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Concomitant Genetic Alterations are Associated with Worse Clinical Outcome in EGFR Mutant NSCLC Patients Treated with Tyrosine Kinase Inhibitors.

ABSTRACT: Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKI) are recommended first-line therapy for advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. It is of clinical interest to identify concurrent genetic mutations in NSCLC patients with EGFR mutations in the hopes of discovering predictive biomarkers towards EGFR-TKI treatment. We retrospectively analyzed a cohort of patients with advanced EGFR mutant NSCLC who underwent treatment with first generation TKIs at our hospital by a multi-gene panel via next generation sequencing. A total of 33 patients with mutant EGFR were enrolled. Up to 26 (78.8%) patients had at least one concomitant genetic alteration coexisting with mutant EGFR. Among the concomitant genetic alterations discovered, TP53 mutation was most common (n = 10,30.3%), followed by CDK4 (n = 8, 24.2%) and CDKN2A (n = 7, 21.2%)copy number variation (CNV). Progression-free survival was shorter in patients with concomitant FGFR3 mutation (1.6 vs. 12.6 months, P = .003) and CDKN2A CNV loss (6.5 vs. 13.4months, P = .019). Patients with any concomitant genetic alterations also had significant worse overall survival (24.1 vs. 40.8 months, P = .029). In summary, our study revealed an unfavorable association between concomitant genetic mutations and treatment response towards EGFR-TKI. FGFR3 mutation and CDKN2A CNV loss may be potential predictive markers for treatment outcome and warrant further investigation.

SUBMITTER: Chang SC

PROVIDER: S-EPMC6700434 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Concomitant Genetic Alterations are Associated with Worse Clinical Outcome in EGFR Mutant NSCLC Patients Treated with Tyrosine Kinase Inhibitors.

Chang Shih-Chieh SC Lai Yi-Chun YC Chang Cheng-Yu CY Huang Li-Kuo LK Chen Shu-Jen SJ Tan Kien Thiam KT Yu Pei-Ning PN Lai Jiun-I JI

Translational oncology 20190808 11

Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKI) are recommended first-line therapy for advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. It is of clinical interest to identify concurrent genetic mutations in NSCLC patients with EGFR mutations in the hopes of discovering predictive biomarkers towards EGFR-TKI treatment. We retrospectively analyzed a cohort of patients with advanced EGFR mutant NSCLC who underwent treatment with first generation T ...[more]

PMID: 31401335

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Project description:IntroductionGrowing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.Materials and methodsWe investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients' outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh-Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).ResultsAmong the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients' biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.ConclusionThese data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.

Project description:BACKGROUND:In previous studies, the predictive role of BIM deletion polymorphism with respect to responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been controversial. The potential reasons for these inconsistent findings were unknown. METHODS:Data from CTONG0901 clinical trial and medical records of Guangdong Lung Cancer Institute (GLCI) were retrospectively pooled. A total of 194 and 141 EGFR-mutant non-small cell lung cancer (NSCLC) patients treated with first- and second-generation EGFR-TKIs were examined in the CTONG0901 and GLCI cohorts, respectively. Sixty-eight patients were treated with third-generation EGFR-TKIs in the GLCI cohort. The BIM gene status was examined by next-generation sequencing. RESULTS:The frequency of BIM deletion polymorphism was 11.3% and 17.0% in CTONG0901 and GLCI cohorts, respectively. For first- and second-generation EGFR-TKIs in CTONG0901 cohort, objective response (ORR) was 54.5% in BIM deletion group versus 56.4% in wild-type BIM group (P = .87); disease control rate (DCR) was 90.9% versus 88.4% (P = 1.00); progression-free survival (PFS) was 10.5 versus 11.2 months (P = .59); and overall survival (OS) was 20.5 versus 20.5 months (P = .73). In GLCI cohort, ORR was 54.2% versus 60.7% (P = .55); DCR was 91.7% versus 96.6% (P = .27); PFS was 10.1 versus 11.6 months (P = .63); and OS was 58.5 versus 45.0 months (P = .93). For third-generation EGFR-TKIs, ORR was 18.2% versus 63.2% (P = .02); DCR was 81.8% versus 96.5%, (P = .12); PFS was 5.8 versus 9.0 months (P = .13); and OS was 30.0 versus 24.8 months (P = .85). Cox regression analysis showed that concomitant genetic alterations could adversely affect the response to EGFR-TKIs, but not BIM deletion. CONCLUSIONS:The presence of BIM deletion showed no relation to an impaired response to first-, second-, and third-generation EGFR-TKIs in NSCLC patients. The factors influencing the response of EGFR-TKIs were concomitant genetic alterations, but not BIM deletion.

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Concomitant Genetic Alterations are Associated with Worse Clinical Outcome in EGFR Mutant NSCLC Patients Treated with Tyrosine Kinase Inhibitors.

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Concomitant Genetic Alterations are Associated with Worse Clinical Outcome in EGFR Mutant NSCLC Patients Treated with Tyrosine Kinase Inhibitors.

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