Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
©2021 The Authors; Published by the American Association for Cancer Research..
PURPOSE: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.
PATIENTS AND METHODS: We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.
RESULTS: Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4-38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.
CONCLUSIONS: B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
|---|---|
| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 27(2021), 16 vom: 15. Aug., Seite 4500-4510 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Brase, Jan C [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
33E86K87QN |
|---|
| Anmerkungen: |
Date Completed 01.04.2022 Date Revised 14.03.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1078-0432.CCR-20-3586 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM326562168 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM326562168 | ||
| 003 | DE-627 | ||
| 005 | 20231225194849.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1078-0432.CCR-20-3586 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1088.xml |
| 035 | |a (DE-627)NLM326562168 | ||
| 035 | |a (NLM)34108180 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Brase, Jan C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib |
| 264 | 1 | |c 2021 | |
| 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 Completed 01.04.2022 | ||
| 500 | |a Date Revised 14.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells | ||
| 520 | |a PATIENTS AND METHODS: We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening | ||
| 520 | |a RESULTS: Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4-38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers | ||
| 520 | |a CONCLUSIONS: B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Oximes |2 NLM | |
| 650 | 7 | |a Pyridones |2 NLM | |
| 650 | 7 | |a Pyrimidinones |2 NLM | |
| 650 | 7 | |a trametinib |2 NLM | |
| 650 | 7 | |a 33E86K87QN |2 NLM | |
| 650 | 7 | |a dabrafenib |2 NLM | |
| 650 | 7 | |a QGP4HA4G1B |2 NLM | |
| 700 | 1 | |a Walter, Robert F H |e verfasserin |4 aut | |
| 700 | 1 | |a Savchenko, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Gusenleitner, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Garrett, James |e verfasserin |4 aut | |
| 700 | 1 | |a Schimming, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Varaljai, Renata |e verfasserin |4 aut | |
| 700 | 1 | |a Castelletti, Deborah |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Ju |e verfasserin |4 aut | |
| 700 | 1 | |a Dakappagari, Naveen |e verfasserin |4 aut | |
| 700 | 1 | |a Schultz, Ken |e verfasserin |4 aut | |
| 700 | 1 | |a Robert, Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Georgina V |e verfasserin |4 aut | |
| 700 | 1 | |a Nathan, Paul D |e verfasserin |4 aut | |
| 700 | 1 | |a Ribas, Antoni |e verfasserin |4 aut | |
| 700 | 1 | |a Flaherty, Keith T |e verfasserin |4 aut | |
| 700 | 1 | |a Karaszewska, Boguslawa |e verfasserin |4 aut | |
| 700 | 1 | |a Schachter, Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a Sucker, Antje |e verfasserin |4 aut | |
| 700 | 1 | |a Schmid, Kurt W |e verfasserin |4 aut | |
| 700 | 1 | |a Zimmer, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Livingstone, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Gasal, Eduard |e verfasserin |4 aut | |
| 700 | 1 | |a Schadendorf, Dirk |e verfasserin |4 aut | |
| 700 | 1 | |a Roesch, Alexander |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Clinical cancer research : an official journal of the American Association for Cancer Research |d 1995 |g 27(2021), 16 vom: 15. Aug., Seite 4500-4510 |w (DE-627)NLM09444479X |x 1557-3265 |7 nnns |
| 773 | 1 | 8 | |g volume:27 |g year:2021 |g number:16 |g day:15 |g month:08 |g pages:4500-4510 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1078-0432.CCR-20-3586 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 27 |j 2021 |e 16 |b 15 |c 08 |h 4500-4510 | ||