Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer Journal Article
| Authors: | Ambrosini, M.; Rousseau, B.; Manca, P.; Artz, O.; Marabelle, A.; André, T.; Maddalena, G.; Mazzoli, G.; Intini, R.; Cohen, R.; Cercek, A.; Segal, N. H.; Saltz, L.; Varghese, A. M.; Yaeger, R.; Nusrat, M.; Goldberg, Z.; Ku, G. Y.; El Dika, I.; Margalit, O.; Grinshpun, A.; Murtaza Kasi, P.; Schilsky, R.; Lutfi, A.; Shacham-Shmueli, E.; Khan Afghan, M.; Weiss, L.; Westphalen, C. B.; Conca, V.; Decker, B.; Randon, G.; Elez, E.; Fakih, M.; Schrock, A. B.; Cremolini, C.; Jayachandran, P.; Overman, M. J.; Lonardi, S.; Pietrantonio, F. |
| Article Title: | Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer |
| Abstract: | Background: 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. Patients and methods: 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. Results: 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. Conclusions: 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. © 2024 The Author(s) |
| Keywords: | adult; cancer survival; clinical article; controlled study; treatment outcome; treatment response; aged; middle aged; gene mutation; overall survival; clinical feature; pathogenesis; comparative study; follow up; genetic analysis; dna repair; progression free survival; cohort analysis; genetic association; retrospective study; oncogene; ras protein; sex difference; age distribution; cytotoxic t lymphocyte antigen 4; b raf kinase; oncogene ras; sample size; braf gene; programmed death 1 ligand 1; metastatic colorectal cancer; overall response rate; immune checkpoint inhibitor; human; male; female; article; immune checkpoint inhibitors; pole gene; tumor mutational burden; molecular fingerprinting; pold1 gene; population structure; pold1 mutations; pole mutations; proofreading deficiency |
| Journal Title: | Annals of Oncology |
| Volume: | 35 |
| Issue: | 7 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2024-07-01 |
| Start Page: | 643 |
| End Page: | 655 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2024.03.009 |
| PUBMED: | 38777726 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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