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Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

ABSTRACT: ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer.Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies.At progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients, and identified ALK resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib.Plasma genotyping by NGS is an effective method for detecting ALK fusions and ALK mutations in patients progressing on ALK TKIs. The correlation between plasma ALK mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.

SUBMITTER: Dagogo-Jack I

PROVIDER: S-EPMC5785105 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

Dagogo-Jack Ibiayi I Brannon A Rose AR Ferris Lorin A LA Campbell Catarina D CD Lin Jessica J JJ Schultz Katherine R KR Ackil Jennifer J Stevens Sara S Dardaei Leila L Yoda Satoshi S Hubbeling Harper H Digumarthy Subba R SR Riester Markus M Hata Aaron N AN Sequist Lecia V LV Lennes Inga T IT Iafrate A John AJ Heist Rebecca S RS Azzoli Christopher G CG Farago Anna F AF Engelman Jeffrey A JA Lennerz Jochen K JK Benes Cyril H CH Leary Rebecca J RJ Shaw Alice T AT Gainor Justin F JF

JCO precision oncology 20180123

<h4>Purpose</h4><i>ALK</i> rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer.<h4>Methods</h4>Using a 566- ...[more]

PMID: 29376144

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Project description:BackgroundSelection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer.Patients and methodsEighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI.ResultsOf the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival.ConclusionsCancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

Dataset Information

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

Publications

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

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