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Clinical efficacy evaluation of tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations.

ABSTRACT: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as a standard therapy have been used in EGFR-mutated adenocarcinoma of non-small-cell lung cancer (NSCLC) patients in recent years. But in current randomized prospective clinical trials, due to few cases of non-adenocarcinoma patients having been found, the efficacy of TKIs for EGFR-mutated non-adenocarcinoma and the relationship with clinicopathological characteristics remained debatable. The results of retrospective studies showed that the frequency of EGFR mutation was significantly associated with nationality, gender, smoking history, and histology type. Being female, never-smoker and adenocarcinoma had a higher mutation rate. Furthermore, the EGFR mutation rate and efficacies of TKIs in adenocarcinoma were higher than those in non-adenocarcinoma. And in non-adenocarcinoma, the EGFR mutation rate and efficacies of TKIs in adenosquamous cell carcinoma were higher than those in squamous cell carcinoma or in large-cell lung carcinoma. In conclusion, it may be necessary to conduct a large sample prospective study to understand the clinicopathological characteristics of non-adenocarcinomas and to evaluate the efficacy of EGFR TKI and/or chemotherapy for EGFR-mutated non-adenocarcinoma NSCLC. So we searched relevant articles between the year 2010 and 2016 through the major indexed literature database PubMed by searching the keywords such as EGFR mutation, Tyrosine kinase inhibitors, and Non-adenocarcinoma.

SUBMITTER: Song X

PROVIDER: S-EPMC5488763 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:BackgroundA subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved.MethodsTargeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package.ResultsIn the study cohort, the C?>?A transversions accounted for 12.9% of all single nucleotide variations (SNVs), comprising the second smallest proportion among SNVs. The E19del-subgroup had a significantly lower mutational burden with significantly higher Ti/Tv ratio than the SNV-subgroup, which includes cases with L858R and other EGFR-TKI sensitizing SNVs. (P?=?0.0326 and 0.0002, respectively, Mann-Whitney U test). In the LUAD cohort, the mutational burden was substantially lower than in other TCGA cancer cohorts, and the frequency of C?>?A transversions was 30.3%, occupying the second frequency. The E19del-subgroup had a lower mutational burden overall and a higher Ti/Tv ratio than the SNV-subgroup (P?=?0.0497 and P?=?0.0055, respectively, Mann-Whitney U test). Smoking-related signature 4 was observed only in the L858R-subgroup, while ignature 30 and 5 was observed in both groups.ConclusionsLung adenocarcinoma with mEGFR(+) has a lower mutational burden and does not show a characteristic mutation pattern influenced by smoking. E19del and L858R, which are representative subtypes of mEGFR(+) lung adenocarcinoma, differ in terms of mutational spectrum, as the E19del-subgroup has a lower mutation burden and a higher Ti/Tv ratio than the SNV-subgroup. These findings could help explain the differences in the responses to EGFR-TKIs and in the clinical courses between the two lung adenocarcinoma subgroups.

Project description:There is a discrepancy in the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). Molecular markers other than mEGFR remain to be investigated to better predict EGFR-TKI efficacy. Here, 49 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received the first-generation EGFR-TKI icotinib therapy were included and stratified into 25 good-responders with a progression-free survival (PFS) longer than 11 months and 24 poor-responders with a PFS shorter than 11 months. We conducted targeted metabolomic detection and next-generation sequencing on serum and tissue samples, respectively. Subsequently, two metabolomic profiling-based discriminant models were constructed for icotinib efficacy prediction, 10 metabolites overlapped in both models ensured high credibility for distinguishing good- and poor-responders. Seven of the 10 metabolites displayed significant differences between the two groups, which belong to lipids including ceramides (Cers), lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), sphingomyelins (SMs), and free fatty acids (FAs). Briefly, LPC 16:1, LPC 22:5-1, and LPE 18:2 decreased in poor-responders, while Cer 36:1-3, Cer 38:1-3, SM 36:1-2 and SM 42:2 increased in poor-responders. In parallel, we identified 6 co-mutated genes (ARID1A, ARID1B, BCR, FANCD2, PTCH1, and RBM10) which were significantly correlated with a shorter PFS. Additionally, 4 efficacy-related metabolites (Cer 36:1-3, Cer 38:1-3, SM 36:1-2, and LPC 16:1) showed significant differences between the mutant and wild-type of 4 efficacy-related genes (ARID1A, ARID1B, BCR, and RBM10). SM 36:1-2 elevated while LPC 16:1 decreased in ARID1A, BCR, and RBM10 mutant groups compared to the wild-type groups. Cer 36:1-3 increased in the ARID1A and BCR mutant groups, and Cer 38:1-3 only rose in the ARID1A mutant group. Furthermore, we observed a causal-mediator-network-based interrelation between the 4 concurrently mutated genes and the 4 metabolites related metabolic genes in glycerophospholipid metabolism and sphingolipid metabolism pathways. This study demonstrated that lipids metabolism and concurrently mutated genes with mEGFR were associated with the icotinib efficacy, which provides novel perspectives in classifying clinical responses of mEGFR LUAD patients and reveals the potential of non-invasive pretreatment serum metabolites in predicting EGFR-TKI efficacy.

Project description:Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFR (L858R) and EGFR (Del19), in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFR (T790M) mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFR (T790M), and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFR (T790M) resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFR (T790M) and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFR (T790M) resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second- and third-generation EGFR/HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.

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Clinical efficacy evaluation of tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations.

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