1216P Prognostic potential of liquid biopsy in advanced HER2 positive esophagogastric adenocarcinoma under HER2 blockade and immune checkpoint therapy

Abstract

Immune therapy and immune checkpoint inhibition (ICI) have drastically improved survival for an increasing number of entities and thereby revolutionized modern oncology. However, even in combined multi-agent approaches, therapy resistance presents a major limitation and imposes the need for tight and sensitive monitoring of the disease status. Liquid biopsy holds the potential to track both the tumor and the patient’s immune response and therefore to monitor even hardly accessible solid tumors as well as to predict therapy outcomes. In the work presented here, we explored the prognostic value of liquid biopsy in patients with advanced HER2+ esophagogastric adenocarcinoma (EGA) receiving first-line treatment of trastuzumab (αHER2) and nivolumab (αPD-1) in combination with ipilimumab (αCTLA-4) or FOLFOX as translational part of the INTEGA trial (NCT03409848). From blood sampled at baseline, after the first treatment cycle (2-3 weeks) and at the end of treatment, we isolated cell-free DNA (cfDNA) to quantify tumor burden and to derive the mutational landscape of the tumor from the contained circulating tumor DNA. Furthermore, we analyzed genomic DNA of blood cells via next-generation sequencing for imprints of the T cell receptor repertoire. We identified a potential tumor driver mutation from cfDNA at baseline in 88 % of cases implying that liquid biopsy is suitable to track malignant lesions in the setting of advanced HER2+ EGA. In some progressive patients, we found truncating or epitope-loss HER2 resistance mutations acquired on therapy, representing a new tumor escape mechanism under ICI with HER2 blockade. Analysis of the T cell immune repertoire in blood showed a significant correlation between high T cell richness and longer survival already after 2-3 weeks, which might represent a read-out for restored T cell activity upon ICI. Moreover, the crude amount of cfDNA per ml blood plasma after 2-3 weeks significantly correlated with response to treatment. Thus, the quantification of cfDNA could offer a relevant prognostic parameter to be implemented into the clinical praxis without the need for time-consuming and cost-intensive analyses.