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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: We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS.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: We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS.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