresponding to OR = 1.45 (95% CI 0.80–2.63, unadjusted Wald P  =   0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06–4.64, P  =   0.035; interaction P  =   0.048). In both arms, significantly increased pCR (P  <   0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P  =   0.045) and for PD-L1-immune cell in placebo arm (P  =   0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. Conclusions Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy. Trial registration ClinicalTrials.gov number: NCT02685059. [ABSTRACT FROM AUTHOR]

Published
2019
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50. DNA methylation classifier to diagnose pancreatic ductal adenocarcinoma metastases from different anatomical sites.

Author

Calina TG, Perez E, Grafenhorst E, Benhamida J, Schallenberg S, Popescu A, Koch I, Janik T, Chen B, Ihlow J, Roessler S, Goeppert B, Sinn B, Bahra M, Calin GA, Taube ET, Pelzer U, Neumann CCM, Horst D, Knutsen E, Capper D, and Dragomir MP

Subjects
Humans, Female, Male, Cholangiocarcinoma genetics, Cholangiocarcinoma pathology, Cholangiocarcinoma diagnosis, Liver Neoplasms genetics, Liver Neoplasms secondary, Liver Neoplasms diagnosis, Middle Aged, Aged, Diagnosis, Differential, Neoplasm Metastasis genetics, Bile Duct Neoplasms genetics, Bile Duct Neoplasms pathology, Bile Duct Neoplasms diagnosis, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms diagnosis, DNA Methylation genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms diagnosis
Abstract

Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites., Methods: For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain., Results: The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition., Conclusions: The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/ ) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the ethics commissions of Charité, Universitätsmedizin Berlin (EA1/079/22 and EA1/157/21). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Published
2024
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