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MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

Chiu CH, Ho HL, Doong H, Yeh YC, Chen MY, Chou TY, Tsai CM - Oncotarget (2015)

Bottom Line: A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy.Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001).Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001).

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT
A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

No MeSH data available.


Related in: MedlinePlus

Progression-free survival stratified by MLH1 V384 statusKaplan-Meier curves of progression-free survival in patients with EGFR L858R lung adenocarcinoma who were treated by EGFR-TKIs, according to the presence (red line) or absence (blue line) of the MLH1 V384D polymorphism.
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Figure 4: Progression-free survival stratified by MLH1 V384 statusKaplan-Meier curves of progression-free survival in patients with EGFR L858R lung adenocarcinoma who were treated by EGFR-TKIs, according to the presence (red line) or absence (blue line) of the MLH1 V384D polymorphism.

Mentions: At the time of analysis, with a median follow-up of 47.4 months, 51 patients remained in use of an EGFR-TKI and 107 patients (67.7%) had experienced PFS. The overall median PFS was 10.5 months (95% CI, 8.1 to 12.8 months). Patients with the MLH1 V384D mutation had a significant shorter PFS (median, 5.1 months; 95% CI, 1.5 to 8.7 months) than that of those without (median, 10.6 months; 95% CI, 8.8 to 12.5 months) (P= 0.001) (Fig. 4). Gender (male vs. female, P= 0.031) and the number of prior chemotherapy (0 vs. ≥ 1, P= 0.002) were also predictor variables for PFS. In the multivariate analysis using the Cox regression model, only the number of prior treatment (HR= 2.3, 95% CI, 1.4 to 3.8; in favor of none; P= 0.001) and the MLH1 mutation status (HR= 3.5, 95% CI, 1.7 to 7.2; in favor of no V384D mutation; P= 0.001) were independent predictors for PFS.


MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

Chiu CH, Ho HL, Doong H, Yeh YC, Chen MY, Chou TY, Tsai CM - Oncotarget (2015)

Progression-free survival stratified by MLH1 V384 statusKaplan-Meier curves of progression-free survival in patients with EGFR L858R lung adenocarcinoma who were treated by EGFR-TKIs, according to the presence (red line) or absence (blue line) of the MLH1 V384D polymorphism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480762&req=5

Figure 4: Progression-free survival stratified by MLH1 V384 statusKaplan-Meier curves of progression-free survival in patients with EGFR L858R lung adenocarcinoma who were treated by EGFR-TKIs, according to the presence (red line) or absence (blue line) of the MLH1 V384D polymorphism.
Mentions: At the time of analysis, with a median follow-up of 47.4 months, 51 patients remained in use of an EGFR-TKI and 107 patients (67.7%) had experienced PFS. The overall median PFS was 10.5 months (95% CI, 8.1 to 12.8 months). Patients with the MLH1 V384D mutation had a significant shorter PFS (median, 5.1 months; 95% CI, 1.5 to 8.7 months) than that of those without (median, 10.6 months; 95% CI, 8.8 to 12.5 months) (P= 0.001) (Fig. 4). Gender (male vs. female, P= 0.031) and the number of prior chemotherapy (0 vs. ≥ 1, P= 0.002) were also predictor variables for PFS. In the multivariate analysis using the Cox regression model, only the number of prior treatment (HR= 2.3, 95% CI, 1.4 to 3.8; in favor of none; P= 0.001) and the MLH1 mutation status (HR= 3.5, 95% CI, 1.7 to 7.2; in favor of no V384D mutation; P= 0.001) were independent predictors for PFS.

Bottom Line: A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy.Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001).Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001).

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT
A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

No MeSH data available.


Related in: MedlinePlus