Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study

Alouani, Emily; Mercier, M.; Flecchia, Clémence; Auclin, Édouard; Hollebecque, Antoine; Mazard, Thibault; Turpin, Anthony; Pernot, Simon; Cohen, Romain; Dutherage, Marie; Kim, Stéfano; Sclafani, Francesco; Benabdelghani, M.; Hervé, Camille; Aparicio, Thomas; Fouchardière, Christelle De La; Perkins, Géraldine; Hautefeuille, Vincent; Jaffrelot, Marion; Gallois, Claire; Bongard, Vanina; Tougeron, David; Taı̈eb, Julien; Guimbaud, Rosine

doi:10.1016/j.esmoop.2023.101574

Cited by 7 publications

(6 citation statements)

References 26 publications

(40 reference statements)

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“…This is in contrast with colorectal cancer, where microsatellite instability (MSI) is present in 15% of non-metastatic disease and in 5% of the metastatic setting [29] and confirmed peculiar molecular characteristics of ITAC. Previous work in experimental models and tumor cell lines suggested that an MMR-deficient profile could be a predictive factor for a poor response to chemotherapeutics, i.e., cisplatin, carboplatin, and methylating agents, at variance with the efficacy of immunotherapy in CRC with MMR/MSI deficiency [43]. Our data are in line with previous studies.…”

Section: Discussionsupporting

confidence: 92%

Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding

Puccio,

Azzarello,

Maffeis

et al. 2024

Cancers

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Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In the latter, tumor budding (TB) is widely recognized as a negative prognostic parameter. The aim of this study was to evaluate the prognostic role of TB in ITAC and to correlate it with other established or emerging biomarkers of the disease, such as p53 and deficient DNA mismatch repair (MMR) system status/microsatellite instability (MSI). We retrospectively analyzed 32 consecutive specimens of patients with ITAC diagnosis treated in two institutions in Northern Italy. We reviewed surgical specimens for TB evaluation (low-intermediate/high); p53 expression and MMR proteins were evaluated via immunohistochemistry. Results were retrospectively stratified using clinical data and patients’ outcomes. According to bud counts, patients were stratified into two groups: intermediate/high budding (>4 TB) and low budding (≤4 TB). Patients with high TB (>4) have an increased risk of recurrence and death compared to those with low TB, with a median survival of 13 and 54 months, respectively. On multivariate analysis, considering TB, therapy, and stage as covariates, TB emerged as an independent prognostic factor net of the stage of disease or type of therapy received. No impact of p53 status as a biomarker of prognosis was observed and no alterations regarding MMR proteins were identified. The results of the present work provide further significant evidence on the prognostic role of TB in ITAC and underline the need for larger multicenter studies to implement the use of TB in clinical practice.

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Section: Discussionsupporting

confidence: 92%

Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding

Puccio,

Azzarello,

Maffeis

et al. 2024

Cancers

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“…Nowadays, immunotherapy is the SOC for irresectable and metastatic dMMR/MSI-H CRC; on the one hand, pembrolizumab, an antiPD-1 agent, is approved in 1 st and further lines because of the remarkable results presented in the KEYNOTE 177 and KEYNOTE 016 vs. SOC chemotherapy ( 13 , 25 , 26 ). Besides, Nivolumab and the combination of Nivolumab plus Ipilimumab are also approved for the same settings as pembrolizumab due to the efficacy demonstrated in the CHECKMATE 142 phase III clinical trial ( 13 , 27 ).…”

Section: Current State Of the Art Challenges And Future Directions: D...mentioning

confidence: 99%

“…Therefore, biomarkers of response to ICIs are required in order to make an adequate selection of the patients that are candidate to neoadjuvant treatment, especially if a surgery option is available. Several retrospective studies have tried to elucidate clinical patterns of response to ICI: TMB high (cut-point was estimated between 37 and 41 mutations/Mb) was predictive of response whereas the presence of peritoneal metastases and poor performance status were predictive of low benefit ( 13 , 49 ). Focusing on the differences that these patients may have on their samples that may guide the response to ICIs, when using a multiplex immunofluorescence (MIF) staining and image analysis a higher pre-existing CD8+ T-cell density has been significantly associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2 [p= 0.013]) as well as a negative or low expression of PD-1 CD8+ cells (defined by an expression of PDCD1 of 0; s (700.24 per.mm2 vs. 288.29 per.mm2, [p=0.007]).…”

Section: Current State Of the Art Challenges And Future Directions: D...mentioning

confidence: 99%

“…The number of TILs is comparatively higher in MSS tumors and may also be even higher than the number of neoplastic cells but there is also an upregulation of the expression of the co-inhibitory signalization through CTLA-4, PD-1, PD-L1, LAG-3, and IDO that support the immune evasion. However, the PD-L1 expression in CRC is strikingly scarce in tumoral cells, being expressed on myeloid cells surrounding and, therefore, it is not a reliable predictive biomarker of response (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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Case report: Efficacy of immunotherapy as conversion therapy in dMMR/MSI-H colorectal cancer: a case series and review of the literature

San-Román-Gil,

Martínez-Delfrade,

Albarrán-Fernández

et al. 2024

Front. Immunol.

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Immunotherapy has demonstrated a role in the therapeutic landscape of a small subset of patients with colorectal carcinoma (CRC) that harbor a microsatellite instability (MSI-H) status due to a deficient DNA mismatch repair (dMMR) system. The remarkable responses to immune checkpoint inhibitors (ICIs) are now being tested in the neoadjuvant setting in localized CRC, where the dMMR/MSI-H status can be found in up to 15% of patients, with remarkable results obtained in NICHE2 and 3 trials, among others. This case series aims to report our experience at a tertiary center and provide a comprehensive analysis of the possible questions and challenges to overcome if ICIs were established as standard of care in a neoadjuvant setting, as well as the potential role they may have as conversion therapy not only in locoregional advanced CRC but also in oligometastatic disease.

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“…ICIs show significant efficacy in MSI-H/dMMR CRC patients ( 17 ). Currently, anti-PD-1 monoclonal antibody is the used most in clinical practice, followed by anti-CTLA-4 monoclonal antibody.…”

Section: Clinical Trials Of Icis In Crcmentioning

confidence: 99%

Immune checkpoint inhibitors in colorectal cancer: limitation and challenges

Yan,

Wang,

Feng

et al. 2024

Front. Immunol.

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Colorectal cancer exhibits a notable prevalence and propensity for metastasis, but the current therapeutic interventions for metastatic colorectal cancer have yielded suboptimal results. ICIs can decrease tumor development by preventing the tumor’s immune evasion, presenting cancer patients with a new treatment alternative. The increased use of immune checkpoint inhibitors (ICIs) in CRC has brought several issues. In particular, ICIs have demonstrated significant clinical effectiveness in patients with MSI-H CRC, whereas their efficacy is limited in MSS. Acquired resistance can still occur in patients with a positive response to ICIs. This paper describes the efficacy of ICIs currently in the clinical treatment of CRC, discusses the mechanisms by which acquired resistance occurs, primarily related to loss and impaired presentation of tumor antigens, reduced response of IFN-λ and cytokine or metabolic dysregulation, and summarizes the incidence of adverse effects. We posit that the future of ICIs hinges upon the advancement of precise prediction biomarkers and the implementation of combination therapies. This study aims to elucidate the constraints associated with ICIs in CRC and foster targeted problem-solving approaches, thereby enhancing the potential benefits for more patients.

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Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study

Cited by 7 publications

References 26 publications

Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding

Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding

Case report: Efficacy of immunotherapy as conversion therapy in dMMR/MSI-H colorectal cancer: a case series and review of the literature

Immune checkpoint inhibitors in colorectal cancer: limitation and challenges

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