Studie van de tumor biologie, en van het verouderend effect van een chemotherapeutische behandeling bij oudere patiënten met borstkanker

The main objective of this doctoral research was to expand the scientific knowledge on the interface between cancer and biological aging. Aging is a multifactorial process that is linked in a very complex way to cancer. Because this had never been done in tumors spontaneously occurring in human patients, we started by studying stromal characteristics of breast cancers arising in young respectively old patients. Based on the description of the SASP (senescence associated secretory profile) and AST (autophagy to senescence transition) in literature, two phenomena supposed to occur in senescent cells (e.g. fibroblasts), and the hypothesis that senescent cells accumulate in the body with aging, tumors arising in older patients could be expected to display a stromal compartment with different characteristics, which ultimately could lead to a different behavior of the tumor cells. By laser capturing the stromal compartments of breast cancers from young and old patients, and comparing the gene expression profiles, we confirmed for the first time in humans, the presence of both phenomena in the older breast cancer stromal samples. Moreover, we found that the older stromal compartment displays significant differences in gene expression compared to younger stroma, which concerned mainly genes responsible for proliferation, dedifferentiation and migration into the extracellular matrix. In a second part of the thesis, we investigated biological aging in the rest of the organism, and the impact from cancer treatment (by chemotherapy) on this process. The main purpose of this research was to provide more evidence-based knowledge, allowing incorporation of the concept ‘biological age’ into therapy decisions for older patients. To do this, it was important to study the value of several biological markers in reflecting the biological age of a patient, as there is no current gold standard for this. In a retrospective study investigating several biological and clinical parameters of aging in young and old breast cancer patients IL-6 showed to be a robust frailty marker. Other markers like Leukocyte Telomere Length, IGF-1 and MCP-1 showed correlations with chronological age but not with frailty level. During this study we also developed the Leuven Oncogeriatric Frailty Score, a tool that summarizes the clinical frailty level of a patient in a more subtle way than do the currently used tools like Balducci classification. Next, we performed a prospective study in early breast cancer patients either or not treated with adjuvant chemotherapy, and tested if the natural evolution of clinical and/or biological aging markers was influenced by chemotherapy. We did not find unexpected changes in the evolution of the most robust aging markers (Leukocyte Telomere Length and Interleukin-6) which means that we do not find convincing evidence that the chemotherapy we studied (Docetaxel-Cyclophosphamide) would accelerate biological aging in breast cancer patients. This is a reassuring finding for oncologists treating older patients. As a secondary endpoint, we checked if clinical or biological markers were correlated with short-term toxicity from chemotherapy, but neither of the aging parameters was useful in predicting grade II-III-IV toxicity, or unplanned hospital readmissions.List of Abbreviations 6 General introduction 7 Objectives of the research 25 Results - Chapter 1: The footprint of the aging stroma in older breast cancers patients 28 - Chapter 2: Biological aging and frailty markers in breast cancer patients 69 - Chapter 3: The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters 85 Concluding discussion and perspectives 105 Appendix 1: Example of a Geriatric Assessment 115 Abstract of the research 135 Nederlandse Samenvatting 136 Curriculum Vitae 138 Bibliography 142nrpages: 147status: publishe