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Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck.
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| Zeitschriftentitel: | Journal of Clinical Oncology |
|---|---|
| Personen und Körperschaften: | , , , , , , |
| In: | Journal of Clinical Oncology, 35, 2017, 15_suppl, S. 6059-6059 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
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| Schlagwörter: |
| author_facet |
Tinhofer, Inge Eder, Theresa Konschak, Robert Niehr, Franziska Jöhrens, Korinna Keilholz, Ulrich Budach, Volker Tinhofer, Inge Eder, Theresa Konschak, Robert Niehr, Franziska Jöhrens, Korinna Keilholz, Ulrich Budach, Volker |
|---|---|
| author |
Tinhofer, Inge Eder, Theresa Konschak, Robert Niehr, Franziska Jöhrens, Korinna Keilholz, Ulrich Budach, Volker |
| spellingShingle |
Tinhofer, Inge Eder, Theresa Konschak, Robert Niehr, Franziska Jöhrens, Korinna Keilholz, Ulrich Budach, Volker Journal of Clinical Oncology Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. Cancer Research Oncology |
| author_sort |
tinhofer, inge |
| spelling |
Tinhofer, Inge Eder, Theresa Konschak, Robert Niehr, Franziska Jöhrens, Korinna Keilholz, Ulrich Budach, Volker 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6059 <jats:p> 6059 </jats:p><jats:p> Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN. </jats:p> Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. Journal of Clinical Oncology |
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| title |
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_unstemmed |
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_full |
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_fullStr |
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_full_unstemmed |
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_short |
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_sort |
comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6059 |
| publishDate |
2017 |
| physical |
6059-6059 |
| description |
<jats:p> 6059 </jats:p><jats:p> Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN. </jats:p> |
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| author | Tinhofer, Inge, Eder, Theresa, Konschak, Robert, Niehr, Franziska, Jöhrens, Korinna, Keilholz, Ulrich, Budach, Volker |
| author_facet | Tinhofer, Inge, Eder, Theresa, Konschak, Robert, Niehr, Franziska, Jöhrens, Korinna, Keilholz, Ulrich, Budach, Volker, Tinhofer, Inge, Eder, Theresa, Konschak, Robert, Niehr, Franziska, Jöhrens, Korinna, Keilholz, Ulrich, Budach, Volker |
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| description | <jats:p> 6059 </jats:p><jats:p> Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN. </jats:p> |
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| spelling | Tinhofer, Inge Eder, Theresa Konschak, Robert Niehr, Franziska Jöhrens, Korinna Keilholz, Ulrich Budach, Volker 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6059 <jats:p> 6059 </jats:p><jats:p> Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN. </jats:p> Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. Journal of Clinical Oncology |
| spellingShingle | Tinhofer, Inge, Eder, Theresa, Konschak, Robert, Niehr, Franziska, Jöhrens, Korinna, Keilholz, Ulrich, Budach, Volker, Journal of Clinical Oncology, Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck., Cancer Research, Oncology |
| title | Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_full | Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_fullStr | Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_full_unstemmed | Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_short | Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_sort | comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| title_unstemmed | Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck. |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6059 |