Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor (GIST) harboring activating mutations of CKIT or PDGFRA
Menée sur 291 échantillons de plasma prélevés sur 38 patients atteints d'une tumeur stromale gastro-intestinale présentant des mutations du gène CKIT ou PDGFRA, cette étude évalue l'intérêt d'analyser les fragments d'ADN librement circulant pour le suivi thérapeutique
Purpose:In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor specific CKIT or PDGFRA mutant DNA fragments can be detected and quantified in plasma samples of GIST patients.
Experimental Design:We prospectively collected 291 plasma samples from 38 subjects with GIST harbouring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific Ligation PCR to detect mutant free circulating (fc)DNA.
Results:We were able to detect fcDNA harbouring the tumor mutation in 15 out of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared to patients in CR. The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations, and found four additional exchanges, including mutations not known from sequentially performed tumor biopsies.
Conclusions:Our results indicate that free circulating DNA harbouring tumor specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies.
Clinical Cancer Research , résumé, 2013