TY - THES A1 - Frey, Lea Sarah T1 - Retrospektive Analyse zur Bedeutung des 21-Gen-Tests (OncotypeDX®) für die Indikationsstellung zu einer adjuvanten Chemotherapie bei Hormonrezeptor-positivem, Her2/neu-negativem Mammakarzinom T1 - Impact of OnctypeDX Recurrence Score on Treatment Recommendations for Patients with early Stage Breast Cancer N2 - Bei der postoperativen Therapieplanung des Mammakarzinoms treten immer wieder Entscheidungsgrenzfälle auf, bei denen keine sicheren Argumente für oder gegen eine adjuvante Chemotherapie gefunden werden können. Bei 50 Hormonrezeptor-positiven, Her2/neu-negativen Mammakarzinomen ohne oder mit nur geringer nodaler Metastasierung (max. pT1a) wurde zusätzlich zu den konventionellen klinisch-pathologischen Risikofaktoren der OncotypeDX®-Multigentest veranlasst. In der Tumorkonferenz wurde bereits vor Eingang des Testergebnisses ein Votum für oder gegen eine Chemotherapie auf Basis konventioneller Parameter protokolliert; die definitive Therapieempfehlung erfolgte nach Vorliegen des Multigentest-Ergebnisses. 32 Mammakarzinome (64 %) zeigten einen niedrigen, 26 (32 %) einen mittleren und 3 (6 %) einen hohen Recurrence-Score (RS). In vielen Fällen konnte das OncotypeDX®-Ergebnis eine auf der Basis konventioneller Parameter getroffene Therapieentscheidung stützen. In fünf Fällen wurde eine zunächst favorisierte Entscheidung für eine adjuvante Therapie revidiert. In drei Fällen wurde eine zunächst nicht geplante Chemotherapie empfohlen. Allerdings führte in einigen Fällen auch eine niedrige oder intermediäre Risikokonstellation in der OncotypeDX®-Testung nicht dazu, von einer adjuvanten Chemotherapie abzuraten. Insgesamt spricht das Ergebnis nicht dafür, einen Multigentest als Standardmethode einzusetzen. Vielmehr sollten zunächst die konventionellen, insbesondere die histopathologischen und immunhistochemischen Parameter mit großer Sorgfalt erhoben und analysiert werden. Im Zweifelsfall und nach Kosten-Nutzen-Abwägung kann ein Multigentest jedoch ein weiteres hilfreiches Argument für oder gegen eine bestimmte Therapieempfehlung liefern. N2 - Repeatedly in therapy planning of breast cancer there are decision borderline cases where no reliable arguments for or against adjuvant chemotherapy can be found. In 50 cases with hormone receptor-positive, Her2-negative, node-negative or low node-positive (max. pN1a) OncotypeDX® assay was induced additionally to conventional parameters. Before receiving results there was a vote in interdisciplinary tumor conference for or against chemotherapy based on conventional parameters. Final treatment recommendations were made after receiving test results. 32 breast cancer cases (64 %) showed low, 26 (32 %) intermediate and 3 (6 %) high recurrence score (RS). In many cases the test result supported the treatment recommendation based on conventional parameters. In five cases initially favoured decision for adjuvant chemotherapy was revised. In three cases there was a recommendation of chemotherapy which was initially not proposed. However, in some cases low or intermediate recurrence score didn´t cause to recommend against adjuvant chemotherapy. In conclusion, results do not suggest using OncotypeDX® as standard. Rather there should be a careful survey of conventional parameters, especially of histopathological and immunohistochemical parameters. In cases of doubt and after cost-benefit-consideration OncotypeDX® assay may provide an additional argument for or against a certain therapy management. KW - Mammakarzinom KW - Multigentests KW - OncotypeDX Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156908 ER - TY - JOUR A1 - Völker, Hans-Ullrich A1 - Weigel, Michael A1 - Strehl, Annette A1 - Frey, Lea T1 - Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array JF - Diagnostic Pathology N2 - Background: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX\(^{®}\), a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test. Methods: The results of Ki67, uPA/PAI-1 and OncotypeDX\(^{®}\) were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed. Results: With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values. Conclusion: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised). KW - breast cancer KW - OncotypeDX\(^{®}\) KW - uPA KW - multigene-array KW - PAI-1 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176960 VL - 13 IS - 67 ER - TY - JOUR A1 - Dirks, Johannes A1 - Haase, Gabriele A1 - Cantaert, Tineke A1 - Frey, Lea A1 - Klaas, Moritz A1 - Rickert, Christian H. A1 - Girschick, Hermann A1 - Meffre, Eric A1 - Morbach, Henner T1 - A novel AICDA splice-site mutation in two siblings with HIGM2 permits somatic hypermutation but abrogates mutational targeting JF - Journal of Clinical Immunology N2 - Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients. KW - hyper-IgM syndrome type 2 (HIGM2) KW - AICDA KW - AID-ΔE4a KW - AD-AID KW - mutational targeting KW - somatic hypermutation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324253 VL - 42 IS - 4 ER -