TY - JOUR
T1 - Role of tumor-infiltrating B cells in clinical outcome of patients with melanoma treated with dabrafenib plus trametinib
AU - Brase, Jan C.
AU - Walter, Robert F.H.
AU - Savchenko, Alexander
AU - Gusenleitner, Daniel
AU - Garrett, James
AU - Schimming, Tobias
AU - Varaljai, Renata
AU - Castelletti, Deborah
AU - Kim, Ju
AU - Dakappagari, Naveen
AU - Schultz, Ken
AU - Robert, Caroline
AU - Long, Georgina V.
AU - Nathan, Paul D.
AU - Ribas, Antoni
AU - Flaherty, Keith T.
AU - Karaszewska, Boguslawa
AU - Schachter, Jacob
AU - Sucker, Antje
AU - Schmid, Kurt W.
AU - Zimmer, Lisa
AU - Livingstone, Elisabeth
AU - Gasal, Eduard
AU - Schadendorf, Dirk
AU - Roesch, Alexander
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/8/15
Y1 - 2021/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85113729665&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-3586
DO - 10.1158/1078-0432.CCR-20-3586
M3 - Article
C2 - 34108180
AN - SCOPUS:85113729665
SN - 1078-0432
VL - 27
SP - 4500
EP - 4510
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -