Limits...
Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma.

Bria E, Pilotto S, Amato E, Fassan M, Novello S, Peretti U, Vavalà T, Kinspergher S, Righi L, Santo A, Brunelli M, Corbo V, Giglioli E, Sperduti I, Milella M, Chilosi M, Scarpa A, Tortora G - Oncotarget (2015)

Bottom Line: Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each).Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03).Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

ABSTRACT
Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.

No MeSH data available.


Related in: MedlinePlus

Distribution of TP53, KRAS and CTNNB1 gene mutation according to group (p-value: Fisher's exact test - panel A)A representative case of intratumor histologic and molecular heterogeneity (panel B-C). The poor responder case presented well-differentiated coexisting with de-differentiated areas within the same specimen (panel B; original magnifications 4x and 20x). Of interest, an EGFR deletion in exon 19 was observed in the well-differentiated adenocarcinoma, that was associated with a concomitant TP53 mutation (R248W) in the more de-differentiated area. The representation of the reads obtained by Ion Torrent sequencing, aligned to the reference genome as provided by the Integrative Genomics Viewer (IGV v.2.1, Broad Institute) software for the mutations in EGFR and TP53 genes, and the corresponding Sanger sequencing are reported. (panel C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494974&req=5

Figure 1: Distribution of TP53, KRAS and CTNNB1 gene mutation according to group (p-value: Fisher's exact test - panel A)A representative case of intratumor histologic and molecular heterogeneity (panel B-C). The poor responder case presented well-differentiated coexisting with de-differentiated areas within the same specimen (panel B; original magnifications 4x and 20x). Of interest, an EGFR deletion in exon 19 was observed in the well-differentiated adenocarcinoma, that was associated with a concomitant TP53 mutation (R248W) in the more de-differentiated area. The representation of the reads obtained by Ion Torrent sequencing, aligned to the reference genome as provided by the Integrative Genomics Viewer (IGV v.2.1, Broad Institute) software for the mutations in EGFR and TP53 genes, and the corresponding Sanger sequencing are reported. (panel C).

Mentions: Thirteen mutations in addition to the one in EGFR were found in the TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each) gene. All mutations were confirmed by Sanger sequencing. None of the patients had more than 2 concomitant mutations. The association of additional mutations and prognostic groups are reported in Table 3 and Supplementary Table 1. TP53 mutations (median PMA 0.45) were exclusively found among poor and intermediate patients and lacked in good responders (66.7% versus 0%, p[Fisher]=0.009) (Figure 1, Panel A).


Molecular heterogeneity assessment by next-generation sequencing and response to gefitinib of EGFR mutant advanced lung adenocarcinoma.

Bria E, Pilotto S, Amato E, Fassan M, Novello S, Peretti U, Vavalà T, Kinspergher S, Righi L, Santo A, Brunelli M, Corbo V, Giglioli E, Sperduti I, Milella M, Chilosi M, Scarpa A, Tortora G - Oncotarget (2015)

Distribution of TP53, KRAS and CTNNB1 gene mutation according to group (p-value: Fisher's exact test - panel A)A representative case of intratumor histologic and molecular heterogeneity (panel B-C). The poor responder case presented well-differentiated coexisting with de-differentiated areas within the same specimen (panel B; original magnifications 4x and 20x). Of interest, an EGFR deletion in exon 19 was observed in the well-differentiated adenocarcinoma, that was associated with a concomitant TP53 mutation (R248W) in the more de-differentiated area. The representation of the reads obtained by Ion Torrent sequencing, aligned to the reference genome as provided by the Integrative Genomics Viewer (IGV v.2.1, Broad Institute) software for the mutations in EGFR and TP53 genes, and the corresponding Sanger sequencing are reported. (panel C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494974&req=5

Figure 1: Distribution of TP53, KRAS and CTNNB1 gene mutation according to group (p-value: Fisher's exact test - panel A)A representative case of intratumor histologic and molecular heterogeneity (panel B-C). The poor responder case presented well-differentiated coexisting with de-differentiated areas within the same specimen (panel B; original magnifications 4x and 20x). Of interest, an EGFR deletion in exon 19 was observed in the well-differentiated adenocarcinoma, that was associated with a concomitant TP53 mutation (R248W) in the more de-differentiated area. The representation of the reads obtained by Ion Torrent sequencing, aligned to the reference genome as provided by the Integrative Genomics Viewer (IGV v.2.1, Broad Institute) software for the mutations in EGFR and TP53 genes, and the corresponding Sanger sequencing are reported. (panel C).
Mentions: Thirteen mutations in addition to the one in EGFR were found in the TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each) gene. All mutations were confirmed by Sanger sequencing. None of the patients had more than 2 concomitant mutations. The association of additional mutations and prognostic groups are reported in Table 3 and Supplementary Table 1. TP53 mutations (median PMA 0.45) were exclusively found among poor and intermediate patients and lacked in good responders (66.7% versus 0%, p[Fisher]=0.009) (Figure 1, Panel A).

Bottom Line: Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each).Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03).Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

ABSTRACT
Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.

No MeSH data available.


Related in: MedlinePlus