Next-generation sequencing (NGS) in metastatic colorectal cancer (mCRC): Novel mutated genes and their effect on response to therapy (Alliance)

Innocenti, Federico; Rashid, Naim; Wancen, M.; Ou, Fang Shu; Qu, Xueping; Denning, Stefanie; Bertagnolli, Monica M.; Blanke, Charles D.; Venook, Alan P.; Kabbarah, Omar; Lenz, Heinz‐Josef

doi:10.1093/annonc/mdz246.002

Cited by 5 publications

(5 citation statements)

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“…Finally, APC ‐WT status, as a standalone finding, has been recently associated with a diminished benefit from anti‐EGFR therapy in a retrospective analysis from the CALGB 80405 study. Because our data reflect a modern era of treatment that includes anti‐EGFR therapy, a differential outcome that is in favor of the APC‐ MT group may reflect a benefit from anti‐EGFR driven within its RAS‐ WT subpopulation [11]. Taken together, these results suggest that APC ‐WT colorectal cancer may drive a distinct mechanism of tumorigenesis which then confers relative resistance to chemotherapy or targeted therapy, therefore leading to a worse overall outcome.…”

Section: Discussionmentioning

confidence: 81%

“…RNF43 mutations were mutually exclusive with APC mutation, and have correlated with BRAF V600E mutation and MSI [32, 33]. RNF43 ‐mutated tumors have conferred a worse OS in patients with RAS ‐WT colorectal cancer when treated with cetuximab [11]. Indeed, in our data analysis, patients with RNF43 ‐mutated tumors exhibited earlier death within the APC ‐WT population (supplemental online Fig.…”

Section: Discussionmentioning

confidence: 88%

“…A comparison of genomic alterations between early and late‐onset colorectal cancer showed a decreased incidence of APC mutations in younger patients [10]. Colorectal cancers with mutated APC conferred better overall survival (OS) than wild‐type tumors when treated with an epidermal growth factor receptor (EGFR) inhibitor [11]. These data suggest that APC mutation may account for EGFR inhibitor sensitivity and provide rationale for refining treatment guidelines in addition to extended RAS/RAF testing [11, 12].…”

Section: Introductionmentioning

confidence: 99%

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Wild-typeAPCIs Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

et al. 2020

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Background. The prognostic implication of wild type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Methods. APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results. In comparison to the APC-mutant (APC-MT) population (n=255), APC-WT patients (n = 86) tended to be younger (59% of age <40 vs 26% of age > 50), right-sided (41.7% vs. 27%), BRAF-V600E mutated (23.3% vs. 0.8%), and KRAS WT (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1 were over-represented in the APC-WT vs APC-MT population (7% vs 0.4% and 4.7% vs 0.4%, respectively). APC-WT patients had a worse overall survival (OS) than APC-MT patients (22.6 vs 45.6 months, p<0.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (APC-MT vs APC-WT, HR=0.62, 95%CI 0.44-0.86, P=0.0037). The prognostic implication of APC-WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC-MT vs APC-WT, HR=0.63, 95%CI 0.49-0.81, p<0.0001). Conclusion. APC-WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC-WT patients. The Oncologist 2020;9999:• • Implications for Practice: MSS mCRC patients with APC-WT had a worse OS than patients with APC-MT regardless of RAS/ RAF status. APC status should be considered as a stratification factor in prospective trials and novel therapeutic strategies need to be developed for this subgroup of patients.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Wild-typeAPCIs Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

et al. 2020

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“…While somatic deletions and loss-of-function mutations in FANC genes are responsible for cancer transformation and progression, concurrently, they can provide sensitivity to DNA-damaging therapies [ 17 , 25 ]. A post-hoc analysis of metastatic CRC patients ( n = 520) enrolled in the CALGB (Alliance)/SWOG 80,405 randomized phase III trial, performed by a next-generation sequencing approach, showed that patients treated with cytotoxic agents (i.e., FOLFOX or FOLFIRI) plus cetuximab, whose tumors harbored mutated FANCD2 , had a worse overall survival compared with patients with wild-type FANCD2 tumors [ 97 ]. Such observed worse outcome may be in keeping with the fact that, among the 22 FANC genes, FANCD2 and FANCD1/BRCA2 are classified as mutated cancer driver genes in CRC according to the IntoGen Compendium [ 98 ].…”

Section: Potential Role Of Fanc Gene Mutations In ...mentioning

confidence: 99%

Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy

Parsa

Nobili

Karimpour

et al. 2022

JPM

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Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and has the second highest mortality rate globally. Thanks to the advent of next-generation sequencing technologies, several novel candidate genes have been proposed for CRC susceptibility. Germline biallelic mutations in one or more of the 22 currently recognized Fanconi anemia (FA) genes have been associated with Fanconi anemia disease, while germline monoallelic mutations, somatic mutations, or the promoter hypermethylation of some FANC genes increases the risk of cancer development, including CRC. The FA pathway is a substantial part of the DNA damage response system that participates in the repair of DNA inter-strand crosslinks through homologous recombination (HR) and protects genome stability via replication fork stabilization, respectively. Recent studies revealed associations between FA gene/protein tumor expression levels (i.e., FANC genes) and CRC progression and drug resistance. Moreover, the FA pathway represents a potential target in the CRC treatment. In fact, FANC gene characteristics may contribute to chemosensitize tumor cells to DNA crosslinking agents such as oxaliplatin and cisplatin besides exploiting the synthetic lethal approach for selective targeting of tumor cells. Hence, this review summarizes the current knowledge on the function of the FA pathway in DNA repair and genomic integrity with a focus on the FANC genes as potential predisposition factors to CRC. We then introduce recent literature that highlights the importance of FANC genes in CRC as promising prognostic and predictive biomarkers for disease management and treatment. Finally, we represent a brief overview of the current knowledge around the FANC genes as synthetic lethal therapeutic targets for precision cancer medicine.

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“…Mutated genes that conferred worse overall survival (OS) than wild-type (WT) tumours and mutations that conferred better survival were highlighted. For example, FANCI-mutated tumours (4%) conferred worse OS than WT tumours [HR 2.0 (1.2–3.3), P = 0.005; OR 5.0 (1.9–14.8), P = 0.002][ 34 ]. These findings are very interesting, as they could provide new genes that could become predictors of response to chemotherapy regimens with cetuximab and bevacizumab combinations.…”

Section: Future Directionsmentioning

confidence: 99%

New drugs for the treatment of metastatic colorectal cancer

Cherri¹,

Libertini²,

Zaniboni³

2021

WJGO

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Next-generation sequencing (NGS) in metastatic colorectal cancer (mCRC): Novel mutated genes and their effect on response to therapy (Alliance)

Cited by 5 publications

References 0 publications

Wild-typeAPCIs Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

Wild-typeAPCIs Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy

New drugs for the treatment of metastatic colorectal cancer

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