Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Abstract

We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5‐year relapse‐free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5‐year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX2‐positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2‐negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup

“…Our real-world data shows that mCRC patients who have non-resectable metastatic disease with CDX2 loss have a worse prognosis, receive less first-and second-line chemotherapy with less benefit and rarely receive secondary surgery. The incidence of CDX2 loss was 19%, comparable to previous published results on stage IV CRC patients in population-based cohort studies (8,15). Others have reported lower frequency of CDX2 loss, but most of these studies have very few patients with stage IV disease (21,22).…”

“…Immunohistochemistry (IHC) analysis for CDX2 is implemented in the clinical diagnostics as a biomarker for intestinal differentiation in tumors of unknown origin. It is deregulated in a subset of patients with CRC, and downregulation has been associated with poor prognosis (6)(7)(8)(9)(10)(11)(12)(13). Loss of CDX2 expression has also been associated with other poor prognostic features such as advanced stages, poor differentiation, BRAF mutation (BRAFmut), and microsatellite instability (MSI) (12,14,15).…”

“…No previous studies have fully explored if the negative prognostic effect of CDX2 loss in mCRC could be confounded by these associations. Two recent retrospective studies have reported CDX2 loss as a predictive biomarker for treatment benefit of chemotherapy in stage II (7) and stage III (8) CRC. This has so far not been demonstrated in mCRC (8,9,11).…”

“…Two recent retrospective studies have reported CDX2 loss as a predictive biomarker for treatment benefit of chemotherapy in stage II (7) and stage III (8) CRC. This has so far not been demonstrated in mCRC (8,9,11). Recently, CDX2 loss was reported to be an independent negative prognostic marker in mCRC patients undergoing curative liver metastasis resection, indicating CDX2 loss as a potential biomarker to identify patients with limited benefit from surgery (11).…”

MicroRNA-9-5p-CDX2 Axis: A Useful Prognostic Biomarker for Patients with Stage II/III Colorectal Cancer

“…Recent studies showed that CDX2 targets the multidrug resistance gene MDR1 (ABCB1) and CFTR (ABCC7), coding for two ATP-dependent drug efflet pumps [36][37][38]. These genes are significantly down-regulated in CDX2-negative cell lines and CDX2-negative patient tumors and have also been reported to promote the response to chemotherapy [24,38]. This supports our results showing that CDX2-positive cases show a poor response to chemotherapy which may be effective in patients with CDX2-negative CRC.…”