Limits...
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

Waterfall plots of the maximum percentage change in tumor size of individual EGFR L858R lung adenocarcinomas treated by EGFR-TKIsTumors are listed in order of increasing extent of response to EGFR-TKIs; only those with measurable sizes before and after EGFR-TKI treatment are shown. The upper (20%) and lower (−30%) dashed lines indicate the thresholds used to define a progressive disease and a partial response, respectively, by the RECIST criteria. Panel A shows individual tumor responses in 24 patients analyzed by NGS. Red bars, PFS < 3 months; green bars, PFS < 1 year; asterisks, positive for MHL1 V384D. Panel B shows 155 EGFR L858R tumors analyzed for MLH1 status by direct sequencing of PCR products. Pink bars, positive for MLH1 V384D.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4480762&req=5

Figure 3: Waterfall plots of the maximum percentage change in tumor size of individual EGFR L858R lung adenocarcinomas treated by EGFR-TKIsTumors are listed in order of increasing extent of response to EGFR-TKIs; only those with measurable sizes before and after EGFR-TKI treatment are shown. The upper (20%) and lower (−30%) dashed lines indicate the thresholds used to define a progressive disease and a partial response, respectively, by the RECIST criteria. Panel A shows individual tumor responses in 24 patients analyzed by NGS. Red bars, PFS < 3 months; green bars, PFS < 1 year; asterisks, positive for MHL1 V384D. Panel B shows 155 EGFR L858R tumors analyzed for MLH1 status by direct sequencing of PCR products. Pink bars, positive for MLH1 V384D.

Mentions: A representative tumor with concurrent EGFR L858R and MLH1 V384D mutations displayed primary resistance to EGFR-TKI treatment (Fig. 2B). We evaluated individual tumor responses to EGFR-TKIs in patients whose tumors were of measurable sizes. Twenty-four of the NGS-screened 29 patients were monitored, and the tumor responses and PFS clustered correspondingly (Fig. 3A); 5 of 10 (50%) patients with short PFS had progressive disease whilst on EGFR-TKI treatment and 13 of 14 (92.9%) patients with long PFS had a partial response to EGFR-TKIs. Among the 4 patients with the MLH1 V384D allele, 2 had progressive disease and 2 had stable disease; none of the patients with partial response carried the MLH1 V384D allele.


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)

Waterfall plots of the maximum percentage change in tumor size of individual EGFR L858R lung adenocarcinomas treated by EGFR-TKIsTumors are listed in order of increasing extent of response to EGFR-TKIs; only those with measurable sizes before and after EGFR-TKI treatment are shown. The upper (20%) and lower (−30%) dashed lines indicate the thresholds used to define a progressive disease and a partial response, respectively, by the RECIST criteria. Panel A shows individual tumor responses in 24 patients analyzed by NGS. Red bars, PFS < 3 months; green bars, PFS < 1 year; asterisks, positive for MHL1 V384D. Panel B shows 155 EGFR L858R tumors analyzed for MLH1 status by direct sequencing of PCR products. Pink bars, positive for MLH1 V384D.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Waterfall plots of the maximum percentage change in tumor size of individual EGFR L858R lung adenocarcinomas treated by EGFR-TKIsTumors are listed in order of increasing extent of response to EGFR-TKIs; only those with measurable sizes before and after EGFR-TKI treatment are shown. The upper (20%) and lower (−30%) dashed lines indicate the thresholds used to define a progressive disease and a partial response, respectively, by the RECIST criteria. Panel A shows individual tumor responses in 24 patients analyzed by NGS. Red bars, PFS < 3 months; green bars, PFS < 1 year; asterisks, positive for MHL1 V384D. Panel B shows 155 EGFR L858R tumors analyzed for MLH1 status by direct sequencing of PCR products. Pink bars, positive for MLH1 V384D.
Mentions: A representative tumor with concurrent EGFR L858R and MLH1 V384D mutations displayed primary resistance to EGFR-TKI treatment (Fig. 2B). We evaluated individual tumor responses to EGFR-TKIs in patients whose tumors were of measurable sizes. Twenty-four of the NGS-screened 29 patients were monitored, and the tumor responses and PFS clustered correspondingly (Fig. 3A); 5 of 10 (50%) patients with short PFS had progressive disease whilst on EGFR-TKI treatment and 13 of 14 (92.9%) patients with long PFS had a partial response to EGFR-TKIs. Among the 4 patients with the MLH1 V384D allele, 2 had progressive disease and 2 had stable disease; none of the patients with partial response carried the MLH1 V384D allele.

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