Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors

Manca, Paolo; Corti, Francesca; Intini, Rossanna; Mazzoli, Giacomo; Miceli, Rosalba; Germani, Marco Maria; Bergamo, Francesca; Ambrosini, Margherita; Cristarella, Eleonora; Cerantola, Riccardo; Boccaccio, Chiara; Ricagno, Gianmarco; Ghelardi, Filippo; Randon, Giovanni; Leoncini, Giuseppe; Milione, Massimo; Fassan, Matteo; Cremolini, Chiara; Pietrantonio, Filippo

doi:10.1016/j.ejca.2023.03.029

Cited by 16 publications

(5 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these findings are preliminary and must be cautiously interpreted due to the low number of patients, they suggest that TMB values might have a prognostic significance among MSI CRC patients receiving ICI and confirm the heterogeneity of MSI tumors. In agreement with this hypothesis, it has been recently reported that among 110 dMMR/MSI CRC patients receiving ICI, those with a TMB value ≤ 23 had a significantly shorter PFS (HR 4.26) and OS (HR 5.14) as compared with patients with higher TMB values [ 53 ]. Interestingly, patients receiving anti-CTLA-4 combinations showed a better PFS and OS benefit as compared with anti-PD-(L)1 monotherapy only for values of TMB > 40 mutations/Mb.…”

Section: Tumor Heterogeneity (True Primary Resistance): Biological Ch...mentioning

confidence: 56%

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Normanno,

Caridi,

Fassan

et al. 2024

Exploration of Targeted Anti-Tumor Therapy

Self Cite

View full text Add to dashboard Cite

Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/ microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.

show abstract

Section: Tumor Heterogeneity (True Primary Resistance): Biological Ch...mentioning

confidence: 56%

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Normanno,

Caridi,

Fassan

et al. 2024

Exploration of Targeted Anti-Tumor Therapy

Self Cite

View full text Add to dashboard Cite

show abstract

“…CRC patients with a TMB-high tumor are more likely to respond to ICI treatment compared with a TMB-low tumor ( n =10 studies, OR 4.83, 95%CI 2.16–10.78, I 2 =24%, p =0.23) (Fig. 3 C, Supplementary Figure 1E) [ 3 , 10 , 28 , 32 , 33 , 39 , 40 , 42 , 53 , 55 ]. Of note, the cutoffs varied across studies, ranging from 9.6 to 41 mutations/Mb.…”

Section: Resultsmentioning

confidence: 99%

Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis

Yu,

Liu,

et al. 2024

Clin Exp Med

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICIs) are approved to treat colorectal cancer (CRC) with mismatch-repair gene deficiency, but the response rate remains low. Value of current biomarkers to predict CRC patients’ response to ICIs is unclear due to heterogeneous study designs and small sample sizes. Here, we aim to assess and quantify the magnitude of multiple biomarkers for predicting the efficacy of ICIs in CRC patients. We systematically searched MEDLINE, Embase, the Cochrane Library, and Web of Science databases (to June 2023) for clinical studies examining biomarkers for efficacy of ICIs in CRC patients. Random-effect models were performed for meta-analysis. We pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) for biomarkers predicting response rate and survival. 36 studies with 1867 patients were included in systematic review. We found that a lower pre-treatment blood neutrophil-to-lymphocyte ratio (n=4, HR 0.37, 95%CI 0.21–0.67) predicts good prognosis, higher tumor mutation burden (n=10, OR 4.83, 95%CI 2.16–10.78) predicts response to ICIs, and liver metastasis (n=16, OR 0.32, 95%CI 0.16–0.63) indicates resistance to ICIs, especially when combined with VEGFR inhibitors. But the predictive value of tumor PD-L1 expression (n=9, OR 1.01, 95%CI 0.48–2.14) was insignificant in CRC. Blood neutrophil-to-lymphocyte ratio, tumor mutation burden, and liver metastasis, but not tumor PD-L1 expression, function as significant biomarkers to predict efficacy of ICIs in CRC patients. These findings help stratify CRC patients suitable for ICI treatments, improving efficacy of immunotherapy through precise patient management. (PROSPERO, CRD42022346716).

show abstract

“…Furthermore, MSI-high tumors often exhibit a distinct histological and molecular profile with increased lymphocytic infiltration within the tumor microenvironment, suggesting a heightened immune response against the tumor. Perhaps most importantly, MSI and dMMR status can dictate treatment choices . Immunotherapies targeting immune checkpoint proteins, such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in MSI-high colorectal cancer.…”

Section: Molecular Profiling Of Colorectal Cancermentioning

confidence: 99%

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

Kiran,

Yashaswini,

Maheshwari

et al. 2024

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

Precision medicine is transforming colorectal cancer treatment through the integration of advanced technologies and biomarkers, enhancing personalized and effective disease management. Identification of key driver mutations and molecular profiling have deepened our comprehension of the genetic alterations in colorectal cancer, facilitating targeted therapy and immunotherapy selection. Biomarkers such as microsatellite instability (MSI) and DNA mismatch repair deficiency (dMMR) guide treatment decisions, opening avenues for immunotherapy. Emerging technologies such as liquid biopsies, artificial intelligence, and machine learning promise to revolutionize early detection, monitoring, and treatment selection in precision medicine. Despite these advancements, ethical and regulatory challenges, including equitable access and data privacy, emphasize the importance of responsible implementation. The dynamic nature of colorectal cancer, with its tumor heterogeneity and clonal evolution, underscores the necessity for adaptive and personalized treatment strategies. The future of precision medicine in colorectal cancer lies in its potential to enhance patient care, clinical outcomes, and our understanding of this intricate disease, marked by ongoing evolution in the field. The current reviews focus on providing in-depth knowledge on the various and diverse approaches utilized for precision medicine against colorectal cancer, at both molecular and biochemical levels.

show abstract

Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors

Cited by 16 publications

References 35 publications

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

Contact Info

Product

Resources

About