Genetic alterations during treatment of oligometastatic colorectal cancer

Aim of this pilot study is to assess the influence of local tumor ablation on the evolution of genetic alterations of circulating tumor DNA in metastatic colorectal carcinoma undergoing systemic chemotherapy plus targeted therapy. The assessment of genetic alterations will be done by plasma DNA sampling. Data generated will serve to design future randomized study formats or plasma DNA-alteration tailored treatment approaches.

The study objectives are:

Primary objective:

• Does the slope of decrease of the plasma tumor DNA predict PFS and/or OS? (investigation of deepness of response)

Secondary objectives:

Is tumor recurrence (PFS1, PFS2) associated with a different profile of genetic alterations? (investigation of genetic evolution under drug-induced selection pressure)

Does local ablation after tumor progression eradicate resistant tumor clones selected by prior systemic treatment (investigation of modifiable drug resistance)

Clinically, oligometastastic disease has not been precisely defined yet. However, a rather benign disease character with prolonged disease free survival and emergence of limited numbers of metastases upon progression has been described as prognostically favourable and some patients can even be cured by multimodal treatment including systemic chemotherapy and surgical resection or local ablation of metastases. In contrast, patients with polytope metastatic disease with rather aggressive biological behaviour most likely do not benefit substantially from local treatments.
Besides standard clinical definition, novel biomarkers are needed to biologically define an oligometastatic disease status in the future and to better assess response and the occurrence of resistance during treatment.
Clonal selection pressure has gained increasing interest in various tumor entities and with emerging targeted treatment options. In colorectal cancer, tumor RAS mutation status represents a validated predictive biomarker for the efficacy of EGFR-antibody treatment. However, in a RAS wt population treated with EGFR inhibition, owing to inherent genetic tumor heterogeneity, clonal selection pressure can result in the occurrence of resistance mediated by RAS mutated clones during targeted treatment. Interestingly, these resistant clones can be found by highly sensitive testing within the initial tumor lesions at very low frequency. Recently, different highly sensitive methods have been developed to monitor DNA mutations within the circulating free tumor DNA from blood samples and the term "liquid biopsies” has been coined.
Additionally, miRNA expression profiles from tumor samples have been described that might be useful to characterize an oligometastatic disease status. However, further validation of this concept within clinical trials is needed.
In principle, this pilot study is intended to generate data enabling the design of a larger consecutive (probably randomized) study format. Data of the pilot will be compared with data from the "PlaCol” patient cohort sampled in Paris Université Descartes (PI: Prof. Pierre Laurent-Puig). Second, our intention is to develop a protocol for public funding either as a randomized study or a free plasma DNA alteration-tailored treatment approach.

Pilot study: single-arm, biomarker-driven study to explore the evolution of genetic alterations during treatment of oligometastatic disease