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Tumor- und risikoadaptierte Individualisierung der neoadjuvanten und post-neoadjuvanten Therapie bei PatientInnen mit Mammakarzinom
Get PDFDuring the last decade, modern oncology has switched from a “one therapy fits all” to a risk-tailored and individualized medicine. For breast cancer, the most common malignancy in women worldwide, this has led to early breast cancer nowadays being seen as a curable disease. A great benefit of modern diagnostic options and targeted therapies is the differ-entiation between breast cancer patients at different disease-related risk situations, e.g. regarding recurrence. This differentiation is mainly based on worldwide used classification systems, like the TNM-classification, grading, as well as surrogate-subtyping based on the immunohistological profile of the primary disease. The advancement towards personalized, risk-tailored oncologic therapy will surely continue due to the development of. targeted ther-apies and the specific identification of patients with an increased tumor-associated risk.
The aim of this thesis was on the one hand to identify patients with a high chance for a pathologic complete response with in vivo evaluation of therapeutic response and therefore a high chance for a favorable prognosis. On the other hand, there is a major need to identi-fy patients at increased oncologic risk, even though they receive state-of-the-art systemic therapy. Tumors may develop therapeutic resistance or change biological characteristics, leading to a progredient oncologic disease. These patients are therefore in need of a switch of the systemic therapy, regularly leading to therapeutic escalation.
With the publication
The use of breast ultrasound for prediction of pathologic complete response in different subtypes of early breast cancer within the WSG-ADAPT subtrials (2)
we were able to show that especially for patients with HR-negative/HER2-negative or HR-negative/HER2-positive early breast cancer, ultrasound allows the prediction of pathological complete response is statistically reliable for approximately 2/3 of patients (65 % and 69 % respectively) as early as three weeks into neoadjuvant therapy. This may enable the identi-fication of patients, who could benefit from a dose reduction of systemic therapy to enhance therapeutic compliance and reduce therapy-associated side effects. Moreover, it is of major importance to identify patients who do not have good tumor response to therapy. We were able to demonstrate that in 75,4 % of patients who do not show sonographic response to therapy after three weeks of NACT, no pathologic complete response will be reached. This might be an easy-to-handle future possibility to identify HR-negative/HER2-negative pa-tients, who could potentially benefit from an early therapeutic escalation to reach higher pCR rates. This would have a major impact on prognosis. Future studies need to demon-strate whether individualization of neoadjuvant therapy based on the sonographic findings is feasible.
Furthermore, our publication
Hormone receptor and HER2 status switch in non-pCR breast cancer specimens after neoadjuvant therapy (1)
showed, that breast cancer, especially if treated by neoadjuvant chemotherapy, is a very heterogeneous disease. We were able to show, that in more than ¼ of tumors not achieving a pCR, a switch of tumor specific biomarkers on the surgical specimen, compared to the status at initial diagnosis, appeared. For now, there, is no consensus regarding the prog-nostic value of switched biomarkers after neoadjuvant chemotherapy. The basis for further knowledge regarding a switched biomarker status after neoadjuvant chemotherapy would be comprehensive immunohistological diagnostics of the non-pCR specimen. Besides diag-nostics, post-neoadjuvant therapy is a key feature to tailor risk-adapted therapeutic concepts. In analogy to the recommenda-tions for metastatic breast cancer, it seems reasonable to assume that in case of non-pCR, the biomarker status of the residual tumor tissue may be therapy-determining for the post-neoadjuvant therapy. Future studies need to show whether individualization of therapy based on the biomarker status of the non-pCR specimen is superior to the therapy ap-proach solely based on the biomarker status at initial diagnosis.
Therapy de-escalation and therefore reduction of therapy-associated side-effects are of major importance for the individual patient and potentially substantially increase the quality of life. Moreover, therapeutic escalation of the post-neoadjuvant phase may enable the best possible outcome. The major aim of modern, individualized oncology is not only to pre-vent overtreatment, associated with severe side-effects, but also, to prevent undertreat-ment, which, especially for patients with an increased risk, could result in an inferior long-term prognosis. Future scientific research needs to demonstrate, whether dynamic adapta-tion of oncologic therapy based on recurrent disease-specific examinations is superior for the overall therapeutic success, compared to the current therapeutic concept, solely based on tumor characteristics at initial diagnosis
The usefulness of dynamic approaches in predicting risk of overweight in children within the PEACHES cohort
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Erstellung und Validierung der deutschen Version des Brief Stress and Coping Inventory (BSCI) und Anwendung bei Patienten der Klinik und Poliklinik für Dermatologie und Allergologie der Ludwig-Maximilians-Universität München
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Erstellung und Evaluation eines Onlinekurses im Fach Gerichtliche Veterinärmedizin, Berufs- und Standesrecht
Get PDFAuftreten chronischer gastrointestinaler Symptome nach akutem hämorrhagischem Durchfall beim Hund
Get PDFInvestigating the role of lipids and substrate recognition motifs in the function of aspartyl intramembrane proteases
Get PDFIntramembrane proteases (IMPs) are interesting proteolytic enzymes since they are able to perform the water-requiring hydrolysis reaction in the water-excluding lipid membrane. IMPs are involved in various crucial cellular processes like development or cell signalling but also play a role in the onset and progression of diseases such as Alzheimer’s disease (AD) or certain cancers. The human aspartyl IMP γ-secretase is directly involved in the onset of AD, since it cleaves the C-terminal fragment β (CTFβ) of the β-amyloid precursor protein (APP) releasing amyloid β (Aβ) peptides of which the longer forms like Aβ 42 aggregate into oligomers and plaques which is thought to be causative for AD. γ-Secretase is a multiprotein complex composed of four subunits. The catalytically active subunit is presenilin (PS) which exists in two homologs (PS1 and PS2). PS also has homologs in other organisms like the presenilin/SPP homolog (PSH) found in an archaeabacterium. Like PS, PSH is able to cleave APP-based substrates resulting in the release of an APP intracellular domain (AICD) and Aβ species of various lengths. The Aβ species are released from the substrate in a stepwise cleavage mechanism (processive cleavage). In contrast to PS, the activity of PSH is not dependent on the formation of a complex with accessory proteins and therefore allows to study PS function independent of complex formation. The activity of IMPs is strongly dependent on their environment and can be modulated by several factors like the surrounding pH, the composition of the lipid bilayer or the thickness of the membrane. But little is known about the mechanism underling this modulatory effect of the lipid membrane on IMPs and how the lipid membrane influences the structural dynamics of IMPs. Furthermore, it is also unknown whether – at least – aspartyl IMPs share structural motifs for substrate recognition/binding and what role these motifs might play for their activity. The first part of this study focusses on how the lipid environment modulates the activity of PSH and tries to unravel the underlying mechanism. It was shown that PSH produces longer Aβ peptides when its activity was assessed in a DDM micelle environment. This attenuated processive cleavage was enhanced when PSH was reconstituted into a POPC bilayer and shorter Aβ species were generated. Homology model building could reveal that PSH shares substrate recognition/binding motifs with γ-secretase, namely a small additional helix called transmembrane domain (TMD)6a C-terminal of TMD6 and a cytosolic hybrid β-sheet formed by β-strands from PSH and the APP-based C83 substrate. Mutational analysis could confirm the existence of these elements and their importance for the PSH activity. MD simulations based on this model suggest that the active site geometry is destabilized in the detergent environment compared to the lipid environment and this was validated by performing inhibitor affinity precipitation experiments. Taken together, these results show that PSH share key structural elements with γ-secretase and that the lipid environment is crucial for the correct formation of the active site geometry and promotes the processive cleavage. The second part of this study focused on the hybrid β-sheet of the γ-secretase–C83 complex. To this end, mutational analysis of one of the PS1 β-strands (β2) and of the C83 β-strand (β3) were performed. These mutations were designed to disrupt the β-sheet and all mutations studied here strongly reduced the total activity of γ-secretase. Furthermore, most of the mutations also decreased the processive cleavage resulting in the release of longer Aβ peptides and they also shifted the site of the first γ-secretase cleavage, determining which Aβ product line is used. In addition, the β2-strand mutations also reduced the endoproteolysis of PS1 into an N-terminal fragment (NTF) and a CTF. Taken together, the hybrid β-strand is an important structural element of the γ-secretase–substrate complex which influences the total activity as well as the processive cleavage. The results of this study help to explain how the lipid bilayer can modulate the activity of IMPs by influencing the structural dynamics of the enzymes, especially of important structural elements. One very important structural element of aspartyl IMPs is the hybrid β-sheet formed in the enzyme–substrate complex which influences the total activity as well as the processive cleavage since it is needed to correctly position the scissile bond between the two catalytic aspartates and to drain out excess water molecules from the active site
