Tumor- und risikoadaptierte Individualisierung der neoadjuvanten und post-neoadjuvanten Therapie bei PatientInnen mit Mammakarzinom

Dimpfl, Moritz (2023): Tumor- und risikoadaptierte Individualisierung der neoadjuvanten und post-neoadjuvanten Therapie bei PatientInnen mit Mammakarzinom. Dissertation, LMU München: Medizinische Fakultät

Abstract

During 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.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Mammakarzinom, neoadjuvante Chemotherapie, personalisierte Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Deutsch
• Datum der mündlichen Prüfung: 17. Juli 2023
• 1. Bericht­erstatter:in: Harbeck, Nadia