Molecular Biomarkers to Guide Personalized Treatment in Colorectal Cancer

Suzanna Schraa

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

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Abstract

Colorectal cancer (CRC) remains a significant health issue, with 13,000 new diagnoses annually in the Netherlands. Two promising advancements in molecular diagnostics could improve personalized treatment: circulating tumor DNA (ctDNA) and NTRK gene fusions.

CtDNA serves as a biomarker for minimal residual disease (MRD) and therefore disease recurrence and could help tailor adjuvant treatment post-surgery. However, the prognostic value of ctDNA before surgery remains uncertain according to a systematic review of 29 studies.

Investigation into ctDNA post-surgery indicated its potential in detecting MRD. A comparative study demonstrated that a tumor-informed ctDNA approach is superior in sensitivity and specificity compared to plasma-only or white blood cells-informed methods. Notably, patients with detectable ctDNA post-surgery had significantly worse recurrence-free and overall survival rates, highlighting ctDNA’s role as a powerful prognostic tool.

The MEDOCC-CrEATE trial is an innovative intervention study designed to evaluate whether ctDNA-guided adjuvant chemotherapy can reduce recurrence rates in stage II colon cancer patients. This trial employs the Trials within Cohorts (TwiCs) design, where eligible patients are pre-surgery participants in the PLCRC study and randomized post-surgery. Patients with detectable ctDNA receive additional chemotherapy, aiming to determine the feasibility and efficacy of ctDNA-guided treatment. If successful, this approach could significantly improve patient outcomes by refining adjuvant therapy decisions.

NTRK gene fusions, though rare in metastatic CRC (mCRC), represent another area of promising development. These fusions are more prevalent in tumors with deficient DNA repair genes (dMMR). TRK inhibitors like larotrectinib and entrectinib, approved for solid tumors with NTRK fusions, have shown remarkable efficacy, but their clinical benefits compared to standard therapies remain unclear due to the low prevalence of these fusions.

Research involving 268 patients with MSI-H/dMMR mCRC revealed a 3.4% prevalence of NTRK fusions, with higher rates in specific subgroups. Tumors with NTRK fusions were often BRAF and RAS wild-type and showed hypermethylation of the MLH1 promoter. Patients with these genetic profiles responded poorly to chemotherapy and anti-EGFR therapy but exhibited prolonged survival with PD-(L)1 inhibitors. This suggests that immunotherapy should be the first-line treatment for MSI-H/dMMR mCRC, regardless of NTRK fusion status, with TRK inhibitors considered as second-line options.

Screening for NTRK fusions is recommended using immunohistochemistry (IHC) followed by RNA-based next-generation sequencing (NGS) for confirmation. Alternative assays, such as FFPE Targeted Locus Capture (FFPE-TLC) and the Idylla GeneFusion test, also show high sensitivity and specificity, making them suitable for confirming NTRK fusions post-IHC screening. FISH, however, is not recommended due to limited sensitivity and robustness.

These advancements underscore the importance of integrating molecular diagnostics into clinical practice to enhance the precision of colorectal cancer treatment, potentially improving prognosis and patient quality of life.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
Supervisors/Advisors
  • Koopman, M, Primary supervisor
  • Vink, Geraldine R, Co-supervisor
  • Fijneman, Remond J A, Co-supervisor
Award date13 Jun 2024
Publisher
Print ISBNs978-94-6483-887-9
DOIs
Publication statusPublished - 13 Jun 2024

Keywords

  • Colorectal cancer
  • Circulating tumor DNA
  • ctDNA
  • biomarkers
  • NTRK
  • gene fusion
  • minimal residual disease
  • personalized treatment

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