ONCOTHESIS

Response prediction in clear cell renal cell carcinoma treated with anti-vascular endothelial growth factor-targeted therapy

Several years after approval of anti-vascular endothelial growth factor-targeted therapy for locally advanced and metastatic clear cell renal cell carcinoma, we discovered and/or validated new clinical, biochemical, pathological, pharmacokinetic, molecular and genetic markers predictive for response and/or prognostic in metastatic clear cell renal cell carcinoma patients treated with anti-vascular endothelial growth factor-receptor-tyrosine kinase inhibitors.

(BELG J MED ONCOL 2015;9(1):35–41)

High-risk localised prostate cancer: the role of surgery and the development of clinical outcome prediction models

This PhD thesis is aimed at elucidating some very important issues on high-risk prostate cancer: How can high-risk prostate cancer best be defined? Can we clearly define demarcated prognostic subgroups within the high-risk prostate cancer group which could allow improved patient counselling, comparison of different treatment strategies and proper trial design? What are the outcomes of surgery in high-risk prostate cancer and how can we identify those patients within the heterogeneous group of high-risk prostate cancer who would benefit most from surgery?

(BELG J MED ONCOL 2014;8(5):220–3)

Predictors of lymph node metastasis in patients with breast cancer

The aim of this PhD-project was to identify predictors of lymph node metastasis in patients with breast cancer and to integrate these findings in the surgical management of the axilla.

In first phase, we aimed to provide more insight in the biology of lymph node metastasis. We performed gene and miRNA expression profiles of primary tumour tissue and showed that lymph node involvement is not a genetically random process. In a next step, we built a model to predict lymph node involvement based on clinicopathological variables. Tumour size, presence of lymphovascular invasion, multifocality and the location of the tumour in the breast emerged as independent predictors of the lymph node status. Additionally, our data provided evidence that the axillary lymph node status is not only a reflection of the chronological age of a tumour, but also of tumour biology. We then demonstrated that the macrophage density in primary tumour tissue is related to mitotic grade, but not to lymph node status.

In second phase, we aimed to optimise axillary surgery policy in patients with breast cancer. We showed that sentinel lymph node biopsy is at least as accurate as axillary lymph node dissection to detect positive lymph nodes. Additionally, we developed an algorithm for a tailored surgical approach of the axilla. We suggested omitting completion axillary lymph node dissection in a subgroup of patients with a positive lymph node and a low risk of positive non-sentinel lymph nodes. Finally, our findings indicated that implementation of a tailored surgical approach to the axilla results in significant inter-institutional differences.

(BELG J MED ONCOL 2014;8(4):129–31)

Non-muscle myosin IIA, a new potential molecular target to improve radiotherapy outcome for breast cancer patients

Reduced response to radiotherapy significantly hampers tumour control and cure for breast cancer patients. Aside from well-known genetic and epigenetic alterations, increasing evidence points to extracellular matrix interactions as contributors to acquired or developed cancer cell radio-resistance, called cell adhesion-mediated radio-resistance. Our research group observed a dose-dependent increase of collagen type I matrix reorganisation induced by breast cancer cells and associated decrease in radiation-induced breast cancer cells death. Our results for molecular characterisation confirmed the role of focal adhesion components ß1 integrin and focal adhesion kinase in extracellular matrix remodelling and associated radio-resistance. Furthermore, we introduced a new potential target to counteract cell adhesion-mediated radio-resistance, namely non-muscle myosin IIA. The irradiated breast cancer cells were characterised by an increased non-muscle myosin IIA expression and non-muscle myosin IIA-dependent collagen type I reorganisation. Hereby, we hypothesize that extracellular matrix remodelling by irradiated breast cancer cells worsens treatment outcome and can be counteracted by inhibition of non-muscle myosin IIA.

(BELG J MED ONCOL 2014;8(3):91–3)

Bone marrow derived mesenchymal stem cells in colorectal cancer: neuregulin at the invasion front

Tumour invasion and metastasis are not cell cancer cell-autonomous conditions, but involve complex heterotypic multicellular interactions. Bone marrow derived mesenchymal stem cells migrate to primary colorectal cancers and are precursors of carcinoma-associated fibroblasts, which, in turn, drive tumour progression. The molecular mechanisms of how these supporting host cells modulate colorectal cancer progression are largely unknown and understanding them is of profound clinical importance. Our research group recently discovered that bone marrow mesenchymal stem cells stimulate invasion, survival and tumorigenesis of colorectal cancer cells through the release of soluble factors. Soluble neuregulin 1 secreted by bone marrow mesenchymal stem cells was responsible for the observed effects, and signalled through HER2/HER3-dependent activation of the PI3K/AKT/BAD pathway in colorectal cancer cells. Immunohistochemical data demonstrated that transmembrane neuregulin 1 is expressed in carcinoma-associated fibroblasts in clinical colorectal cancer specimens, with the strongest expression in the immediate vicinity of infiltrative HER2/HER3 expressing cancer cells. High transmembrane neuregulin 1 expression levels were associated with advanced tumour stage, invasion depth and decreased five-year progression free survival. These results indicate that stromal transmembrane neuregulin 1 may serve as a novel prognostic marker for colorectal cancer. Strategies that disable this mesenchymal-epithelial interaction may be of therapeutic value for colorectal cancer.

(BELG J MED ONCOL 2014;8(2):52–4)

Improving post-implant evaluation of permanent seed implant brachytherapy for prostate cancer

Permanent brachytherapy with radioactive seeds is a widely available and effective treatment for low-risk prostate cancer patients. An important factor affecting tumour control and complication rates is implant quality. Therefore, dosimetric post-implant evaluation (postplanning) is recommended as a standard-of-care practice to ensure the quality of the implant technique and to obtain dosimetric data for establishing dose-response relationships. Currently, the relationship between delivered dose and tumour response is not clear, which to a large extent may be attributed to the uncertainties related to post-implant dosimetry. Seed reconstruction, prostate delineation and image fusion inaccuracies play an important role in this, though it is not known how large their impact is on the post-planning evaluation parameters. In this research, we quantified and compared these uncertainties for different imaging techniques. The overall aim was to improve the quality of post-implant evaluation in order to obtain more consistent and reliable dosimetric post-plan information.

(BELG J MED ONCOL 2014;8(1):18–20)

The role of imaging in a patient-tailored approach for prostate cancer

Summary

One of the obstacles for the adequate treatment of prostate cancer is the lack of reliable modalities to detect lymph node involvement in newly diagnosed patients. Until now, the only accurate solution is to perform an extended lymph node dissection. In this dissertation, investigated the role of choline positron emission tomography-computed tomography, diffusion-weighted magnetic resonance imaging and a sentinel node procedure for nodal staging were investigated showing that these novel approaches are not reliable enough to substitute for a lymphadenectomy. Furthermore, we reported which regions are of most importance if a staging lymphadenectomy is performed.

A second part, focused on the accurate localisation of the macroscopic tumour nodule within the prostate since delivering a higher radiation dose to this specific region might reduce the chances of local recurrence after radiotherapy. Therefore, the performance of the aforementioned imaging modalities were tested in the detection of intraprostatic tumour nodule(s). In conclusion, combining different functional magnetic resonance imaging modalities improved visualisation of the tumour but that the additional value of a positron emission tomography scan in this specific setting was limited.

(BELG J MED ONCOL 2013;7(5):156–58)