Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer.
Circulating tumor DNA
Gastroesophageal cancer
Palliative treatment
Predictive factor
Journal
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
ISSN: 1436-3305
Titre abrégé: Gastric Cancer
Pays: Japan
ID NLM: 100886238
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
04
03
2022
accepted:
25
05
2022
pubmed:
29
6
2022
medline:
13
8
2022
entrez:
28
6
2022
Statut:
ppublish
Résumé
Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel. Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses. ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson's R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10-4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28-5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53-16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31-12.75; p = 0.016). Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.
Sections du résumé
BACKGROUND
Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel.
METHODS
Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses.
RESULTS
ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson's R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10-4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28-5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53-16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31-12.75; p = 0.016).
CONCLUSION
Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.
Identifiants
pubmed: 35763187
doi: 10.1007/s10120-022-01313-w
pii: 10.1007/s10120-022-01313-w
pmc: PMC9365750
doi:
Substances chimiques
Biomarkers, Tumor
0
Circulating Tumor DNA
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
906-915Informations de copyright
© 2022. The Author(s).
Références
Clin Cancer Res. 2018 Dec 15;24(24):6248-6256
pubmed: 30348637
Clin Cancer Res. 2019 Dec 1;25(23):7098-7112
pubmed: 31427281
Radiol Bras. 2018 May-Jun;51(3):141-146
pubmed: 29991833
Cancers (Basel). 2020 Jul 24;12(8):
pubmed: 32722340
Exp Mol Med. 2019 Aug 8;51(8):1-10
pubmed: 31395853
Eur J Cancer. 2016 Jul;62:132-7
pubmed: 27189322
Nat Methods. 2014 Apr;11(4):361-2
pubmed: 24681721
J Natl Cancer Inst. 2016 Aug 30;108(10):
pubmed: 27576566
Cancer Discov. 2021 Feb;11(2):308-325
pubmed: 33234578
Cell Death Dis. 2020 May 11;11(5):346
pubmed: 32393783
Lancet. 2010 Aug 28;376(9742):687-97
pubmed: 20728210
Ann Thorac Surg. 2019 Aug;108(2):343-349
pubmed: 31059681
Ann Oncol. 2021 Apr;32(4):522-532
pubmed: 33359547
Nat Commun. 2020 Jan 27;11(1):525
pubmed: 31988276
Circ Cardiovasc Qual Outcomes. 2010 Jan;3(1):98-105
pubmed: 20123676
Cancer Discov. 2018 Jan;8(1):37-48
pubmed: 28978556
Multidiscip Respir Med. 2014 Oct 31;9(1):53
pubmed: 25379180
Int J Cancer. 2020 Apr 1;146(7):1889-1901
pubmed: 31340065
Sci Transl Med. 2014 Feb 19;6(224):224ra24
pubmed: 24553385
Br J Cancer. 2020 Oct;123(8):1271-1279
pubmed: 32719550
Cancers (Basel). 2019 Jun 14;11(6):
pubmed: 31207904
J Biomed Biotechnol. 2012;2012:891961
pubmed: 22919278
EBioMedicine. 2019 May;43:261-269
pubmed: 31031019
Int J Cancer. 2020 Mar 1;146(5):1445-1456
pubmed: 31340061
Eur J Cancer. 2018 Nov;103:214-226
pubmed: 30268922
Chin J Cancer. 2016 Apr 07;35:36
pubmed: 27056366
Gut. 2019 Jul;68(7):1152-1161
pubmed: 30269082
J Gastrointest Oncol. 2019 Jun;10(3):400-406
pubmed: 31183188
Lancet. 2021 Jul 3;398(10294):27-40
pubmed: 34102137
Biochim Biophys Acta Rev Cancer. 2017 Dec;1868(2):394-403
pubmed: 28801248