ctDNA in Neuroendocrine Carcinoma of Gastroenteropancreatic Origin or of Unknown Primary: The CIRCAN-NEC Pilot Study

Abstract

<b><i>Introduction:</i></b> Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterized by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. <b><i>Methods:</i></b> The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first- or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA was sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction. <b><i>Results:</i></b> All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post-first-line regimen. Twenty-two patients had at least one driver mutation: <i>TP53</i> (<i>n</i> = 21), <i>RB1</i> (<i>n</i> = 2), <i>KRAS</i> (<i>n</i> = 4), and <i>BRAF</i> (<i>n</i> = 3). Ten (42%) had an “adenocarcinoma-like” profile. Five of 6 patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA mutation/immunohistochemistry profile was 64% (7/11) for <i>TP53</i>/p53+ and 14% (1/7) for <i>RB1</i>/pRb−. In this pilot study including few patients by subgroups, patients with <i>KRAS</i> (HR = 3.60, 95% CI [1.06–12.04]) and <i>BRAF</i> (HR = 4.25, 95% CI [1.11–16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the 2 patients with <i>RB1</i> mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR = 0.37, 95% CI [0.15; 0.91]). <b><i>Conclusion:</i></b> This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).