Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers
© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc..
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
Nature cancer - (2024) vom: 25. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Muquith, Maishara [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 26.03.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1038/s43018-024-00752-x |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370176693 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370176693 | ||
| 003 | DE-627 | ||
| 005 | 20240327000616.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240327s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s43018-024-00752-x |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1349.xml |
| 035 | |a (DE-627)NLM370176693 | ||
| 035 | |a (NLM)38528112 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Muquith, Maishara |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 26.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc. | ||
| 520 | |a Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Espinoza, Magdalena |e verfasserin |4 aut | |
| 700 | 1 | |a Elliott, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Xiu, Joanne |e verfasserin |4 aut | |
| 700 | 1 | |a Seeber, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a El-Deiry, Wafik |e verfasserin |4 aut | |
| 700 | 1 | |a Antonarakis, Emmanuel S |e verfasserin |4 aut | |
| 700 | 1 | |a Graff, Stephanie L |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Borghaei, Hossein |e verfasserin |4 aut | |
| 700 | 1 | |a Hoon, Dave S B |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Stephen V |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Patrick C |e verfasserin |4 aut | |
| 700 | 1 | |a McKay, Rana R |e verfasserin |4 aut | |
| 700 | 1 | |a Wise-Draper, Trisha |e verfasserin |4 aut | |
| 700 | 1 | |a Marshall, John |e verfasserin |4 aut | |
| 700 | 1 | |a Sledge, George W |e verfasserin |4 aut | |
| 700 | 1 | |a Spetzler, David |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Hsiehchen, David |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature cancer |d 2020 |g (2024) vom: 25. März |w (DE-627)NLM307030067 |x 2662-1347 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:25 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s43018-024-00752-x |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 25 |c 03 | ||