49% reduction in risk of disease progression! Discover new genes that predict colorectal cancer treatment outcomes!

Anti-BRAF/EGFR therapy was recently approved for the treatment
of metastatic BRAF V600E colorectal cancer (mCRC^BRAF-V600E).
However, a large proportion of patients do not respond to treatment, illustrating the need to identify the
molecular determinants of treatment response.
Recently, a research team performed whole exome sequencing on the discovery cohort of mCRC^{BRAF-V600E patients receiving anti-BRAF}/EGFR therapy, and found that the inactivation mutation of the negative regulator of WNT, RNF43, predicted improved response rate and survival outcomes in patients with microsatellite stable (MSS) tumors
.

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Author: Mia

Recently, the team of Elena Elez and Rodrigo A.
T oledo of the Waldsieburen University Hospital in Spain and the Rodrigo A.
T oledo of the Waldsieblen Cancer Institute reported in the journal Nature Medicine that the ORR of patients in the RNF43 mutation group doubled, the risk of disease progression was reduced by 49%, and the risk of death was reduced by 68%, and the RNF43 mutation type could be used as a biomarker to predict the efficacy of BRAF/EGFR combined inhibition
.

https://doi.
org/10.
1038/s41591-022-01976-z

Lack of molecular markers

 01 

BRAF^V600E mutations occur in approximately 10% of patients with metastatic colorectal cancer (mCRC) and are strongly associated
with poor prognosis.
BRAF^V600E tumors (abbreviated as mCRC^BRAF-V600E) have also been associated with specific molecular features compared to mCRC^{BRAF-wild-type}, including low-frequency APC mutations and high-frequency mutations
in the tumor suppressor gene RNF43.
In addition, RING E3 ubiquitin ligase participates in inhibiting the WNT-β-catenin pathway
by promoting degradation of FZD/WNT receptors.

Studies have shown that the combined blockade of BRAF and EGFR, with or without simultaneous inhibition of MEK, improves ORR (26% in triple therapy, 20% in dual therapy, and 2% in control group) and prolong overall survival (OS) and progression-free survival (PFS)
in patients with CRC tumors.
However, this combination is still ineffective
in a large proportion of patients with advanced CRC.
Therefore, exploring molecular markers that can predict treatment response is the key to
improving response rates.

RNF43 mutations have predictive value for clinical outcome biomarkers

 02 

In this study, the research team sought to explore genetic biomarkers with predictive value to refine the stratification
of mCRC^{BRAF-V600E patients receiving anti-BRAF}/EGFR combination therapy.
The researchers applied whole exome sequencing (WES) and/or targeted gene sequencing to baseline tumor and/or plasma cell-free DNA (cfDNA) samples and combined
these data with clinically relevant factors for response and survival.
The samples were from a large cohort of mCRC^BRAF-V600E patients receiving anti-BRAF/EGFR therapy, and a control cohort
of mCRC^BRAF-V600E patients receiving standard chemotherapy and antiangiogenic drugs (not exposed to anti-BRAF).

Study the design drawing

This finding identifies molecular subtypes based on microsatellite stabilization (MSS)/MSI status and RNF43 alterations, and reveals the predictive value of RNF43 mutations as biomarkers of clinical outcomes, including increased ORR, PFS, and OS
for anti-BRAF/EGFR± combination therapy.

The study data showed that patients with MSS-mCRC^BRAF-V600E tumors with loss-of-function mutations of RNF43 responded well to anti-BRAF/EGFR combination therapy, while patients with normal RNF43 function benefited from this regimen to a limited
extent 。 Compared with MSS-RNF43 wild-type tumors, MSS-RNF43 mutant tumors were more associated with predicted clinical benefit (72.
7% vs.
30.
8%; P = 0.
03), and had a longer progression-free survival (hazard ratio (HR), 0.
30; 95% confidence interval (CI), 0.
12–0.
75; P = 0.
01) and overall survival (HR, 0.
26; 95% CI, 0.
10–0.
71; P = 0.
008)
。

In conclusion, RNF43 mutations represent a new biomarker whose potential
needs to be further validated.
Future studies should explore the inclusion of this biomarker in routine testing along with BRAF and MSS/MSI status, and evaluate its integration with other transcriptomes to optimize microbiome, or microenvironmental markers
, for the clinical management of this heterogeneous and complex disease, the researchers said.

Resources:

https://doi.
org/10.
1038/s41591-022-01976-z

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
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