Abstract 4634
Background
Several studies in BRAFV600E colorectal cancers (CRC) have failed to replicate the efficacy of BRAF inhibitors in treatment of BRAFV600E melanomas (Mel), suggesting the existence of different resistance mechanisms as well as molecular and biological differences between the 2 tumor types. Herein, we examine these differences.
Methods
Tumor samples submitted to Caris Life Sciences for NGS DNA sequencing (592 gene panel) and RNA sequencing (54 gene panel) between the years 2015 and 2019 were retrospectively studied. Only microsatellite stable (MSS) tumors with either BRAFV600E mutation or wild type (WT) BRAF status were included in this initial analysis. Chi-square tests determined differences.
Results
A total of 8409 tumor samples were analyzed: CRC (N = 7453: BRAFV600E=373; WT = 7080) and Mel samples (N = 956: BRAFV600E=274; WT = 682). The most frequently mutated genes in BRAFV600E CRC were TP53 (81%), APC (26%), and SMAD4 (22.4%), compared to CDKN2A (22%), PTEN (13%), and TP53 (13%) in BRAFV600E Mel. Molecular alterations that are significantly more frequent in BRAFV600E CRC vs BRAFV600E Mel but not significantly different between BRAF WT CRC vs BRAF WT Mel included RSPO3 fusions (CRC=22.6% vs Mel=0%, P = 0.027); RNF43 deletions (2.0% vs 0%, p = 0.019); and mutations in RNF43 (18.8% vs 0%, P < 0.001), AKT1 (3.5% vs 0.4%, p = 0.008), and MTOR (2.4% vs 0.4%, p = 0.037). RSPO3 fusions and RNF43 mutations/deletions are mutually exclusive. Significantly more frequent alterations in BRAFV600E Mel compared to BRAFV600E CRC (but not in either WT) included deletions in PTEN (7% vs 3%, p = 0.005) and mutations in PTEN (12.9% vs 5.4%), MITF (1.9% vs 0%), STK11 (1.5% vs 0%), ERCC2 (1.1% vs 0%), FANCC (1.2% vs 0%), and CDK4 (1.5% vs 0%) (p < 0.05 for all).
Conclusions
BRAFV600E CRC carry molecular alterations that are distinct from BRAFV600E Mel. RSPO3 fusions and RNF43 alterations are prevalent in BRAFV600E CRC tumors in a mutually exclusive manner, suggesting that Wnt pathway activation via genetic alterations in upstream Wnt pathway regulators may play an important role in BRAFV600E CRC tumorigenesis and resistance to BRAF inhibitors. Drug combinations that target both the MAPK and Wnt pathways may warrant further investigation.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M.E. Salem: Travel / Accommodation / Expenses: Caris Life Sciences. J. Xiu: Full / Part-time employment: Caris Life Sciences. A. Grothey: Travel / Accommodation / Expenses: Caris Life Sciences. R.M. Goldberg: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. Z. Gatalica: Full / Part-time employment: Caris Life Sciences. R. Feldman: Full / Part-time employment: Caris Life Sciences. M. Saul: Full / Part-time employment: Caris Life Sciences. W..M. Korn: Full / Part-time employment: Caris Life Sciences. A.F. Shields: Research grant / Funding (institution), Travel / Accommodation / Expenses: Caris Life Sciences. J.L. Marshall: Advisory / Consultancy: Caris Life Sciences. H.J. Lenz: Travel / Accommodation / Expenses: Caris Life Sciences. All other authors have declared no conflicts of interest.
Resources from the same session
4543 - Long-term real-world (RW) outcomes in patients with advanced melanoma (MEL) treated with ipilimumab (IPI) and non-IPI therapies: IMAGE study
Presenter: Stéphane Dalle
Session: Poster Display session 3
Resources:
Abstract
4523 - Prognostic Factors for efficacy of Ipilimumab used after AntiPD1 and/or BRAF+MEK inhibitors in Melanoma Patients: an Italian Melanoma Intergroup study
Presenter: Riccardo Marconcini
Session: Poster Display session 3
Resources:
Abstract
3632 - Rechallenge with combination ipilimumab and anti-PD-1 (IPI+PD1) in metastatic melanoma after acquired resistance to IPI+PD1 immunotherapy
Presenter: Adriana Hepner
Session: Poster Display session 3
Resources:
Abstract
3732 - Clinicopathologic characteristics of immune colitis in melanoma patients treated with combination ipilimumab and anti-PD1 (IPI+PD1) and PD1 monotherapy.
Presenter: Kazi Nahar
Session: Poster Display session 3
Resources:
Abstract
5005 - Real-world outcomes of ipilimumab plus nivolumab for advanced melanoma in the Netherlands
Presenter: Michiel van Zeijl
Session: Poster Display session 3
Resources:
Abstract
5524 - Utilization of Real-World Data to Assess the Effectiveness of Immune Checkpoint Inhibitors (ICIs) in Elderly Patients with Metastatic Melanoma
Presenter: D Scott Ernst
Session: Poster Display session 3
Resources:
Abstract
5884 - Tumor mutational burden and response to PD-1 inhibitors: an analysis of 89 cases of metastatic melanoma.
Presenter: Léa Dousset
Session: Poster Display session 3
Resources:
Abstract
3120 - Increase in S100B and LDH as early outcome predictors for non-responsiveness to anti-PD-1 monotherapy in advanced melanoma.
Presenter: Elisa Rozeman
Session: Poster Display session 3
Resources:
Abstract
2157 - Immune status defined by molecular information layers predicts response to pembrolizumab treatment in advanced melanoma
Presenter: Guillermo Prado-Vázquez
Session: Poster Display session 3
Resources:
Abstract
2553 - Interim analysis of a phase Ib study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild type melanoma progressing on prior anti-PD-L1 therapy
Presenter: Shahneen Sandhu
Session: Poster Display session 3
Resources:
Abstract