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Frontiers in Immunology 2023Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with... (Review)
Review
Immunotherapy has transformed treatment for various types of malignancy. However, the benefit of immunotherapy is limited to a minority of patients with mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) (dMMR-MSI-H) colorectal cancer (CRC). Understanding the complexity and heterogeneity of the tumor immune microenvironment (TIME) and identifying immune-related CRC subtypes will improve antitumor immunotherapy. Here, we review the current status of immunotherapy and typing schemes for CRC. Immune subtypes have been identified based on TIME and prognostic gene signatures that can both partially explain clinical responses to immune checkpoint inhibitors and the prognosis of patients with CRC. Identifying immune subtypes will improve understanding of complex CRC tumor heterogeneity and refine current immunotherapeutic strategies.
Topics: Humans; Immunotherapy; Prognosis; Colorectal Neoplasms; Microsatellite Instability; Tumor Microenvironment
PubMed: 37876934
DOI: 10.3389/fimmu.2023.1259461 -
Annals of Oncology : Official Journal... Nov 2023The prognostic value of KRAS and BRAF mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite...
Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials.
BACKGROUND
The prognostic value of KRAS and BRAF mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis.
PATIENTS AND METHODS
We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAF mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations.
RESULTS
Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAF, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAF, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAF-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence.
CONCLUSIONS
Testing for both KRAS and BRAF mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.
Topics: Prognosis; Colonic Neoplasms; Microsatellite Instability; Randomized Controlled Trials as Topic; Humans; Proto-Oncogene Proteins p21(ras); Exons; Proto-Oncogene Proteins B-raf; Male; Female; Middle Aged; Treatment Outcome
PubMed: 37619846
DOI: 10.1016/j.annonc.2023.08.006 -
British Journal of Cancer Oct 2023Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast... (Review)
Review
Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.
Topics: Animals; Mice; Humans; Translational Research, Biomedical; Medical Oncology; Brain Neoplasms; Colorectal Neoplasms; Microsatellite Instability; DNA Mismatch Repair
PubMed: 37563222
DOI: 10.1038/s41416-023-02392-x -
MedComm Oct 2023Currently, checkpoint inhibitor-based immunotherapy has emerged as prevailing treatment modality for diverse cancers. However, immunotherapy as a first-line therapy has... (Review)
Review
Currently, checkpoint inhibitor-based immunotherapy has emerged as prevailing treatment modality for diverse cancers. However, immunotherapy as a first-line therapy has not consistently yielded durable responses. Moreover, the risk of immune-related adverse events increases with combination regimens. Thus, the development of predictive biomarkers is needed to optimize individuals benefit, minimize risk of toxicities, and guide combination approaches. The greatest focus has been on tumor programmed cell death-ligand 1 (PD-L1), microsatellite instability (MSI), and tumor mutational burden (TMB). However, there remains a subject of debate due to thresholds variability and significant heterogeneity. Major unmet challenges in immunotherapy are the discovery and validation of predictive biomarkers. Here, we show the status of tumor PD-L1, MSI, TMB, and emerging data on novel biomarker strategies with oncogenic signaling and epigenetic regulation. Considering the exploration of peripheral and intestinal immunity has served as noninvasive alternative in predicting immunotherapy, this review also summarizes current data in systemic immunity, encompassing solute PD-L1 and TMB, circulating tumor DNA and infiltrating lymphocytes, routine emerging inflammatory markers and cytokines, as well as gut microbiota. This review provides up-to-date information on the evolving field of currently available biomarkers in predicting immunotherapy. Future exploration of novel biomarkers is warranted.
PubMed: 37799808
DOI: 10.1002/mco2.387 -
Life (Basel, Switzerland) Oct 2023Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with... (Review)
Review
Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 () fusion, in addition to less frequently observed targets such as , deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and high tumor mutation burden (TMB-H). These targets are observed in varying frequency among patients with intrahepatic CCA and extrahepatic CCA. Multiple novel therapies have been developed to exploit each of these targets, with some having received United States Food and Drug Administration approval for use in the second-line setting. In the current review, we discuss targets of interest in CCA and summarize current evidence evaluating available therapies directed at these targets.
PubMed: 37895447
DOI: 10.3390/life13102066 -
Clinical Cancer Research : An Official... Nov 2023This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an...
PURPOSE
This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.
PATIENTS AND METHODS
A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR).
RESULTS
A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports.
CONCLUSIONS
Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. See related commentary by Jangra and Dhani, p. 4521.
Topics: Female; Humans; Neoplasm Recurrence, Local; Antibodies, Monoclonal, Humanized; Endometrial Neoplasms; Colorectal Neoplasms; Microsatellite Instability; Biomarkers, Tumor; DNA Mismatch Repair
PubMed: 37363992
DOI: 10.1158/1078-0432.CCR-22-3915 -
Translational Cancer Research Oct 2023
PubMed: 37969375
DOI: 10.21037/tcr-23-1343 -
Genes & Development Oct 2023Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN...
Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN-knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We found that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we found no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low-dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provide the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggest that dual targeting of WRN and ATR might be a useful strategy for treating MSI-H cancers.
Topics: Humans; DNA Replication; DNA Helicases; Microsatellite Repeats; DNA Damage; Neoplasms; RecQ Helicases; Exodeoxyribonucleases; Werner Syndrome Helicase; Ataxia Telangiectasia Mutated Proteins
PubMed: 37932011
DOI: 10.1101/gad.351085.123 -
Nature May 2024The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens....
The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens. Despite advances in treatment with immune checkpoint inhibitors, there is an unmet need in the treatment of MSI cancers. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.
Topics: Animals; Female; Humans; Mice; Administration, Oral; Allosteric Regulation; Antineoplastic Agents; Cell Line, Tumor; Clinical Trials as Topic; Colorectal Neoplasms; DNA Damage; Drug Discovery; Enzyme Inhibitors; Mice, Nude; Microsatellite Instability; Neoplasms; Protein Domains; Reproducibility of Results; Suppression, Genetic; Synthetic Lethal Mutations; Tumor Suppressor Protein p53; Werner Syndrome Helicase; Xenograft Model Antitumor Assays
PubMed: 38658754
DOI: 10.1038/s41586-024-07350-y -
NAR Cancer Sep 2023Tumors defective in DNA mismatch repair (dMMR) exhibit microsatellite instability (MSI). Currently, patients with dMMR tumors are benefitted from anti-PD-1/PDL1-based...
Tumors defective in DNA mismatch repair (dMMR) exhibit microsatellite instability (MSI). Currently, patients with dMMR tumors are benefitted from anti-PD-1/PDL1-based immune checkpoint inhibitor (ICI) therapy. Over the past several years, great progress has been made in understanding the mechanisms by which dMMR tumors respond to ICI, including the identification of mutator phenotype-generated neoantigens, cytosolic DNA-mediated activation of the cGAS-STING pathway, type-I interferon signaling and high tumor-infiltration of lymphocytes in dMMR tumors. Although ICI therapy shows great clinical benefits, ∼50% of dMMR tumors are eventually not responsive. Here we review the discovery, development and molecular basis of dMMR-mediated immunotherapy, as well as tumor resistant problems and potential therapeutic interventions to overcome the resistance.
PubMed: 37325548
DOI: 10.1093/narcan/zcad031