Dataset Information

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer.

ABSTRACT:

Background

The prognostic implication of wild-type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.

Materials and 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 with the APC-mutant (APC-MT) population (n =?255), APC-WT patients (n =?86) tended to be younger (59% of age ?50), right-sided (41.7% vs. 27%), BRAF^V600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over-represented in the APC-WT versus 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 < .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, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86, p = .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 < .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.

Implications for practice

Patients with microsatellite stable metastatic colorectal cancer with wild-type APC had a worse overall survival than patients with mutated APC 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.

SUBMITTER: Wang C

PROVIDER: S-EPMC7930429 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer.

Wang Chongkai C Ouyang Ching C Cho May M Ji Jingran J Sandhu Jaideep J Goel Ajay A Kahn Michael M Fakih Marwan M

The oncologist 20201207 3

<h4>Background</h4>The prognostic implication of wild-type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.<h4>Materials and methods</h4>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).<h4>Results</h4>In comparison with the APC-mutant (APC-MT) population (n = 255), APC-WT patients (n = 86 ...[more]

PMID: 33230914

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Project description:PurposeSeveral uncommon genomic alterations beyond RAS and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations.Materials and methodsA prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included NTRKs, ERBB3, NF1, MAP2K1/2/4, AKT2 pathogenic mutations; PTEN/NF1 loss; ERBB3, FGFR2, IGF1R, KRAS, ARAF, and AKT1-2 amplification; and EGFR rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, RAS/BRAF wild-type, PRESSING-negative, and microsatellite stable.ResultsAmong 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% v 13%; P = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival 6.4 v 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 v 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes.ConclusionNegative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with RAS and BRAF wild-type, microsatellite stable mCRC.

Dataset Information

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer.

Background

Materials and methods

Results

Conclusion

Implications for practice

Publications

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer.

Similar Datasets

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