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Ref Type Journal Article
PMID (38777726)
Authors Ambrosini M, Rousseau B, Manca P, Artz O, Marabelle A, André T, Maddalena G, Mazzoli G, Intini R, Cohen R, Cercek A, Segal NH, Saltz L, Varghese AM, Yaeger R, Nusrat M, Goldberg Z, Ku GY, El Dika I, Margalit O, Grinshpun A, Kasi P, Schilsky R, Lutfi A, Shacham-Shmueli E, Khan Afghan M, Weiss L, Westphalen CB, Conca V, Decker B, Randon G, Elez E, Fakih M, Schrock AB, Cremolini C, Jayachandran P, Overman MJ, Lonardi S, Pietrantonio F
Title Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.
Journal Vol Issue Date Pages Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology 2024 May 03 Ann Oncol
URL
Abstract Text POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures.POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature.Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
POLE V411L colorectal cancer predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in two patients harboring POLE V411L treated with Keytruda (pembrolizumab) (PMID: 38777726). 38777726
POLE A456P colorectal cancer predicted - sensitive Ipilimumab + Nivolumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in a patient harboring POLE A456P treated with the combination of Yervoy (ipilimumab) and Opdivo (nivolumab) (PMID: 38777726). 38777726
POLE P286R colorectal cancer predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in 2 patients and complete response in 2 patients out of 5 patients harboring POLE P286R and treated with Keytruda (pembrolizumab) (PMID: 38777726). 38777726
POLE P286R colorectal cancer predicted - sensitive Ipilimumab + Nivolumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in 4 patients and a complete response in 1 patient, all harboring POLE P286R and treated with Yervoy (ipilimumab) plus Opdivo (nivolumab) (PMID: 38777726). 38777726
POLE P286R colorectal cancer predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a complete response in a patient harboring POLE P286R treated with Opdivo (nivolumab) (PMID: 38777726). 38777726
POLE F367S colorectal cancer predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a complete response in a patient harboring POLE F367S treated with Keytruda (pembrolizumab) (PMID: 38777726). 38777726
POLD1 L606M colorectal cancer predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in a patient harboring POLD1 L606M treated with Keytruda (pembrolizumab) (PMID: 38777726). 38777726
POLE V411L colorectal cancer predicted - sensitive Ipilimumab + Nivolumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in two patients harboring POLE V411L treated with the combination of Yervoy (ipilimumab) and Opdivo (nivolumab) (PMID: 38777726). 38777726
POLE S459F colorectal cancer predicted - sensitive Durvalumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a complete response in a patient harboring POLE S459F treated with Imfinzi (durvalumab) (PMID: 38777726). 38777726
POLE A456P colorectal cancer predicted - sensitive Pembrolizumab Case Reports/Case Series Actionable In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a partial response in a patient harboring POLE A456P treated with Keytruda (pembrolizumab) (PMID: 38777726). 38777726