Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer.

Autor:	Piotrowska Z; Massachusetts General Hospital, Boston., Hazar-Rethinam M; Massachusetts General Hospital, Boston., Rizzo C; Massachusetts General Hospital, Boston., Nadres B; Massachusetts General Hospital, Boston., Van Seventer EE; Massachusetts General Hospital, Boston., Shahzade HA; Massachusetts General Hospital, Boston., Lennes IT; Massachusetts General Hospital, Boston., Iafrate AJ; Massachusetts General Hospital, Boston., Dias-Santagata D; Massachusetts General Hospital, Boston., Leshchiner I; Eli and Edythe L. Broad Institute of MIT and Harvard., Jessop NA; Massachusetts General Hospital, Boston., Hu H; Massachusetts General Hospital, Boston., Digumarthy SR; Massachusetts General Hospital, Boston., Nagy RJ; Guardant Health, Redwood City, CA., Lanman RB; Guardant Health, Redwood City, CA., Moody S; Novartis Institutes for Biomedical Research, Cambridge, MA., Niederst MJ; Novartis Institutes for Biomedical Research, Cambridge, MA., Engelman JA; Novartis Institutes for Biomedical Research, Cambridge, MA., Hata AN; Massachusetts General Hospital, Boston., Corcoran RB; Massachusetts General Hospital, Boston., Sequist LV; Massachusetts General Hospital, Boston.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2018; Vol. 2018. Date of Electronic Publication: 2018 Jul 16.
DOI:	10.1200/PO.17.00263
Abstrakt:	Purpose: Third-generation epidermal growth factor receptor (EGFR) inhibitors like nazartinib are active against EGFR mutation-positive lung cancers with T790M-mediated acquired resistance to initial anti-EGFR treatment, but some patients have mixed responses. Methods: Multiple serial tumor and liquid biopsies were obtained from two patients before, during, and after treatment with nazartinib. Next-generation sequencing and droplet digital polymerase chain reaction were performed to assess heterogeneity and clonal dynamics. Results: We observed the simultaneous emergence of T790M-dependent and -independent clones in both patients. Serial plasma droplet digital polymerase chain reaction illustrated shifts in relative clonal abundance in response to various systemic therapies, confirming a molecular basis for the clinical mixed radiographic responses observed. Conclusion: Heterogeneous responses to treatment targeting a solitary resistance mechanism can be explained by coexistent tumor subclones harboring distinct genetic signatures. Serial liquid biopsies offer an opportunity to monitor clonal dynamics and the emergence of resistance and may represent a useful tool to guide therapeutic strategies.
Databáze:	MEDLINE
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