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Early responses of EGFR circulating tumor DNA to EGFR tyrosine kinase inhibitors in lung cancer treatment.

ABSTRACT: Early evaluation of the effect of treatment is helpful in the management of cancer patients. Circulating biomarkers are an ideal tool for this if they are highly specific to tumors and respond rapidly to tumor volume changes. Circulating tumor DNA (ctDNA) is one such candidate. We conducted a prospective study to test the utility of EGFR ctDNA in early evaluation of EGFR-TKI effects.Twenty-one patients with EGFR-mutant lung cancer who were naïve to EGFR-TKI were enrolled. PM scores of EGFR ctDNA with activating mutations decreased rapidly in response to EGFR-TKI. Of the 14 patients with positive pretreatment PM scores, complete disappearance of major EGFR ctDNA was observed in 14.3%, 42.9%, and 57.1% on days 2 - 4, 8, and 15, respectively. These responses of EGFR ctDNA were most prominent among the measures used to evaluate responses, and correlated with early radiologic responses evaluated by chest X-rays.EGFR ctDNA in serial plasma samples was amplified and 105 copies were sequenced with a next-generation sequencer. Plasma mutation (PM) score was defined as the number of reads containing deletions/substitutions in 105EGFR cell free DNA (cfDNA). When EGFR mutation in ctDNA was the same as that detected in cancer tissue, the ctDNA was defined as major EGFR ctDNA.The results indicate the usefulness of ctDNA as a highly specific biomarker for prediction of early response to treatment and that it can be applied to various types of cancer.

SUBMITTER: Imamura F

PROVIDER: S-EPMC5342122 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Early responses of EGFR circulating tumor DNA to EGFR tyrosine kinase inhibitors in lung cancer treatment.

Imamura Fumio F Uchida Junji J Kukita Yoji Y Kumagai Toru T Nishino Kazumi K Inoue Takako T Kimura Madoka M Kato Kikuya K

Oncotarget 20161101 44

<h4>Objectives</h4>Early evaluation of the effect of treatment is helpful in the management of cancer patients. Circulating biomarkers are an ideal tool for this if they are highly specific to tumors and respond rapidly to tumor volume changes. Circulating tumor DNA (ctDNA) is one such candidate. We conducted a prospective study to test the utility of EGFR ctDNA in early evaluation of EGFR-TKI effects.<h4>Results</h4>Twenty-one patients with EGFR-mutant lung cancer who were naïve to EGFR-TKI wer ...[more]

PMID: 27708242

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Project description:ObjectiveCirculating tumor DNA (ctDNA) monitoring proves to be a promising approach to assess response and predict survival in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs). However, whether the dynamic changes in ctDNA EGFR mutation status have the same predictive value as ctDNA remains unknown. This study aims to explore the predictive value of dynamic changes in both ctDNA and ctDNA EGFR status.MethodsA retrospective analysis was performed using 91 ctDNA samples from a cohort of 28 patients who were diagnosed with EGFR-mutated NSCLC and treated with EGFR-TKIs, including 14 patients treated with first-/second-generation TKIs and 14 treated with osimertinib. Blood samples at baseline (BL), within 4 weeks after TKI initiation (Week4), within 12 weeks before progression (pre-PD), and at progression were collected. The relationship alternatives in ctDNA status, ctDNA EGFR status and response to EGFR-TKIs as well as progression-free survival (PFS) were analyzed.ResultsWe categorized 20 BL-ctDNA positive patients with available Week4-ctDNA into two groups: ctDNA-clearance (N = 7, 35%) and ctDNA-non-clearance (N = 13, 65%). The ctDNA-clearance group had better PFS than the ctDNA-non-clearance group (ctDNA-clearance vs. ctDNA-non-clearance, p = 0.091, hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.15-1.19). According to Week4-EGFR status, we observed that PFS was significantly longer in EGFR-clearance patients than EGFR-non-clearance groups, (p = 0.011, HR = 0.23, 95% CI = 0.08-0.72). We then categorized patients into three subgroups according to Week4-ctDNA and Week4-EGFR status: non-clearance (N = 9), only-EGFR-clearance (concomitant alterations non-clearance) (N = 4), and all-clearance (N = 7). The nonclearance group had a significantly worse PFS than the all-clearance group (median PFS = 5.07 vs. 11.40 months, p = 0.029, HR = 3.45, 95% CI = 1.05-11.49). The only-EGFR-clearance group had a similar PFS to the all-clearance group (p = 0.607), which was longer than that of the non-clearance group (median PFS = 9.20 vs. 5.07 months, p = 0.060, HR = 0.25, 95% CI = 0.05-1.18). We found that the all-clearance group had a similar objective response rate (ORR) to the only-EGFR-clearance group (p = 1.000) and a higher ORR than the non-clearance group (p = 0.012).ConclusionMonitoring of EGFR clearance in ctDNA is promising and cost-effective in assessing response and predicting survival in EGFR-mutated NSCLC patients treated with EGFR-TKIs, with similar predictive value to ctDNA surveillance.

Project description:Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12?months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.

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Early responses of EGFR circulating tumor DNA to EGFR tyrosine kinase inhibitors in lung cancer treatment.

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Early responses of EGFR circulating tumor DNA to EGFR tyrosine kinase inhibitors in lung cancer treatment.

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