Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study

Molecular Cancer
Arnaud Bayle1, Laïla Belcaid1, Lola‐Jade Palmieri2, Diego Teysonneau2, Sophie Cousin2, Mariella Spalato Ceruso2, Mihaela Aldea3, Damien Vasseur4, Mélissa Alamé5, Laura Blouin5, Isabelle Soubeyran5, Claudio Nicotra1, Maud Ngo-Camus1, Antoine Hollebecque1, Yohann Loriot1, Benjamin Besse3, Ludovic Lacroix4, Etienne Rouleau4, Fabrice Barlési6, Fabrice André6, Antoîne Italiano7
1DITEP, Gustave Roussy, Villejuif, France
2Department of Medicine, Institut Bergonié, Bordeaux, France
3Department of Medicine, Gustave Roussy, Villejuif, France
4Department of Biopathology, Gustave Roussy, Villejuif, France
5Department of Biopathology, Institut Bergonié, Bordeaux, France
6Faculty of Medicine, Paris Saclay University, Kremlin-Bicêtre, France
7Faculty of Medicine, University of Bordeaux, Bordeaux, France

Tóm tắt

Abstract Background Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. Methods We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies. Results Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types. Conclusion This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.

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Molecular Cancer

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