CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification

Pilati, Camilla; Taı̈eb, Julien; Balogoun, Ralyath; Marisa, Laëtitia; Reyniès, Aurélien de; Laurent‐Puig, Pierre

doi:10.1093/annonc/mdx066

Cited by 47 publications

(60 citation statements)

References 21 publications

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“…With regard to CDX2 expression, it should be noted that the CDX2‐negative tumors represent a larger fraction in this cohort compared with the original Dalerba et al cohort . Our results are in concordance with recent studies that exhibited higher expression rates of CDX2 absence/loss in stage II tumors . Nevertheless, our results confirm the role of CDX2 expression as a prognostic factor, as has been previously demonstrated, and also display its correlation to tumor location.…”

Section: Discussionsupporting

confidence: 93%

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

et al. 2019

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Background Anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left‐sided tumors may exhibit superior survival compared with right‐sided tumors. The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC). Previous studies had indicated that without adjuvant chemotherapy, CDX2‐negative stage II CRC tumors are associated with a lower rate of disease‐free survival than CDX2‐positive stage II CRC tumors. We aimed to evaluate whether these two validated prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Materials and Methods We retrospectively analyzed patients with T3 mismatch repair‐proficient (MMR‐P) stage II CRC for whom RS assay was performed. Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. RS and CDX2 expression were correlated with primary tumor location. Results The analysis included 1,147 patients with MMR‐P stage II CRC (median age 69 years [range 29–93]). Tumor distribution across the colon was as follows: 46% (n = 551) were right‐sided and 54% (n = 596) were left‐sided. RS was higher in right‐sided tumors (p = .01). The RS results gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = .04). Right‐sided tumors exhibited more CDX2‐negative tumors (p = .07). Conclusion Our study indicates that right‐sided colorectal tumors may display worse prognosis compared with left‐sided tumors in MMR‐P stage II CRC. Primary tumor location may serve as a prognostic factor that should be taken into account for recurrence risk assessment and consideration of adjuvant treatment. Implications for Practice Sidedness matters, even in stage II colorectal cancer (CRC). Using two previously established prognostic tools, the Oncotype DX assay and CDX2 expression, this study found that right‐sided tumors may display worse prognosis compared with left‐sided tumors in mismatch repair‐proficient stage II CRC. Therefore, primary tumor location should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

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Section: Discussionsupporting

confidence: 93%

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

et al. 2019

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“…Initial studies have found an association between lack of CDX2 expression and reduced survival in dMMR colorectal cancer (CMS1/immune subtype). Some studies have reported discordant results. Olsen and colleagues found that low CDX2 protein or mRNA expression was not associated with recurrence risk in a study of 119 patients with colorectal cancer, including 44 dMMR tumours.…”

Section: Discussionmentioning

confidence: 99%

Effects of CDX2 on prognosis and chemotherapy responsiveness in mismatch repair-deficient colorectal cancer

et al. 2018

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BackgroundCaudal‐related homeobox transcription factor 2 (CDX2) is an intestine‐specific transcription factor implicated in tumour differentiation, proliferation, cell adhesion and migration. Negative CDX2 status (CDX2−) is associated with worse prognosis in colorectal cancer and may identify high‐risk stage II disease that benefits from adjuvant chemotherapy. This observational study investigated whether CDX2− is associated with prognosis or response to chemotherapy in the mismatch repair‐deficient (dMMR) phenotype of colorectal cancer.MethodsPatients with resectable dMMR colorectal cancer were eligible for inclusion. The prognostic and predictive value of CDX2 expression on the presence of lymph node metastasis (LNM) and survival was investigated. CDX2 status was determined via immunohistochemistry using the Leica Bond™ CDX2 (clone EP25) ready‐to‐use primary antibody.ResultsSome 235 of 238 consecutive dMMR tumours were assessed for CDX2 status. CDX2− was observed in 15·7 per cent of colorectal cancer. Interobserver agreement was excellent (κ = 0·863; P < 0·001). CDX2− was significantly associated with female sex, increased size, advanced stage, worse conventional and poorly differentiated cluster (PDC) grade, mucinous morphology, perineural and lymphovascular invasion, and pN status (all P ≤ 0·038). CDX2− was not associated with LNM or survival in multivariable analysis. Independent predictors of LNM were PDC grade (odds ratio (OR) 4·12, 95 per cent c.i. 1·76 to 9·63; P = 0·001) and extramural venous invasion (OR 3·79, 1·62 to 8·85; P = 0·002). Budding (hazard ratio (HR) 2·79, 95 per cent c.i. 1·60 to 4·87; P < 0·001), pT status (HR 3·59, 1·29 to 10·01; P = 0·015) and adjuvant chemotherapy (HR 2·07, 1·15 to 3·74; P = 0·016) were independently associated with worse disease‐free survival.ConclusionCDX2− does not confer a worse prognosis in the dMMR phenotype of colorectal cancer. The MMR status of patients with colorectal cancer should be determined before assessing CDX2 status.

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“…MIR31HG expression was used to define MIR31 outliers as samples with expression higher than median ( x MIR 31 HG ) + 3 × MAD ( x MIR 31 HG ) where x MIR 31 HG represents either

2^{italiclo g_{2}}

justRMA signal values (microarray) or normalized read values (sequencing) and MAD represents the corresponding within‐dataset cross‐sample median absolute deviation. Samples with CDX2 expression below the 15.6% percentile in each dataset were classified as CDX2 negative . CMS labels for pCRCs from the CIT, LICR and TCGA (COADREAD) datasets were retrieved from Sage Bionetworks Synapse (identifier syn4978511).…”

Section: Methodsmentioning

confidence: 99%

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Eide

Eilertsen

Sveen

2019

Intl Journal of Cancer

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Elevated miR‐31 expression is associated with poor outcome in colorectal cancer (CRC). Whether the prognostic information is independent of known molecular subgroups and gene expression‐based consensus molecular subtypes (CMS) is currently unknown. To investigate this, we analyzed nearly 2000 CRC biopsies and preclinical models. The expression of miR‐31‐5p and its host transcript, long noncoding RNA MIR31HG , was strongly correlated (Spearman's ρ > 0.80). MIR31HG outlier expression was observed in 158/1265 (12%) of pCRCs and was associated with depletion of CMS2‐canonical subgroup (odds ratio = 0.21 [0.11–0.35]) and shorter relapse‐free survival (RFS) in multivariable analysis (adjusted hazard ratio = 2.2 [1.6–3.0]). For stage II disease, 5‐year RFS for patients with MIR31HG outlier status was 49% compared to 77% for those with normal‐like expression. MIR31HG outlier status was associated with inferior outcome also within clinical high risk groups and within the poor prognostic CMS4‐mesenchymal gene expression subtype specifically. Preclinical models with MIR31HG outlier expression were characterized by reduced expression of MYC targets as well as elevated epithelial‐mesenchymal transition, TNF‐α/NFκB, TGF‐β, and IFN‐α/γ gene expression signatures, indicating cancer cell‐intrinsic properties resembling the CMS4 subgroup—associations which were recapitulated in patient biopsies. Moreover, the prognostic value of MIR31HG outlier status was independent of cytotoxic T lymphocyte and fibroblast infiltration. We here present evidence that MIR31HG expression provides clinical stratification beyond major gene expression phenotypes and tumor immune and stromal cell infiltration and propose a model where increased expression is an indicator of a cellular state conferring intrinsic invasive and/or immuno‐evasive capabilities.

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CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification

Abstract: Our work suggests that combination of the consensual CMS classification and lack of CDX2 expression could be a useful marker to identify CMS4/CDX2-negative patients with a very poor prognosis.

Cited by 47 publications

References 21 publications

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

Effects of CDX2 on prognosis and chemotherapy responsiveness in mismatch repair-deficient colorectal cancer

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

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