Prognostic and predictive impact of molecular tumor burden index in non-small cell lung cancer patients.
circulating tumor DNA
immunotherapy
molecular tumor burden index
non-small cell lung cancer
prognostic
Journal
Thoracic cancer
ISSN: 1759-7714
Titre abrégé: Thorac Cancer
Pays: Singapore
ID NLM: 101531441
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
23
08
2023
received:
07
06
2023
accepted:
24
08
2023
medline:
7
11
2023
pubmed:
19
9
2023
entrez:
19
9
2023
Statut:
ppublish
Résumé
The biomarkers of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC) patients have limited predictive performance. In this study we aimed to investigate the feasibility of molecular tumor burden index (mTBI) in circulating tumor DNA (ctDNA) as a predictor for immunotherapy in patients with NSCLC. From February 2017 to November 2020, pretreatment and on-treatment (3~6 weeks after first cycle of immunotherapy) dynamic plasma ctDNA samples from NSCLC patients receiving immune monotherapy or combination therapy were analyzed by targeted capture sequencing of 1021 genes. PyClone was used to infer the mTBI. The impact of pretreatment mTBI on survival outcomes was verified in the POPLAR/OAK trials. We found that patients without detectable baseline ctDNA had better survival outcomes (median overall survival [OS]: not reached vs. 12.8 months; hazard ratio [HR], 0.15; p = 0.035]). RB1 and SMARCA4 mutations were remarkably associated with worse survival outcomes. Furthermore, lower pretreatment mTBI was associated with superior OS (median: not reached vs. 8.1 months; HR, 0.22; p = 0.024) and PFS (median: 32.9 vs. 5.4 months; HR, 0.35; p = 0.045), but not objective response, which was validated in the POPLAR/OAK cohort, suggesting that baseline mTBI was a prognostic factor for NSCLC immunotherapy. Early dynamic changes of mTBI (ΔmTBI) significantly distinguished responsive patients, and patients with mTBI decrease to more than 68% at the final tumor evaluation had longer OS (median: 38.2 vs. 4.0 months; HR, 0.18; p = 0.017) and PFS (median: not reached vs. 2.3 months; HR, 0.24; p = 0.030). ΔmTBI had a good sensitivity to identify potential beneficial patients based on the best effect CT scans, demonstrating that mTBI dynamics were predictive of benefit from immune checkpoint blockade.
Sections du résumé
BACKGROUND
The biomarkers of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC) patients have limited predictive performance. In this study we aimed to investigate the feasibility of molecular tumor burden index (mTBI) in circulating tumor DNA (ctDNA) as a predictor for immunotherapy in patients with NSCLC.
METHODS
From February 2017 to November 2020, pretreatment and on-treatment (3~6 weeks after first cycle of immunotherapy) dynamic plasma ctDNA samples from NSCLC patients receiving immune monotherapy or combination therapy were analyzed by targeted capture sequencing of 1021 genes. PyClone was used to infer the mTBI. The impact of pretreatment mTBI on survival outcomes was verified in the POPLAR/OAK trials.
RESULTS
We found that patients without detectable baseline ctDNA had better survival outcomes (median overall survival [OS]: not reached vs. 12.8 months; hazard ratio [HR], 0.15; p = 0.035]). RB1 and SMARCA4 mutations were remarkably associated with worse survival outcomes. Furthermore, lower pretreatment mTBI was associated with superior OS (median: not reached vs. 8.1 months; HR, 0.22; p = 0.024) and PFS (median: 32.9 vs. 5.4 months; HR, 0.35; p = 0.045), but not objective response, which was validated in the POPLAR/OAK cohort, suggesting that baseline mTBI was a prognostic factor for NSCLC immunotherapy. Early dynamic changes of mTBI (ΔmTBI) significantly distinguished responsive patients, and patients with mTBI decrease to more than 68% at the final tumor evaluation had longer OS (median: 38.2 vs. 4.0 months; HR, 0.18; p = 0.017) and PFS (median: not reached vs. 2.3 months; HR, 0.24; p = 0.030).
CONCLUSION
ΔmTBI had a good sensitivity to identify potential beneficial patients based on the best effect CT scans, demonstrating that mTBI dynamics were predictive of benefit from immune checkpoint blockade.
Identifiants
pubmed: 37724484
doi: 10.1111/1759-7714.15098
pmc: PMC10626252
doi:
Substances chimiques
Biomarkers, Tumor
0
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Nuclear Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3097-3107Informations de copyright
© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.
Références
Front Immunol. 2021 Oct 04;12:762598
pubmed: 34675941
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
Biomark Res. 2022 Mar 7;10(1):9
pubmed: 35255999
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Clin Cancer Res. 2017 Sep 1;23(17):5101-5111
pubmed: 28539465
Nat Med. 2018 Sep;24(9):1441-1448
pubmed: 30082870
EBioMedicine. 2019 May;43:261-269
pubmed: 31031019
Front Immunol. 2021 Feb 25;12:598671
pubmed: 33717076
Mayo Clin Proc. 2019 Aug;94(8):1623-1640
pubmed: 31378236
Lancet. 2019 May 4;393(10183):1819-1830
pubmed: 30955977
Cancer Res Treat. 2022 Jul;54(3):753-766
pubmed: 34645133
Ann Oncol. 2020 Dec;31(12):1746-1754
pubmed: 32866624
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Cancer Discov. 2020 Dec;10(12):1842-1853
pubmed: 32816849
Clin Cancer Res. 2017 Oct 1;23(19):5729-5736
pubmed: 28972084
Cancer Res. 2022 Feb 1;82(3):349-358
pubmed: 34815256
J Clin Med. 2019 Jul 10;8(7):
pubmed: 31295929
Cancer Med. 2019 Dec;8(18):7669-7678
pubmed: 31692284
J Thorac Oncol. 2022 Feb;17(2):289-308
pubmed: 34648948
CA Cancer J Clin. 2021 May;71(3):209-249
pubmed: 33538338
J Thorac Oncol. 2020 Aug;15(8):e133-e136
pubmed: 32718537
Ann Oncol. 2022 Jan;33(1):42-56
pubmed: 34653632
Nat Methods. 2014 Apr;11(4):396-8
pubmed: 24633410
N Engl J Med. 2016 Nov 10;375(19):1823-1833
pubmed: 27718847
Nature. 2018 Jan 24;553(7689):446-454
pubmed: 29364287
Front Genet. 2021 Sep 07;12:723670
pubmed: 34557222
Cancer Res. 2019 Mar 15;79(6):1204-1213
pubmed: 30573519
Cancer Med. 2019 Apr;8(4):1459-1466
pubmed: 30773851
J Clin Oncol. 2003 Nov 1;21(21):3909-17
pubmed: 14581415
Clin Cancer Res. 2018 Apr 15;24(8):1872-1880
pubmed: 29330207
N Engl J Med. 2018 May 31;378(22):2093-2104
pubmed: 29658845
Science. 2016 Mar 25;351(6280):1463-9
pubmed: 26940869
Science. 2018 Oct 12;362(6411):
pubmed: 30309915
J Clin Oncol. 2008 Jul 20;26(21):3543-51
pubmed: 18506025
Ann Oncol. 2019 Jan 1;30(1):44-56
pubmed: 30395155
Lung Cancer. 2019 Nov;137:1-6
pubmed: 31518912
Cancer Res. 2018 Nov 15;78(22):6486-6496
pubmed: 30171052
Lung Cancer. 2004 Oct;46(1):87-98
pubmed: 15364136
J Thorac Oncol. 2021 Jul;16(7):1176-1187
pubmed: 33845210
Thorac Cancer. 2023 Nov;14(31):3097-3107
pubmed: 37724484
N Engl J Med. 2017 Oct 12;377(15):1409-1412
pubmed: 29020592
Signal Transduct Target Ther. 2021 Jul 7;6(1):251
pubmed: 34230452
Cell. 2020 Oct 15;183(2):363-376.e13
pubmed: 33007267
Int J Cancer. 2020 Mar 1;146(5):1359-1368
pubmed: 31241775
Clin Cancer Res. 2020 Nov 1;26(21):5701-5708
pubmed: 32709715