The impact of germline genetic variability on chemotherapy-induced toxicity and survival in early breast cancer patients

Datum: 15 oktober 2015

Locatie: University of Antwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK

Tijdstip: 16.30 uur

Organisatie / co-organisatie: Faculty of Medicine and Health Sciences

Promovendus: Christof Vulsteke

Promotor: Prof M. Peeters & Prof P. Van Dam

Korte beschrijving: PhD defence Christof Vulsteke - Faculty of Medicine and Health Sciences



Abstract

An important part of breast cancer research is focused on genetic biomarkers in which much of the focus has been on somatic mutations determined on tumor tissue (matching the treatment to the cancer).

However, it should not be forgotten that we also need to ensure the treatment is matched to the patient. In fact, cancer patients receiving chemotherapy display a large patient-to-patient variability, which is of major clinical importance, since it can lead to therapeutic failures or adverse drug reactions. Therefore we wanted to investigate if germline genetic biomarkers impact on toxicity in early breast cancer patients allowing a better match of the treatment to the patient. We were interested in polymorphisms that were already reported to impact on toxicity/efficacy, as well as in polymorphisms involved in the metabolism of the studied drugs. However, the studies which assessed the influence of single nucleotide polymorphisms (SNPs) on toxicity/outcome have been small in size or were limited to testing only a single or a few SNPs at most, thereby limiting the validity and applicability of the obtained results.

The initial aim of our research was to assess a comprehensive and large set of relevant SNPs in key metabolic genes in a large study cohort receiving the same chemotherapy for early BC, and study its correlation with development of short-term severe toxicity. In a second phase of our research we wanted to assess the impact of these SNPs on outcome (relapse free interval and breast cancer specific survival). The third phase was to develop a predictive model of patient-related, chemotherapy-related and genetic risk factors on hematological toxicity. During the final phase of our research, long-term toxicity was evaluated.

Our research evidently demonstrated that germline genetic variability, especially in the ABC genes encoding for the human ATP-binding cassette (ABC) transporter family, has an impact on chemotherapy induced toxicity and outcome of early breast cancer patients and can partially explain the large patient-to-patient variability observed. Given the fact that breast cancer is the first most frequent cancer in women and the leading cause of cancer-related deaths, further research in the field of pharmacogenomics is crucial.