Strategies to implement and execute precision oncology

Abstract

Anti-cancer treatment has come a long way, and there probably is a long way to go before we can offer every patient a therapy that works, is safe, and affordable. Many paths may be pursued to ultimately achieve this goal, and precision oncology could be one of them: by matching treatment to specific characteristics of a patient, his or her tumor, and its micro-environment, higher response rates may be achieved whilst toxicity and unnecessary costs could be avoided. This thesis discusses several biomarker-based strategies to tailor treatment to specific tumor- or patient-characteristics, ultimately aimed at improving outcomes for individual patients. Part II is dedicated to tumor micro-environment, and how it may be employed to counteract chemotherapy resistance. It describes two prospective studies, both build on the observation that (A) mesenchymal stem cells (MSCs) mediate platinum-induced chemoresistance in mice, and that (B) indomethacin prevented this type of chemoresistance. Present research has demonstrated that translation to human cancer patients is safe and probably worthwhile, given that patients with advanced cancer have higher levels of circulating MSCs; especially once they have received systemic anti-cancer treatment. Part III focusses on biomarkers for targeted- and immunotherapy. It describes the set-up and first results of the Drug Rediscovery Protocol (DRUP), a nationwide, prospective, multi-drug and pan-tumor trial aimed at identifying new tumor type/molecular variant-combinations that are sensitive to approved anti-cancer drugs. Analysis of the first ~500 clinical case submissions showed that there are many patients (>50% in our dataset) whose molecular tumor profile can potentially be targeted by an already available anti-cancer drug, to which these patients would otherwise not have access. So far, one cohort (nivolumab for patients with MSI tumors) has completed accrual: clinical benefit was observed in twenty patients (67%), including eleven patients (37%) with an objective response. Yet, outside the context of clinical trials, most of these patients do currently not have access to nivolumab treatment. Negotiations with Dutch health authorities are therefore ongoing. Ideally, this will lead to nivolumab-reimbursement under the condition that further / confirmatory data will be gathered (“coverage with evidence development”). If successful, other DRUP cohorts will hopefully follow. Part IV discusses two aspects of precision oncology in daily practice. First, the relationship between somatic mutations and treatment consequences is complex and can’t be fully captured by most currently used gene panels. Adequate interpretation of extensive tumor sequencing, on the other hand, requires expertise from clinical, pathological, biological, genetical and technical perspective. A new type of tumor board is therefore rising: the multidisciplinary genetic- or Molecular Tumor Board (MTB). Three recommendations were formulated that may serve as a roadmap for successful MTB implementation. We feel that standardization of MTB practice would not only prevent variation in quality of care, but would also help to move the emerging field of tumor sequencing forward. Second, the need for cross-disciplinary evidence development is addressed: anti-cancer treatment options now range from systemic therapies, to interventional radiology, and so forth. Evidence directly comparing across these modalities, however, is scarce.