Combination of CDX2 H-score quantitative analysis with CD3 AI-guided analysis identifies patients with a good prognosis only in stage III colon cancer

Dérangère, Valentin; Lecuelle, Julie; Lepage, Côme; Salem, Oumaima Aoulad-Ben; Allatessem, Ben M; Ilie, Alis; Bouché, Olivier; Phélip, Jean-Marc; Baconnier, Mathieu; Pezet, Denis; Sebbagh, Virginie; Terrebonne, Éric; Bouard, G.; Jooste, Valérie; Bouvier, Anne-Marie; Molimard, Chloé; Monnien, Franck; González, Daniel; Malicot, Karine Le; Rageot, David; Truntzer, Caroline; Bibeau, Frédéric; Ghiringhelli, François

doi:10.1016/j.ejca.2022.05.040

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…Various studies have demonstrated the prognostic role of CD3 immune infiltrate for improved assessment of patient prognosis in early stage CRC. 32 , 33 , 34 , 35 , 36 Using a single CD3 slide, we were able to observe, in different datasets of patients treated for stage III CRC by surgery and adjuvant chemotherapy, that machine learning scoring of CD3 slides through our CD3ML model could predict DFS in each cohort. This information provides added value on top of clinical stage, and improves DFS prediction in patients with low or high clinical risk.…”

Section: Discussionmentioning

confidence: 89%

Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts

Lecuelle,

Truntzer,

Basile

et al. 2024

eBioMedicine

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Section: Discussionmentioning

confidence: 89%

Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts

Lecuelle,

Truntzer,

Basile

et al. 2024

eBioMedicine

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“…Several studies have demonstrated that loss of CDX2 expression is correlated with poor outcomes in patients with colorectal cancer. [4][5][6][7] In 2016, Dalerba et…”

Section: Introductionmentioning

confidence: 99%

“…Caudal‐type homeobox transcription factor 2 (CDX2), which mainly regulates intestinal functions in stem/progenitor cells, 4 is an undoubtedly promising candidate for further analysis and validation. Several studies have demonstrated that loss of CDX2 expression is correlated with poor outcomes in patients with colorectal cancer 4–7 . In 2016, Dalerba et al published a study in The New England Journal of Medicine that showed that in addition to being associated with poor survival, a lack of CDX2 expression signature in colon cancer patients has been correlated with improved chemotherapy response 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have demonstrated that loss of CDX2 expression is correlated with poor outcomes in patients with colorectal cancer. 4 , 5 , 6 , 7 In 2016, Dalerba et al published a study in The New England Journal of Medicine that showed that in addition to being associated with poor survival, a lack of CDX2 expression signature in colon cancer patients has been correlated with improved chemotherapy response. 4 Subsequent studies validated the prognostic impact of CDX2 in colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

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Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

Gao,

Han,

Chen

et al. 2023

Cancer Medicine

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BackgroundBetter predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil‐based adjuvant chemotherapy benefits.MethodsCDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193).ResultsIn the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2‐negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2‐negative and CDX2‐positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5‐year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery‐only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts.ConclusionsNegative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.

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“…Numerous groups have since reproduced the prognostic claims [11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Thirty-two independent studies, involving >13,000 unique subjects, most that used IHC and one that used IHC in combination with quantitative mass spectrometry 25 , have determined that CDX2-neg CRCs are associated with lower overall survival (OS) and DFS independent of ethnicity, DNA mismatch repair (MMR) status or stage 7,20,24,26 [Figure 1- Step 1].…”

Section: Introductionmentioning

confidence: 99%

Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors

Sinha,

Alcantara,

Perry

et al. 2023

Preprint

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Background: Lack of expression of the transcription factor CDX2 identifies a subset of poorly differentiated colorectal cancers (CRCs) that are associated with lower overall (OS) and disease-free (DFS) survival, independent of ethnicity, MSI status, or stage. Reinstatement of CDX2 is predicted to lower the risk of death and recurrence by 50% but such a therapeutic strategy is yet to emerge. Methods: A network-based computational model, validated using healthy colon and CRC tissues in diverse gene expression datasets (~5,000 human and >300 mouse samples), was used to identify therapeutic targets that can augment CDX2 expression. The top candidate with available clinical-grade drug (PRKAB1) was tested on 3 models: CRC lines in vitro, xenografts in mice, and in a prospective cohort of healthy (n = 3) and CRC (n = 23) patient-derived organoids (PDOs). Results: In all 3 models, PRKAB1-agonism predictably shifted the network, induced CDX2 and crypt differentiation signatures and showed selective cytotoxicity towards CDX2-negative CRCs. Xenotransplantation studies in mice reduced tumour volume by 68% and abolished mortality (Hazard ratio; H.R = 0.09). Effective pairing of therapeutic efficacy (IC50 for PRKAB1-agonism) and biomarker (CDX2-low state) was validated in an independent cohort of PDOs. A multivariate analysis revealed CDX2-low state as the key determinant of therapeutic efficacy. A 50-gene signature of therapeutic response tested on 9 cohorts (n = 1701 patients) showed that CDX2-reinstatement therapy will reduce the risk of mortality/recurrence by ~50%. Conclusions: CDX2-reinstatement therapy selectively triggers cell differentiation and death in CDX2-low CRCs. Realization of the benefit of such therapy-biomarker pairing requires confirmatory studies in randomized clinical trials.

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Combination of CDX2 H-score quantitative analysis with CD3 AI-guided analysis identifies patients with a good prognosis only in stage III colon cancer

Cited by 9 publications

References 29 publications

Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts

Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

Machine-Learning Identifies a Strategy for Differentiation Therapy in Solid Tumors

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