Best of AACR Journals

Clinical Cancer Research
Research Article
BRAF Inhibition Is Associated with Enhanced Melanoma Antigen
Expression and a More Favorable Tumor Microenvironment in
Patients with Metastatic Melanoma
Jennifer A. Wargo
Dennie T. Frederick, Adriano Piris, Alexandria P. Cogdill, Zachary A. Cooper, Cecilia Lezcano, Cristina R. Ferrone,
Devarati Mitra, Andrea Boni, Lindsay P. Newton, Chengwen Liu, Weiyi Peng, Ryan J. Sullivan, Donald P. Lawrence,
F. Stephen Hodi, Willem W. Overwijk, Gregory Lizée, George F. Murphy, Patrick Hwu, Keith T. Flaherty, David E. Fisher, and Jennifer A. Wargo
Abstract
Purpose: To evaluate the effects of BRAF inhibition on the tumor
microenvironment in patients with metastatic melanoma.
Experimental Design: Thirty-five biopsies were collected
from 16 patients with metastatic melanoma pretreatment (day
0) and at 10 to 14 days after initiation of treatment with either
BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition
(dabrafenib + trametinib) and were also taken at time of
progression. Biopsies were analyzed for melanoma antigens,
T-cell markers, and immunomodulatory cytokines.
Results: Treatment with either BRAF inhibitor alone or BRAF + MEK
inhibitor was associated with an increased expression of melanoma
antigens and an increase in CD8+ T-cell infiltrate. This was also
associated with a decrease in immunosuppressive cytokines
[interleukin (IL)-6 and IL-8] and an increase in markers of T-cell
cytotoxicity. Interestingly, expression of exhaustion markers TIM-3
and PD1 and the immunosuppressive ligand PDL1 was increased
on treatment. A decrease in melanoma antigen expression and CD8
T-cell infiltrate was noted at time of progression on BRAF inhibitor
alone and was reversed with combined BRAF and MEK inhibition.
Conclusions: Together, these data suggest that treatment
with BRAF inhibition enhances melanoma antigen expression
and facilitates T-cell cytotoxicity and a more favorable tumor
microenvironment, providing support for potential synergy
of BRAF-targeted therapy and immunotherapy. Interestingly,
markers of T-cell exhaustion and the immunosuppressive ligand
PDL1 are also increased with BRAF inhibition, further implying
that immune checkpoint blockade may be critical in augmenting
responses to BRAF-targeted therapy in patients with melanoma.
Clin Cancer Res; 19(5); 1225–31. ©2013 AACR.
Clin Cancer Res March 1, 2013 19:5 1225–31; Published OnlineFirst
January 10, 2013; doi:10.1158/1078-0432.CCR-12-1630
Research Article
Analysis of Tumor Specimens at the Time of Acquired Resistance to
EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers
Helena A. Yu, Maria E. Arcila, Natasha Rekhtman, Camelia S. Sima, Maureen F. Zakowski, William Pao, Mark G. Kris,
Vincent A. Miller, Marc Ladanyi, and Gregory J. Riely
Gregory J. Riely
Abstract
Purpose: All patients with EGF receptor (EGFR)–mutant lung
cancers eventually develop acquired resistance to EGFR tyrosine
kinase inhibitors (TKI). Smaller series have identified various
mechanisms of resistance, but systematic evaluation of a large
number of patients to definitively establish the frequency of
various mechanisms has not been conducted.
Experimental Design: Patients with lung adenocarcinomas
and acquired resistance to erlotinib or gefitinib enrolled onto a
prospective biopsy protocol and underwent a rebiopsy after the
development of acquired resistance. Histology was reviewed.
Samples underwent genotyping for mutations in EGFR, AKT1, BRAF,
ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2.
Results: Adequate tumor samples for molecular analysis were obtained
in 155 patients. Ninety-eight had second-site EGFR T790M mutations
[63%; 95% confidence interval (CI), 55%–70%] and four had small cell
transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4
of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%;
95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA,
AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%–4%).
Overlap among mechanisms of acquired resistance was seen in 4%.
Conclusions: This is the largest series reporting mechanisms of
acquired resistance to EGFR-TKI therapy. We identified EGFR T790M
as the most common mechanism of acquired resistance, whereas
MET amplification, HER2 amplification, and small cell histologic
transformation occur less frequently. More comprehensive methods
to characterize molecular alterations in this setting are needed to
improve our understanding of acquired resistance to EGFR-TKIs.
Clin Cancer Res; 19(8); 2240–7. ©2013 AACR.
Clin Cancer Res April 15, 2013 19:8 2240–7; Published OnlineFirst
March 7, 2013; doi:10.1158/1078-0432.CCR-12-2246
The Best of the AACR Journals 17