Reference Detail

Ref Type

Journal Article

PMID

(32796636)

Authors

Riera P, Rodríguez-Santiago B, Lasa A, Gonzalez-Quereda L, Martín B, Salazar J, Sebio A, Virgili AC, Minguillón J, Camps C, Surrallés J, Páez D

Title

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancers	12	8	2020 Aug 11		Cancers (Basel)

URL

Abstract Text

About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response.Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results.Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response.This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS G115Efs*46	colorectal cancer	predicted - resistant	Cetuximab	Clinical Study - Cohort	Actionable	In a retrospective analysis, NRAS G115Efs*46 was identified at a frequency of >1% in 3 of 23 patients with metastatic colorectal cancer who did not respond to anti-EGFR therapy (Erbitux (cetuximab), n=12 or Vectibix (panitumumab), n=11), and was associated with a lack of response (p=0.029) to EGFR-targeted therapy (PMID: 32796636).	32796636
NRAS G115Efs*46	colorectal cancer	predicted - resistant	Panitumumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, NRAS G115Efs*46 was identified at a frequency of >1% in 3 of 23 patients with metastatic colorectal cancer who did not respond to anti-EGFR therapy (Erbitux (cetuximab), n=12 or Vectibix (panitumumab), n=11), and was associated with a lack of response (p=0.029) to EGFR-targeted therapy (PMID: 32796636).	32796636