Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.

Autor:	Piotrowska Z; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Niederst MJ; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Karlovich CA; Clovis Oncology, San Francisco, California., Wakelee HA; Stanford Cancer Institute, Stanford University, Stanford, California., Neal JW; Stanford Cancer Institute, Stanford University, Stanford, California., Mino-Kenudson M; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Fulton L; Massachusetts General Hospital, Boston, Massachusetts., Hata AN; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Lockerman EL; Massachusetts General Hospital, Boston, Massachusetts., Kalsy A; Massachusetts General Hospital, Boston, Massachusetts., Digumarthy S; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Muzikansky A; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Raponi M; Clovis Oncology, San Francisco, California., Garcia AR; Massachusetts General Hospital, Boston, Massachusetts., Mulvey HE; Massachusetts General Hospital, Boston, Massachusetts., Parks MK; Massachusetts General Hospital, Boston, Massachusetts., DiCecca RH; Massachusetts General Hospital, Boston, Massachusetts., Dias-Santagata D; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Iafrate AJ; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Shaw AT; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Allen AR; Clovis Oncology, San Francisco, California., Engelman JA; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts., Sequist LV; Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. lvsequist@partners.org.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2015 Jul; Vol. 5 (7), pp. 713-22. Date of Electronic Publication: 2015 May 01.
DOI:	10.1158/2159-8290.CD-15-0399
Abstrakt:	Unlabelled: Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required. Significance: This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. (©2015 American Association for Cancer Research.)
Databáze:	MEDLINE
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