{"id":46647,"date":"2024-05-31T07:00:00","date_gmt":"2024-05-31T07:00:00","guid":{"rendered":"http:\/\/400735c12582d9716db58ba69acb2a3b"},"modified":"2024-11-03T15:11:50","modified_gmt":"2024-11-03T15:11:50","slug":"exceptional-response-rates-and-survival-among-patients-with-pole-d1-proofreading-deficient-mcrc-treated-with-icis-surpass-the-benefit-observed-in-dmmr-msi-h-mcrc","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/exceptional-response-rates-and-survival-among-patients-with-pole-d1-proofreading-deficient-mcrc-treated-with-icis-surpass-the-benefit-observed-in-dmmr-msi-h-mcrc\/","title":{"rendered":"Exceptional Response Rates and Survival Among Patients with POLE\/D1 Proofreading Deficient mCRC Treated with ICIs Surpass the Benefit Observed in dMMR\/MSI-H mCRC"},"content":{"rendered":"

Recent advances in the molecular dissection of colorectal cancer (CRC) uncovered a rare subtype of ultramutated tumours with polymerases epsilon (POLE<\/em>) or delta (POLD1<\/em>) proofreading deficiency (pd). To better establish the benefit of immune checkpoint inhibitors (ICIs) in this population, a group of investigators assembled a unique dataset of patients with POLE\/D1pd<\/em> metastatic CRC (mCRC) who received ICIs, with comprehensive clinical, pathological, and molecular profiling.<\/p>\n

The study unveils exceptional response rates and survival among patients with POLE\/D1pd<\/em> mCRC treated with ICIs, even in those with heavily pretreated disease. This benefit from ICIs even surpasses that observed in mismatch repair-deficient (dMMR) and\/or microsatellite instability-high (MSI-H) mCRC, despite genomic differences according to Dr. Filippo Pietrantonio of the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy and colleagues who published the findings on 21 May 2024 in the Annals of Oncology<\/em>.<\/p>\n

The immune sensitivity of dMMR\/MSI-H tumours relies on high tumour mutational burden (TMB), neoantigen load, and T-cell infiltration, with up-regulation of immune checkpoints as immune-escape mechanism. A rare subset of ultramutated CRCs with an exceptionally high number of somatic mutations (over 100 mut\/Mb) has been identified despite the usual absence of MMR defects. This ultramutator genotype has been linked to mutations in POLE<\/em>\/<\/em>D1<\/em>. POLEpd<\/em> is associated with T-cell-rich microenvironment and expression of immune checkpoints.<\/p>\n

POLE\/D1pd<\/em> mutations have been mainly described in endometrial cancer and CRC (5%-10% and 2%-4% across all disease stages), while passenger POLE<\/em>\/<\/em>D1<\/em> mutations are often found in cancers driven by environmental carcinogens, such as non-small cell lung cancer and melanoma, or MSI-H tumours. The frequency of POLEpd<\/em> is extremely low in patients with mCRC (<1%), because of immunosurveillance and excellent outcomes after primary tumour resection, seemingly better than dMMR\/MSI-H tumours. POLD1pd<\/em> has been initially only described in dMMR\/MSI-H, and its prevalence and molecular profile in MMR-proficient\/microsatellite stable (pMMR\/MSS) CRC remains poorly understood.<\/p>\n

Previous studies suggested the association of any POLE\/D1<\/em> mutations with tumour sensitivity to ICIs regardless of dMMR\/MSI-H status across metastatic tumours, but definitive conclusions were limited because of the inclusion of immunosensitive tumours such as melanoma, or lung cancers. Subsequently, an agnostic clinical trial demonstrated a promising activity of nivolumab in POLEpd<\/em> solid tumours, while no activity was observed for POLE<\/em> mutations neutral for proofreading activity. This clinical benefit was corroborated in a pan-cancer study including both POLEpd<\/em> and POLD1pd<\/em> tumours.<\/p>\n

Disease-specific data regarding the effectiveness of ICIs in treating POLE\/D1pd<\/em> mCRC are limited. It also remains unknown whether these tumours have different immunosensitivity compared to dMMR\/MSI-H mCRC. Therefore, the investigators conducted a multinational effort to collect patients with POLE\/D1pd<\/em> mCRC treated with ICIs. Subsequently, they compared the characteristics and outcomes of this group with a control cohort of patients with dMMR\/MSI-H without POLE\/D1pd<\/em> mutations. They analyzed a large cohort of CRC to precisely measure the clinicogenomic landscape of these tumours and link with ICI activity.<\/p>\n

In this global study, data from 27 patients with mCRC harbouring POLE\/D1<\/em> mutations leading to proofreading deficiency and treated with anti-PD1 alone or with anti-CTLA4 agents were collected in terms of clinicopathological and genomic characteristics, response, and survival outcomes and compared with a cohort of 610 patients with dMMR\/MSI-H mCRC treated with ICIs. Genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE<\/em>\/D1pd<\/em> molecular profiles and mutational signatures.<\/p>\n

POLE\/D1pd<\/em> was associated with younger age, male sex, fewer RAS\/BRAF<\/em> driver mutations, and predominance of right-sided colon cancers. Patients with POLE\/D1pd<\/em> 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<\/em> 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).<\/p>\n

In multivariable analyses including the type of DNA repair defect, POLE\/D1pd<\/em> 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<\/em> tumours have higher TMB. Responses were observed in both subtypes and were associated with the intensity of POLE\/D1pd<\/em> signature.<\/p>\n

The study has some limitations given its retrospective nature, the imbalance between the number of patients in the two cohorts reflecting the different frequencies of these alterations, and the wider diffusion of the MMR\/MSI screening. Other limitations are the shorter follow-up and the limited available genomic data of the POLE\/D1pd<\/em> mCRC cohort.<\/p>\n

While it is widely acknowledged that immunotherapy can lead to durable tumour responses and even cure for patients with dMMR\/MSI-H mCRC, characterising the predictive role of POLE\/D1pd<\/em> in the pMMR\/MSS setting is crucial according to the authors. Recognising the significance of this subgroup is of primary clinical relevance for patient prognosis, to potentially tailor neo\/adjuvant strategies and allow early access to ICIs in patients with pMMR\/MSS mCRC.<\/p>\n

In the presence of clinical characteristics, even small NGS panels with a limited number of genes, but including POLE<\/em> and POLD1<\/em> genes, may be useful when concomitant RAS<\/em> and BRAF<\/em> testing is carried out as part of routine assessment. Active efforts directed toward the identification of this subgroup are important to potentially allow cancer cure and long-term survival.<\/p>\n

This research was partially funded by Italian Ministry of Health \u201cRicerca Corrente\u201d funds, and supported by Nuovo Soldati foundation, MSKCC T32-CA009512, Molecular Cytology Core Grant, Swim Across America, Dalton Family Foundation. The sequencing of tumours of the AcS\u00e9 clinical trial (TMB) was part of an ancillary analysis programme of Acs\u00e9 Nivolumab (Acs\u00e9 Cible) funded by a research grant from the Ligue contre le Cancer and has been previously published (Rousseau et<\/em> al<\/em>.<\/em> Cancer Discovery<\/em> 2022).<\/p>\n

The authors acknowledged the use of the Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant, Cycle for Survival, and the Marie-Jos\u00e9e and Henry R. Kravis Center for Molecular Oncology. The Acs\u00e9 Nivolumab trial was sponsored by French Unicancer and the Institut National du Cancer (INCa). The funding of the trial has been supported by Bristol Myers Squibb, the Ligue contre le Cancer, and the INCa. The supply of nivolumab in the Acs\u00e9 Nivolumab trial was kindly provided by Bristol Myers Squibb. Blood PBMCs and tumour FFPE blocks in the Acs\u00e9 Nivolumab trial were prospectively collected, stored, and prepared for analysis by the L\u00e9on B\u00e9rard Cancer Center in Lyon, France.<\/p>\n

Reference<\/h3>\n

Ambrosini M, Rousseau B, Manca P, et al.<\/em> Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer<\/a>. Annals of Oncology<\/em>; Published online 21 May 2024. DOI: https:\/\/doi.org\/10.1016\/j.annonc.2024.03.009<\/a><\/p>\n

Source<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

Recent advances in the molecular dissection of colorectal cancer (CRC) uncovered a rare subtype of ultramutated tumours with polymerases epsilon (POLE) or delta (POLD1) proofreading deficiency (pd). To better establish the benefit of immune checkpoint inhibitors (ICIs) in this population, a group of investigators assembled a unique dataset of patients with POLE\/D1pd metastatic CRC (mCRC) […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-46647","post","type-post","status-publish","format-standard","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46647","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=46647"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46647\/revisions"}],"predecessor-version":[{"id":47019,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46647\/revisions\/47019"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=46647"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=46647"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=46647"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}