Implementation of up-front ctDNA analysis into lung cancer care and development of liquid biopsy-based decision support models - the Lungmarker2 study

In the Netherlands, 14,700 new patients were diagnosed with lung cancer (LC) in
2021. LC ranks sixth regarding burden of disease, and first compared to other
malignancies. Diagnosis is based on imaging and histopathology/cytology of
suspicious tissue. Depending on tumor type and stage, additional analyses like
next-generation sequencing (NGS) and protein analysis on tissue are needed.
With new, biomarker-based therapeutic options that improve survival, it is of
importance to obtain all relevant tumor characteristics to ensure the best
match between tumor and therapy. Tumor biopsies are not always informative, and
many patients undergo re-biopsies, increasing patient burden and strain on
health care resources. Still, for a substantial number of patients, information
required for decision making is lacking and a significant number of patients
with poor performance status die before therapy is started.
Liquid biopsy (LB) is the analysis of tumor remnants, e.g. circulating tumor
cells (CTCs), circulating tumor DNA (ctDNA) and tumor-enhanced endogenous
proteins (tumor markers, TMs), in body fluids and can be used as complementary
source of tumor information. Despite scientific evidence, use of LB in
diagnosis and monitoring of lung cancer (LC) is limited since it requires major
changes in diagnostic and care pathways. Analyzing TMs, CTCs and ctDNA in blood
can inform about the nature of the tumor, the most appropriate therapy, therapy
response and resistance.

This study implements up-front ctDNA analysis ('plasma first approach') into
routine diagnostic work-up of all advanced stage LC patients in the Southeast
of the Netherlands (the participating hospitals in the OncoZON region).
Thereby, additional information about the molecular make-up of the tumor
becomes available, the number of tissue NGS analyses will decrease and time to
therapeutic decision making is shortened. Next, using ctDNA, TM and other
information, multiparametric decision support models are built and validated
that may support diagnosis, predict the outcome of the next imaging procedure
and progression-free survival during follow up. The final goal is to develop a
super-resolution microscopy test that can detect PD-L1 expression on CTCs.

Multicenter, prospective, implementation and diagnostic cohort study

At diagnosis, an extra 10 mL of blood are drawn during a routine venipuncture.
If the subject has advanced stage LC, an additional venipuncture is performed
and 40 mL of blood are drawn for ctDNA analysis. Some of the patients undergo
LBs during treatment. The follow up period is 36 months max. with a maximum of
20 blood draws. The volume per draw ranges from 10-40 mL. The risks of a
venipuncture are negligible and the burden minimal.