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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

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.
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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: 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