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Purpose of Review: This review will explore various strategies to rendering MSS mCRCs susceptible to ICI. Moreover, we will provide an overview of potential biomarkers that may aid to better patient selection, and discuss ongoing efforts in this area of research. Recent Findings: Colorectal cancer (CRC) ranks among the top three most common cancers worldwide. While significant advances in treatment strategies have improved the prognosis for patients in the early stages of the disease, treatment options for metastatic CRC (mCRC) remain limited. Although immune checkpoint inhibitors (ICI) have revolutionized the treatment of several malignancies, its efficacy in mCRC is largely confined to patients exhibiting a high microsatellite instability status (MSI-H). However, the vast majority of mCRC patients do not exhibit a MSI-H, but are microsatellite stable (MSS). In these patients ICIs are largely ineffective. Summary: So far, ICIs do not play a crucial role in patients with MSS mCRC, despite the promising data for inducing long-term remissions in other tumour entities. For this reason, novel treatment strategies are needed to overcome the primary resistance upon ICI in patients with MSS. [ABSTRACT FROM AUTHOR]

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Background: Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules that contribute to tumor immune evasion. However, the main treatment modalities for patients with early and intermediate stage colorectal cancer (CRC) are surgery, and the role of PD-1/PD-L1 inhibitors in these patients is not yet clear. Therefore, this study aims to review the treatment progress of PD-1/PD-L1 inhibitors for early- and intermediate-stage microsatellite high-instability (MSI-H) and stable (MSS) colorectal cancer, in order to provide more options for patients with early- and intermediate-stage colorectal cancer. Materials and methods: A scoping review of clinical trial registries (Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on PD-1/PD-L1 Inhibitors for early and middle-stage MSI-H and MSS CRC was done up to March 2024. Results: A total of 19 trials related to early to mid-stage MSH-I or MSS CRC were included. Among them, 6 trials are in recruiting status, 3 trials are in active, not recruiting status, 3 trials are completed, 1 trial is terminated, and 1 trial is unknown. Of these, 9 trials involve MSI-H type CRC, and 10 trials involve MSS type CRC. Preclinical phase I/II trials are predominant, with only 3 clinical phase III trials. In trials related to MSI-H type CRC, 4 studies involve PD-1/PD-L1 inhibitors combined with neoadjuvant therapy, and 5 studies involve combination therapy. In trials related to MSS type CRC, 3 studies involve PD-1/PD-L1 inhibitors combined with targeted therapy, 2 studies involve PD-1/PD-L1 inhibitors combined with chemotherapy, 1 study involves PD-1/PD-L1 inhibitor combined immunotherapy, 1 study involves PD-1/PD-L1 inhibitors combined with bacterial therapy, and 3 studies involve PD-1/PD-L1 inhibitors combined with comprehensive therapy. As for primary outcome measures, 4 trials select pathological complete response rates, 3 trials select progression-free survival rate, 3 trials select objective response rate, 3 trials select overall survival rate, 4 trials select disease-free survival rate, 1 trial selects clinical complete response rate, and 1 trial selects percentage of participants with a dose-limiting toxicity. Conclusion: For early- and middle-stage MSI-H and MSS CRC, PD-1/PD-L1 inhibitors have shown some therapeutic efficacy, as evidenced by phase I/II studies. However, contemporary trial designs exhibit heterogeneity, with relatively few inclusion criteria, the use of various drug combinations and regimens, and significant variations in reported endpoints. Nevertheless, more double-arm, multicenter, randomized controlled trials are still needed to confirm the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics. [ABSTRACT FROM AUTHOR]

Purpose: Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers. Methods: Multicenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages. Results: Three hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy. Conclusion: Our study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Opinion statement: Neoadjuvant chemotherapy is safe for patients with locally advanced colon cancer (LACC). The FOxTROT trial demonstrated a reduction in residual and recurrent cancer at 2 years with neoadjuvant chemotherapy for patients with cT3-4 LACC. Preoperative chemotherapy should be avoided, if possible, for patients with dMMR LACC, as over 50% of dMMR cancers have no pathologic response. Early universal testing of MMR status is critical to selecting the appropriate neoadjuvant therapy. Concerns about CT staging of LACC have limited uptake of neoadjuvant chemotherapy, as approximately 25% of patients with cT3-T4 cancer on CT have low-risk stage II disease. Development of CT criteria for malignant nodes should reduce the risk of over-staging. A multidisciplinary approach is needed to identify patients for neoadjuvant therapy. Neoadjuvant immunotherapy is safe and results in dramatic pathologic responses in patients with dMMR LACC. Longer follow-up is needed to determine if the exceptionally high pathologic response rates observed will translate into long-term remission. Remarkably, neoadjuvant immunotherapy has been found to cause major pathologic responses in a subset of patients with pMMR LACC, indicating the potential to cure more patients with this common cancer. Patients with cT4 LACC, whether stage II or III, have a substantial risk of recurrence despite adjuvant fluoropyrimidine plus oxaliplatin chemotherapy. We recommend neoadjuvant systemic therapy for all patients with cT4b LACC (dMMR and pMMR). Features of T4b disease are routinely reported by radiology. We use three cycles of FOLFOX chemotherapy for patients with cT4b pMMR LACC, due to the high rate of compliance and improvement in residual and recurrent disease. Patients with cT4b dMMR LACC should receive neoadjuvant immunotherapy, if there are no contraindications. Clinical trials of neoadjuvant therapy for LACC are of great interest and should provide training for radiologists to identify eligible patients. Results are anticipated from multiple ongoing trials of neoadjuvant chemotherapy, immunotherapy, and targeted therapy for pMMR LACC and immunotherapy for dMMR LACC. [ABSTRACT FROM AUTHOR]

Purpose: Several studies have demonstrated the effectiveness of anti-angiogenic drugs in combination with immune checkpoint inhibitors (ICIs) in patients with microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC). However, whether combination radiotherapy (RT) can further improve the prognosis of mCRC patients after second-line treatment remains to be explored. Methods: Retrospective analysis of data from mCRC patients who received antiangiogenic targeted therapy (TT) and immunotherapy (IT) with or without RT after the failure of standard therapy. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated. Results: A total of 82 patients who received TT + IT were analyzed. For RT group (n = 42) versus NRT group (n = 40), ORR was 21.4% (9/42) versus 5.0% (2/40); DCR was 83.8% (35/42) versus 65.0% (26/40). Compared with NRT group, RT improved PFS (median: 5.0 vs. 3.6 months; p = 0.04) and OS (median: 15.2 vs. 7.2 months; p = 0.01). In addition, in the population receiving RT, the PFS of RT sequential/simultaneous TT + IT was superior to TT + IT sequential RT (median: 7.1 vs. 6.2 vs. 3.5 months, p = 0.004). Multivariate analysis suggested RT was an independent prognostic factor for PFS and OS. No treatment-related deaths were reported.Conclusions: Compared with TT + IT, RT combined with TT + IT improved survival outcomes in MSS/pMMR mCRC patients, with manageable toxicity. RT sequential/simultaneous TT + IT treatment is expected to be the optimal strategy for MSS/PMMR mCRC. [ABSTRACT FROM AUTHOR]

Copyright of Cancer Research on Prevention & Treatment is the property of Cancer Research on Prevention & Treatment Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic CRC failed to meet surgical indications or achieve pathological complete response after surgery. Perioperative therapy has been proven to effectively lower tumor staging and reduce recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have shown unprecedented prolongation of survival time and satisfactory safety in patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), while the therapeutic effect obtained by patients with mismatch repair-proficient or microsatellite stable (pMMR/MSS) was considered minimal. However, recent studies found that certain CRC patients with dMMR/MSI-H presented intrinsic or acquired immune resistance, and pMMR/MSS CRC patients can also achieve better efficacy. Therefore, more predictors are required for screening patients with potential clinical benefits. Since the discovery of synergistic effects between immunotherapy, chemotherapy, and radiotherapy, different immunotherapy-based therapies have been applied to the perioperative therapy of CRC in an increasing number of research. This review comprehensively summarized the past and current progress of different combinations of immunotherapy in perioperative clinical trials for CRC, focusing on the efficacy and safety, and points out the direction for future development. [ABSTRACT FROM AUTHOR]

Rectal cancer is a heterogeneous disease with complex genetic and molecular subtypes. Emerging progress of neoadjuvant therapy has led to increased pathological and clinical complete response (cCR) rates for microsatellite stable (MSS) rectal cancer, which responds poorly to immune checkpoint inhibitor alone. As a result, organ preservation of MSS rectal cancer as an alternative to radical surgery has gradually become a feasible option. For patients with cCR or near-cCR after neoadjuvant treatment, organ preservation can be implemented safely with less morbidity. Patient selection can be done either before the neoadjuvant treatment for higher probability or after with careful assessment for a favorable outcome. Those patients who achieved a good clinical response are managed with nonoperative management, organ preservation surgery, or radiation therapy alone followed by strict surveillance. The oncological outcomes of patients with careful selection and organ preservation seem to be noninferior compared with those of radical surgery, with lower postoperative morbidity. However, more studies should be done to seek better regression of tumor and maximize the possibility of organ preservation in MSS rectal cancer. [ABSTRACT FROM AUTHOR]

Objective: To assess the clinical efficacy of neoadjuvant chemoradiotherapy combined with immunotherapy for patients with microsatellite stable (MSS) locally advanced rectal cancer and provide evidence to support clinical decision-making. Methods: A systematic search was conducted on the PubMed, Embase, Cochrane Collaboration databases, conference summaries, and Chinese databases for clinical studies that investigated neoadjuvant chemoradiotherapy combined with immunotherapy for the treatment of locally advanced rectal cancer with MSS status. The search spanned from the inception of each database through July 2023. Data from the identified studies were extracted using a predesigned table, and efficacy outcomes were analyzed. An integrated analysis was conducted using Stata 12.0 software. Results: Eight studies were included, comprising 204 patients with locally advanced MSS rectal cancer who received chemoradiotherapy combined with immunotherapy. The integrated analysis revealed a pathologic complete remission rate of 0.33, a sphincter preservation rate of 0.86, an R0 resection rate of 0.83, a major pathologic remission rate of 0.33, and a clinical complete remission rate of 0.30. Conclusion: Neoadjuvant chemoradiotherapy combined with immunotherapy demonstrates significant short-term efficacy in MSS-type locally advanced rectal cancer, notably enhancing the pathologic complete remission and sphincter preservation rates. This combination is a recommended treatment for patients with MSS-type rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Microsatellite stable (MSS) colorectal cancer (CRC) has been referred to as the "cold tumor" because of almost no response to anti-- programmed death-1 (PD-1) antibody. A recent REGONIVO trial showed that regorafenib plus nivolumab had an encouraging efficacy in MSS metastatic CRC (mCRC). However, only a small subset of patients may benefit from the combination therapy. We aim to evaluate the efficacy and safety data of immune checkpoint inhibitors combined with regorafenib in refractory MSS mCRC and to discover biomarkers that can effectively stratify the beneficial patient population. Methods: We retrospectively analyzed patients with MSS mCRC who received regorafenib combined with anti--PD-1 antibody therapy. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and status of gene mutation were reviewed and evaluated. Results: Twenty-one patients received combination treatment. At a median treatment duration of 4 months, one patient achieved complete response, three patients achieved partial response, and two patients achieved stable disease as the best response. The ORR and DCR were 19% and 28.5% in the overall population, respectively. The median PFS was 4 months, and the median OS was 25 months. Only erbb2 receptor tyrosine kinase 2/erbb3 receptor tyrosine kinase 3 (ERBB2/ ERBB3) mutation status was confirmed to be a potential predictive factor for effective treatment. In patients with ERBB2/ERBB3 mutation, ORR, DCR, and PFS exhibited significant improvements in comparison with that in wild-type patients. Grade 3 or higher treatment-related adverse events occurred in three patients (14.3%). Conclusions: Regorafenib in combination with PD-1 inhibitor provides a feasible treatment regimen for refractory MSS mCRC with tolerated toxicity. Patients with ERBB2/ERBB3 mutation may be the preferred population for this combination regimen. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator. [ABSTRACT FROM AUTHOR]

Background: Although the use of regorafenib plus nivolumab demonstrates promising outcomes in patients with refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC), this effect has not been substantiated in other studies. Moreover, a comparison between the outcomes of regorafenib and programmed cell death protein 1 (PD‐1) antibody combination therapy and regorafenib monotherapy remains unexplored. In this study, we aimed to assess whether regorafenib and PD‐1 antibody combination therapy is superior to regorafenib monotherapy as a third‐line treatment for MSS mCRC. Methods: Patients with MSS mCRC who received regorafenib and PD‐1 antibody or regorafenib monotherapy as third‐line treatment were eligible for inclusion. Results: In total, 179 patients were enrolled, of which 84 were administered regorafenib combined with a PD‐1 antibody and 95 were administered regorafenib monotherapy. Patients administered regorafenib combined with a PD‐1 antibody had similar progression‐free survival (PFS) as those on regorafenib monotherapy (median PFS was 2.4 months and 1.9 months, respectively, p = 0.086). The administration of regorafenib combined with a PD‐1 antibody resulted in significantly longer PFS than that seen with regorafenib monotherapy in both male (5.2 months vs. 2.4 months, p = 0.001) and female (3.9 months vs. 1.8 months, p = 0.037) patients without liver metastasis. Female patients with liver metastasis who were administered regorafenib combined with a PD‐1 antibody had shorter PFS than those administered regorafenib monotherapy (1.8 months vs. 2.0 months, p = 0.030). Conclusion: Liver metastasis and sex are predictors of survival benefit following the addition of a PD‐1 antibody to regorafenib in patients with MSS mCRC. [ABSTRACT FROM AUTHOR]

Objective: Immune checkpoint inhibitors have been widely used in the treatment of endometrial cancer (EC) with microsatellite instability-hypermutated (MSI-H). However, there is an unmet need for microsatellite stable (MSS) EC because of their modest activity. This study aimed to identify potential immune-related biomarkers in MSS EC. Methods: One hundred and twenty-three patients with EC who underwent hysterectomy were enrolled. MSI status was determined using MSI analysis and/or immunohistochemical staining for mismatch repair proteins. Immunohistochemical analysis of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), PD-L2, cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), cluster of differentiation 3 (CD3), CD8, lymphocyte activation gene-3 (LAG-3), indoleamine 2,3-dioxygenase 1 (IDO1), phosphatase and tensin homolog (PTEN), p53, AT-rich interactive domain-containing protein 1A (ARID1A), and ß-catenin was performed using tissue microarray blocks. Results: Among 123 patients, 95 (77.2%) were classified as having MSS. Within EC with MSS, PD-L1 positivity was significantly associated with positive PD-1 (p<0.001), CTLA-4 (p<0.001), CD3 (p=0.002), CD8 (p<0.001), and LAG-3 (p<0.001). In the univariate analysis, positive PD-1 (odds ratio [OR]=9.281; 95% confidence interval [CI]=2.560-33.653; p<0.001), CTLA-4 (OR=5.33; 95% CI=1.418-19.307; p=0.005), CD3 (OR=5.571; 95% CI=1.746-17.775; p=0.004), CD8 (OR=6.909; 95% CI=2.647-18.037; p<0.001), and LAG-3 (OR=9.75; 95% CI=1.947-48.828; p=0.005) were significantly associated with PD-L1 positivity in MSS EC. In the multivariate analysis, LAG-3 demonstrated a significant association with positive PD-L1 expression in MSS EC (OR=5.061; 95% CI=1.534-16.693; p=0.023). Conclusion: In patients with MSS EC harboring PD-L1, LAG-3 may be a potential immunotherapeutic target. Clinical trials investigating the role of anti-LAG-3 antibodies, alone or in combination with other immunotherapies, are warranted. [ABSTRACT FROM AUTHOR]

Copyright of Cancer Research on Prevention & Treatment is the property of Cancer Research on Prevention & Treatment Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: A large proportion of indigenous African (IA) colorectal cancer (CRC) patients in South Africa are young (< 50 years), with no unique histopathological or molecular characteristics. Anatomical site as well as microsatellite instability (MSI) status have shown to be associated with different clinicopathological and molecular features. This study aimed to ascertain key histopathological features in microsatellite stable (MSS) and low-frequency MSI (MSI-L) patients, to provide insight into the mechanism of the disease.Methods: A retrospective cohort (2011-2015) of MSS/MSI-L CRC patient samples diagnosed at Charlotte Maxeke Johannesburg Academic Hospital was analyzed. Samples were categorized by site [right colon cancer (RCC) versus left (LCC)], ethnicity [IA versus other ethnic groups (OEG)] and MSI status (MSI-L vs MSS). T-test, Fischer's exact and Chi-square tests were conducted.Results: IA patients with LCC demonstrated an increased prevalence in males, sigmoid colon, signet-ring-cell morphology, MSI-L with BAT25/26 marker instability and advanced disease association.Conclusion: This study revealed distinct histopathological features for LCC, and suggests BAT25 and BAT26 as negative prognostic markers in African CRC patients. Larger confirmatory studies are recommended. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Oncology Prevention & Treatment is the property of Editorial Department of Chinese Journal of Oncology Prevention & Treatment and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: The antitumor activity of nivolumab plus regorafenib in colorectal cancer from a phase Ib REGONIVO study is encouraging. The present study was conducted to evaluate the efficacy and safety of regorafenib or fruquintinib plus sintilimab as third-line or above therapy in patients with microsatellite stable (MSS) metastatic colorectal cancer. Methods: Patients with MSS metastatic colorectal cancer who have failed from prior treatment and received regorafenib or fruquintinib plus sintilimab as thirdline or above therapy from January 2019 to December 2020 were prospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: 42 patients received regorafenib plus sintilimab(RS), and the other 30 patients received fruquintinib plus sintilimab(FS). In the general population, the ORR and DCR were 13.9% and 70.8%, and the median PFS and OS was 4.2(95% CI=2.9-5.5) and 10.5 (95% CI=8.6-12.4) months, respectively. There were no statistically significant differences between RS and FS group in PFS (3.5(2.2-4.8) vs. 5.5(3.5-7.5) months, P=0.434) and OS (11.0(7.0-15.0) vs. 10.5(3.8-17.2) months, P=0.486). Subgroup analysis suggested that patients without liver metastasis responded well to this combination regimen (ORR: 21.4% vs. 9.1%) and obtained better OS (26(8.8-43.2) vs. 10.0(7.4-12.6) months, P=0.016). The incidence of Grade 3-4 adverse events (AEs) was 15.3% and the toxicities were generally tolerable and manageable. Conclusions: Regorafenib or fruquintinib plus sintilimab as third-line or above therapy provide a feasible treatment regimen for MSS metastatic colorectal cancer with tolerated toxicity. Patients without liver metastasis may be the preferred population for this combination regimen. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings. Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study. [ABSTRACT FROM AUTHOR]

DNA transposons are exposed to a molecular domestication process, which results in the formation of neogenes, which may play a role in human genetic instability. TIGD3 (Tigger-derived [TIGD] family of proteins) is one of these Neogene, and its role in the human genome is unknown. Aim: The expression of Neogene TIGD3 in colorectal cancer cell lines and its putative function in carcinogenesis are being investigated. Method: The protein expression of the TIGD3 gene was investigated using the western blot method in twelve colorectal cancer cell lines (HCT116, SW48, LOVO, DLD1) that are microsatellite instable MSI, (SW480, SW620, HT29, LS123, COLO205, T84, SW403, SW1463) that are microsatellite stable MSS, and in healthy colon tissue as a control in our study. Results: The expression of the TIGD3 protein was found in all twelve colorectal cancer cell lines, with varying degrees of expression and numerous isoforms, which was not found in healthy colon tissue. Conclusion: There may be a link between colorectal cancer evolution or progression and TIGD3 gene expression. [ABSTRACT FROM AUTHOR]

Colon adenocarcinoma (COAD) is one of the leading causes of cancer-associated deaths worldwide. Patients with microsatellite instability-high (MSI-H) tumors were shown to highly benefit from immune checkpoint inhibitors (ICIs) than patients with microsatellite stable (MSS) tumors. Furthermore, the infiltration of immune cells and the expression of cancer stem cells (CSCs) in COAD were associated with the anti-tumor immune response. However, the potential mechanisms showing the relationship between microsatellite instability and CSCs or tumor-infiltrating immune cells (TIICs) have not been elucidated. Accumulating evidence reveals that achaete-scute family bHLH transcription factor 2 (ASCL2) plays a crucial role in the initiation and progression of COAD and drug resistance. However, the specific biological functions of ASCL2 in COAD remain unknown. In this study, we performed weighted gene co-expression network analysis (WGCNA) between MSS and MSI-H subsets of COAD. The results revealed that ASCL2 was a potential key candidate in COAD. Subsequently, the single-cell RNA-seq revealed that ASCL2 was positively associated with CSCs. Further, ASCL2 was shown to indirectly affect tumor immune cell infiltration by negatively regulating the expression of DUSP4. Finally, we inferred that the immunotherapy-sensitive role of ASCL2/DUSP4 axis on COAD is partly attributed to the activation of WNT/β-catenin pathway. In conclusion, this study revealed that ASCL2 was positively correlated to CSCs and tumor immune infiltration in COAD. Therefore, ASCL2 is a promising predictor of clinical responsiveness to anti-PD-1/PD-L1 therapy in COAD. [ABSTRACT FROM AUTHOR]

Colorectal carcinoma (CRC) is the second leading cause of cancer mortality worldwide. CRC is stratified into two major groups: microsatellite stable (MSS) and microsatellite instability‐high (MSI‐H). MSS CRC constitutes the majority of cases, has worse overall prognosis, and thus far has failed to respond to immunotherapies targeting the immune checkpoint receptors PD‐1, PD‐L1, and CTLA‐4. Here we examined the alternate immunotherapy targets Tim‐3 and Lag‐3, as well as PD‐1, on immune cells in a cohort of MSS CRC using immunohistochemistry and flow cytometry together with mutational analysis and clinical data. We found that PD‐1 was variably expressed across CD4+ tumor‐infiltrating lymphocyte (TIL) subtypes, and Tim‐3 was mostly restricted to CD4+ regulatory T cells. Lag‐3, when detected by flow cytometry, was largely coexpressed with Tim‐3 and PD‐1 in CD4+ TILs. Furthermore, Tim‐3+PD‐1+ CD8+ TILs accumulated in the tumor and exhibited a dysfunctional or 'exhausted' phenotype. Notably, we observed a subset of patients with a high proportion of Tim‐3−PD‐1− CD8+ TILs and, conversely, a low proportion of Tim‐3+PD‐1+ CD8+ TILs, thus stratifying MSS CRC patients based on a feature of immune exhaustion (MSS‐ImmEx). MSS‐ImmExhi patients had abundant Tim‐3+PD‐1+ CD8+ TILs, PD‐1+ CD4+ effector, and regulatory T cells, and were enriched for left‐sided colon tumors and mutations in the APC tumor‐suppressor gene. We further investigated the spatial organization of Tim‐3, Lag‐3, PD‐1, and PD‐L1 by immunohistochemistry and found higher levels in the tumor margin; however, MSS‐ImmExhi tumors exhibited a higher density of Tim‐3+ cells in the tumor center over MSS‐ImmExlow tumors. Immunofluorescence revealed a higher density of PD‐1+/CD8+ cells in the tumor center in this group. Our findings identify a subset of MSS CRC that exhibits evidence of higher prior immune activation (MSS‐ImmExhi) in which therapies targeting Tim‐3 in conjunction with anti‐PD‐1 or other immunotherapies may provide clinical benefit. © 2022 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background/Aim: Better stratification of the risk of relapse will help select the right patients for adjuvant treatment and improve targeted therapies for patients with colon cancer. Materials and Methods: To understand why a subset of tumors relapse, we compared the proteome of two groups of patients with colon cancer with similar stage, stratified based on the presence or absence of recurrence. Results: Using tumor biopsies from the primary operation, we identified dissimilarity between recurrent and nonrecurrent mismatch satellite stable colon cancer and found that signaling related to immune activation and inflammation was associated with relapse. Conclusion: Immune modulation may have an effect on mismatch satellite stable colon cancer. At present, immune therapy is offered primarily to microsatellite instable colon cancer. Hopefully, immune therapy in mismatch satellite stable colon cancer beyond PD-1 and PD-L1 inhibitors can be implemented. [ABSTRACT FROM AUTHOR]

Background: For a majority of patients with metastatic colorectal cancer (mCRC) with MS stable (MSS) or mismatch repair proficient (pMMR), the role of immunotherapy is undetermined. This study investigated the efficacy and safety of camrelizumab when added to XELOX chemotherapy plus bevacizumab or regorafenib as first-line therapy for mCRC. Materials and Methods: Medical records of mCRC patients who received camrelizumab and XELOX plus bevacizumab or regorafenib at the First Hospital of Quanzhou Affiliated to Fujian Medical University between June 1, 2019, and April 30, 2021, were retrospectively collected. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed. Results: Twenty-five eligible patients received combination therapy, including bevacizumab in 19 patients and regorafenib in 6. Twenty-one patients had pMMR/MSS and one MSI-H. Of the 25 patients who could be evaluated for efficacy, 18 (72%) achieved PR, 6 (24%) achieved SD, and 1 (4%) achieved PD. The ORR and DCR were 72% (18/25) and 96% (24/25), respectively. The median progression-free survival (PFS) was 11.2 months (95% CI 8.9–13.9), and OS had not yet been reached. The combination regimen of regorafenib in six (24%) patients was unassociated with treatment outcomes. Most AEs were either grade 1 or 2, and treatment-related grade 3 toxicities were observed in 8/25 (32%) patients. Conclusion: Camrelizumab combined with XELOX plus bevacizumab or regorafenib was feasible, producing high rates of responses as first-line therapy in unselected Chinese patients with MSS mCRC. The toxicities were generally tolerable and manageable. Prospective randomized trials with large sample sizes are needed to evaluate these findings. [ABSTRACT FROM AUTHOR]

Background: Microsatellite stability (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. Studies have shown that antiangiogenic drugs combined with programmed death receptor-1 (PD-1) inhibitors can improve immunosuppression. The purpose of this study was to compare the efficacy of fruquintinib combined with PD-1 inhibitor (FP) and regorafenib combined with PD-1 inhibitor (RP) in the treatment of advanced mCRC with MSS or pMMR. Materials and Methods: We retrospectively collected advanced MSS or pMMR mCRC patient data from The Second Affiliated Hospital of Nanchang, China, from June 2019 to March 2021. Then, we analyzed and compared the efficacy and safety of FP and RP. Results: A total of 51 patients who met the criteria were divided into FP (n = 28) and RP groups (n = 23). The overall response rate of the FP and RP groups was 7.1% and 8.7% and the disease control rate was 89.3% and 56.5%, respectively. The median progression-free survival (PFS) time was higher in the FP group than in the RP group (6.4 vs. 3.9 months, respectively; P = 0.0209). Patients with no liver metastasis, KRAS wild type, and left colon tumor may benefit from FP. Eight patients (15.7%) had grade 3 toxicity related to treatment. Cox multivariate regression analysis showed that the treatment method was an independent risk factor for median PFS time. Conclusion: Our study indicates that FP could improve PFS time of patients with advanced mCRC compared with RP. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of mismatch repair deficiency in colorectal carcinoma determined by immunohistochemistry. Study Design: Cross-sectional study. Place and Duration of Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from Aug 2018 to Jan 2019. Methodology: A total of 101 patients of adenocarcinoma of colorectum who underwent surgical resections and their characteristic and clinical data were recorded. Immunohistochemical stains were performed using antibodies MLH1, MSH2, PMS2 and MSH6. Results were interpreted and mismatch repair deficiency status of all patients was determined. Patients with loss of expression for MLH1, MSH2, PMS2 and MSH6 antibodies were observed and noted. Results: In this study, out of 101 patients with CRC, 71 (70.3%) were male and 30 (29.7%) female. The mean age was (54 years ± 15.9). Amongst the 101 cases loss of immunohistochemical staining for MMR proteins was noted in 19 patients (18.8%). The combined loss of all four antibodies was seen in one case, loss of MLH1 and PMS2 in 7, MSH2 and MSH6 in 5 and MLH1 only in 6 patients. However, no mismatch repair deficiency was detected in remaining 82 cases. According to statistical analysis no significant association between mismatch repair deficiency and variables was found. Conclusion: The frequency of mismatch repair deficiency in colorectal carcinoma patients was found to be 18.8% in our population. [ABSTRACT FROM AUTHOR]

The neogenic recombinases are potentially a source of genetic variability possibly implicated in the mechanisms of genetic instability involved in the processes of carcinogenesis. One of these neogenic recombinases is the nuclear apoptosis-inducing factor 1(NAIF1), which codes the protein NAIF1 that induces apoptosis in various human cancers. The aim of this work is to study the expression of NAIF1 neogene in cancerous and non-cancerous colorectal tissues. The protein expression of NAIF1gene has been studied by western blot method in the samples of protein extracted from 29 patients with colorectal cancer. The result of this study showed that the protein expression of NAIF1 was found in both cancerous and non-cancerous colorectal tissues, but it is highly expressed in non-cancerous tissues adjacent to cancerous one. Its expression is higher in non-metastatic cancerous tissues compared with metastatic one. Also this expression is higher in microsatellite instable (MSI) group of cancer compared with microsatellite stable (MSS) group. It can be concluded that NAIF1 protein expression inversely related with more advanced stage or grade of colorectal cancer and it may have a role in inhibition of proliferation, migration and invasion of colorectal cancer by inducing apoptosis. [ABSTRACT FROM AUTHOR]

Background: The prognostic implication of wild‐type APC (APC‐WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Materials and Methods: APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results: In comparison with the APC‐mutant (APC‐MT) population (n = 255), APC‐WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right‐sided (41.7% vs. 27%), BRAFV600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over‐represented in the APC‐WT versus APC‐MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC‐WT patients had a worse overall survival (OS) than APC‐MT patients (22.6 vs. 45.6 months, p <.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC‐WT was predictive of poor survival (APC‐MT vs. APC‐WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86, p =.0037). The prognostic implication of APC‐WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC‐MT vs. APC‐WT, HR, 0.63, 95% CI, 0.49–0.81, p <.0001). Conclusion: APC‐WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC‐MT mCRC tumors, APC‐WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC‐WT patients. Implications for Practice: Patients with microsatellite stable metastatic colorectal cancer with wild‐type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients. Despite advancements in therapy, colorectal cancer is still a leading cause of cancer‐related death in the U.S. This article evaluates the prognostic value of wild‐type APC in patients with microsatellite stable colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs. Materials and Methods: We retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China. Results: Twenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients. Conclusion: No objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration. [ABSTRACT FROM AUTHOR]

Programmed death 1 (PD-1)-targeted therapy has benefited patients with microsatellite instability-high metastatic colorectal cancer (mCRC). However, the efficacy of PD-1-targeted therapy is poor in patients with microsatellite-stable (MSS) mCRC. Therefore, it is imperative to explore additional co-inhibitory molecular signalling pathways to improve the efficacy of immunotherapy in MSS mCRC treatment. In the present study, the association between cyclin-dependent kinase 9 (CDK9) expression and the survival of patients with CRC was analysed using RNA sequencing data from 605 patients, including 121 cases of mortality, from human cancer datasets. Furthermore, 35 clinical MSS stage III–IV CRC specimens were collected to assess CDK9 protein expression by immunohistochemistry, and the frequency of tumor-infiltrating CD8+ T cells was assessed by flow cytometry. The human cancer datasets demonstrated that upregulation CDK9 significantly shortened the survival of patients with stage II–IV colon cancer. Additionally, CDK9 mRNA expression was positively correlated with the expression levels of genes associated with immune evasion in the tumor. Notably, CDK9 was expression was upregulated in stage IV CRC compared with para-cancerous tissues and early-stage tumors. Interestingly, CDK9 expression was negatively associated with the infiltration of CD8+ T cells at the tumor site. In addition, the expression levels of T-cell immunoglobulin mucin family member 3 and CD39, proteins associated with exhaustion, on tumor-infiltrating CD8+ T cells were significantly elevated in patients with abnormal CDK9 expression levels. The present study demonstrated that CDK9 expression was negatively associated with CD8+ T cell infiltration and positively associated with CD8+ T cell exhaustion in MSS mCRC. In conclusion, CDK9 may be utilized to evaluate the prognosis and the immune-type of the tumor microenvironment in patients with MSS mCRC. [ABSTRACT FROM AUTHOR]

A small subset of patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)-colorectal cancer (CRC) benefit from immunotherapy with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade. Therefore, the aim of the current study was to evaluate the immune status of patients with pMMR/microsatellite instability-low (MSI-L)/MSS-CRC and deficient MMR (dMMR)/MSI-high (MSI-H)-CRC in order to identify responders to anti-PD-1/PD-L1 inhibitors. The current study used a dataset downloaded from The Cancer Genome Atlas (TCGA) as well as 219 clinical tissue samples to investigate the infiltrating grade of cluster of differentiation (CD) 4 and CD8 tumor infiltrating lymphocytes (TILs), the expression levels of PD-L1 and PD-L2, the interferon-γ (IFN-γ) and CD8 T effector gene signatures, and the phosphorylated signal transducer and activator of transcription 1 (p-STAT1) status in patients with pMMR/MSI-L/MSS-CRC and dMMR/MSI-H-CRC. Analysis of TCGA dataset revealed that the mRNA expression levels of PD-L1 and PD-L2, the IFN-γ gene signature and the CD8 T effector gene signature were significantly upregulated in MSI-H tumors compared with MSI-L/MSS tumors. Additionally, a subpopulation of patients with upregulation of the IFN-γ and CD8 T effector gene signatures was observed in those with MSI-L/MSS-CRC. Immunohistochemical staining of the clinical samples revealed a subpopulation of patients with pMMR-CRC that were positive for PD-L1 and p-STAT1, and whom had levels of elevated CD8(+) and CD4(+) TILs infiltration similar to those observed in patients with dMMR-CRC. The results obtained in the current study suggested that a subpopulation of patients with MSI-L/MSS-CRC and pMMR-CRC with upregulated IFN-γ and CD8 T effector gene signatures may benefit from immunotherapy with antibodies against PD-1 and PD-L1. [ABSTRACT FROM AUTHOR]

Background: Microsatellite instability (MSI) accounts for 15-20% of colorectal cancer (CRC) and is considered to have favorable stage-adjusted prognosis compared to Microsatellite stable (MSS) CRCs. Determination of MSI in stage II CRC is important for management decisions regarding adjuvant chemotherapy administration. The aim of this study was to determine the prognostic and predictive significance of MSI in stage 2 CRC in the Indian scenario.Materials and Methods: A total of 195 patients who underwent curative surgery for stage II CRC from 2010 to 2017 were included. MSI testing by immunohistochemistry (DNA MisMatch Repair proteins) was performed in all. Various clinicopathological factors and disease-free survival and overall survival were assessed between MSI and MSS groups. The effect of treatment in terms of survival benefits with adjuvant therapy in the MSI group was also assessed.Results: 27.1% of the CRCs' showed MSI. Younger age (<50 years), family history of cancer, synchronous/metachronous malignancies, proximal (right sided) location, poor morphological tumour differentiation, mucin production, and presence of peritumoral (Crohn's-like) lymphocytic response showed statistically significant association with MSI. Majority (56%) of our patients showed combined loss of MLH1 and PMS2. Overall, survival among the MSI patients was significantly higher (76.6 ± 4.149 months) than the MSS patients (65.05 ± 3.555)P= 0.04. MSI patients did not show any differences in survival with or without treatment.Conclusion: This study highlights the distinct clinicopathological features of MSI-related CRC and the relevance of MSI testing of stage II CRC for management decisions and prognostication. [ABSTRACT FROM AUTHOR]

KRAS mutation is a well‐known marker for poor response to targeted treatment and patient prognosis in microsatellite stable (MSS) colorectal cancer (CRC). However, variation in clinical outcomes among patients wild‐type for KRAS underlines that this is not a homogeneous population. Here, we evaluated the prognostic impact of KRAS alternative splicing in relation to mutation status in a single‐hospital series of primary MSS CRCs (N = 258). Using splicing‐sensitive microarrays and RNA sequencing, the relative expression of KRAS‐4A versus KRAS‐4B transcript variants was confirmed to be down‐regulated in CRC compared to normal colonic mucosa (N = 41; p ≤ 0.001). This was independent of mutation status, however, gene set enrichment analysis revealed that the effect of splicing on KRAS signaling was specific to the KRAS wild‐type subgroup, in which low relative KRAS‐4A expression was associated with a higher level of KRAS signaling (p = 0.005). In concordance, the prognostic value of KRAS splicing was also dependent on mutation status, and for patients with Stage I–III KRAS wild‐type MSS CRC, low relative KRAS‐4A expression was associated with inferior overall survival (HR: 2.36, 95% CI: 1.07–5.18, p = 0.033), a result not found in mutant cases (pinteraction = 0.026). The prognostic association in the wild‐type subgroup was independent of clinicopathological factors, including cancer stage in multivariable analysis (HR: 2.68, 95% CI: 1.18–6.09, p = 0.018). This suggests that KRAS has prognostic value beyond mutation status in MSS CRC, and highlights the importance of molecular heterogeneity in the clinically relevant KRAS wild‐type subgroup. What's new? Patients with microsatellite stable (MSS) colorectal cancer (CRC) that lacks KRAS mutation benefit from targeted therapy. Nonetheless, variations in clinical outcome suggest that KRAS wild‐type CRC is a heterogeneous disease. Here, two KRAS transcript variants, KRAS‐4A and KRAS‐4B, generated through alternative splicing, were investigated in relation to KRAS mutation status and MSS CRC prognosis. Aberrant splicing resulting in low expression of the KRAS‐4A transcript variant, relative to the KRAS‐4B transcript, was associated with increased KRAS signaling and poor patient prognosis specifically in KRAS wild‐type MSS CRC. The findings suggest that KRAS splicing is of prognostic relevance in KRAS wild‐type CRC. [ABSTRACT FROM AUTHOR]

Copyright of AL-yarmouk Journall is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

About half of hereditary non-polyposis colorectal cancers (HNPCCs) fulfilling the Amsterdam criteria (AC) do not display evidence of mismatch repair defects, and the difference between microsatellite-stable (MSS) and microsatellite-unstable HNPCC remains poorly understood. The study was to compare overall copy number variation (CNV) and loss of heterozygosity (LOH) of the entire genome in HNPCCs with MSS and microsatellite-instability (MSI) using the Cytoscan HD Array. This was a study carried out in samples from 20 patients with MSS HNPCC and four patients with MSI HNPCC from the Fudan University Shanghai Cancer Center (China). The microsatellite status was examined using a panel of microsatellite markers. MMR expression status was evaluated by immunohistochemistry. Tumor samples were analyzed with the Genome-Wide Human CytoScan HD Array. CNV and LOH were determined. Fourteen specific CNVs (eight gains: 5p13.1, 7p13, 7q22.3, 8q11.21, 8q12.2, 19q13.11, 20q11.21, and 20q11.23; and six losses: 8p22, 8p23.1, 8p23.1, 17p13.1, 17p13.2, and 18q21.3) were associated with MSS HNPCC. Of these 14 CNVs, gain on 8q12.2 and loss on 17p13.1 were novel. The total length of 8q gains and 20q gains were greater in MSS tumors than in MSI ( P < 0.05). The presence of similar levels of copy-neutral-LOH in MSS (31.7%) and MSI (29.7%) HNPCC suggested that unknown DNA repair genes might be involved in the tumorigenesis of MSS HNPCC. MSS HNPCC is a genetically specific population with increased CNV, which are different from MSI HNPCC. The results may help to clarify the genetic basis of MSS HNPCC tumorigenesis. [ABSTRACT FROM AUTHOR]

Copyright of AL-yarmouk Journall is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Differences in the pathogenesis of microsatellite stable (MSS) sporadic colorectal cancers (CRCs) between left-sided CRC (LC) and right-sided CRC (RC) have not been clarified. To identify pathogenesis-related genomic differences between MSS CRCs within the two locations, we performed a comprehensive molecular analysis using crypt isolation with samples from 92 sporadic CRCs. Microsatellite instability (MSI; high and low/negative) and DNA methylation status (low methylation epigenome; intermediate methylation epigenome [IME] or high methylation epigenome [HME]) were determined using polymerase chain reaction (PCR) microsatellite analysis and PCR-bisulfite pyrosequencing, respectively. Additionally, mutations in the TP53, KRAS, BRAF and PIK3CA genes were examined using PCR-bisulfite pyrosequencing (for KRAS and BRAF mutations) or PCR-single conformation polymorphism (for TP53 and PIK3CA mutations), followed by sequencing of aberrant bands. Finally, a genome-wide study using a copy number alteration (CNA)-targeted single nucleotide polymorphism array was performed. Ninety-two CRCs were classified into 71 MSS and 21 MSI phenotypes. We examined 71 CRCs with the MSS phenotype (LC, 56; RC, 15). Mutations in KRAS were associated with RC with the MSS phenotype, whereas mutations in TP53 were more frequently found in LC with the MSS phenotype. There were significant differences in the frequencies of KRAS and TP53 mutations in the IME between LC and RC with the MSS phenotype. Although CNA gains were associated with LC with the MSS phenotype, CNA losses were not major alterations associated with the MSS phenotype. These findings suggested that the molecular pathogenesis of the MSS phenotype in LC was different from that in RC. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) is increasingly being investigated as a tool to detect minimal residual disease in resected, stage I-III colorectal cancer. Recent ctDNA studies have indicated that detection of ctDNA following surgery for resectable colorectal cancer confers a significantly higher risk of recurrence than those with negative ctDNA postoperatively. In those with postoperative ctDNA positivity, clearance of minimal residual disease with adjuvant chemotherapy is a positive prognostic indicator. Lastly, ctDNA has demonstrated superior sensitivity to the conventional blood tumor marker carcinoembryonic antigen (CEA) and can offer median lead times of up to 11 months for radiographic detection of recurrence during the surveillance of resected, stage I-III colorectal cancer. In metastatic colorectal cancer (mCRC), there is growing evidence to suggest that plasma ctDNA can be used to monitor tumor response to conventional chemotherapy as well. The present case series demonstrated that plasma ctDNA is a predictor of tumor response to immunotherapy in patients with mCRC that are microsatellite stable or microsatellite instability high. Plasma ctDNA could serve as a dynamic marker of immunotherapy response even in colorectal tumors that were CEA non-producers. Overall, these findings add to ongoing efforts to establish the role of plasma ctDNA in monitoring response to immunotherapy in CRC. [ABSTRACT FROM AUTHOR]

Chromosomal instability (CIN) and microsatellite instability (MSI) are two major causes of colorectal cancers. Recently, a percentage of colorectal cancers were found to be neither CIN nor MSI. This study was performed to explore whether microsatellite- and chromosomal-stable (MACS) colorectal cancers comprise a substantially distinct subtype. Sixty-nine sporadic colorectal cancers were classified into three subsets according to ploidy and microsatellite instability status: CIN+, MSI+, and MACS. Clinicopathologic, genetic, and epigenetic differences among these three groups were investigated by immunohistochemical analysis of p53, APC, hMLH1, and BAX and methylation study of p14 ARF , hMLH1, p16 INK4a , MGMT, and MINT1 with methylation-specific polymerase chain reaction. The 69 cases included 49 CIN+, 7 MSI+, and 13 MACS. MACS were found to differ from CIN+ and MSI+ in three aspects. The clinicopathologic features of MACS were similar to MSI+ but distinguished from CIN+. Comparatively, MACS preferred proximal location and poor differentiation ( p < 0.05). An immunohistochemical study demonstrated that MACS had a lower rate of loss of hMLH1 or BAX protein than MSI+ and less loss of APC protein than CIN+. In an epigenetic aspect, both MACS and MSI+ had a high rate of CpG island methylator phenotype (46.2 and 42.9%). However, they differed in the presence of hMLH1 methylation (7.7 vs 57.1%, p < 0.05). Otherwise, compared with CIN+, MACS had a more frequent CpG island methylator phenotype and MINT1 methylation ( p < 0.05) and relatively more common p16 INK4a methylation with marginal significance ( p = 0.056). MACS sporadic colorectal cancers may compose a unique phenotype with distinct clinicopathologic and molecular characteristics. [ABSTRACT FROM AUTHOR]

An early step in the carcinogenesis of hereditary non-polyposis colorectal cancer (HNPCC) and some sporadic colorectal cancers (CRCs) is the acquisition of a 'mutator phenotype' resulting from defects in DNA mismatch repair (MMR) genes, which normally maintain genomic stability. This mutator phenotype causes an approximately 100-1000-fold increase in base substitutions and small insertion/deletion mutations thereby driving carcinogenesis. It also causes genome-wide microsatellite instability (MSI) due to the inability to repair mutations within these small, hard to replicate, repetitive DNA elements. In contrast, less is known about the role of mutator phenotypes in microsatellite stable (MSS) CRC. In this report, we have measured the mutation rates in 11 MSS CRC cell lines to obtain an estimate of the prevalence of mutator phenotypes in MSS carcinogenesis. Of the 11 cell lines, three of them (27%) possess spontaneous hypoxanthine phosphoribosyltransferase mutation rates approximately 10-100-fold above background. When challenged with alkylating and oxidising agents, the degree of survival and apoptotic responses are different, indicating that these cell lines may represent more than one mutator phenotype. These data demonstrate that a significant portion of MSS CRC cell lines has increased mutation rates and that this may play a role in MSS CRC carcinogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Given that most patients with MSS mCRC do not respond to immunotherapy agents or do not have durable clinical responses, there is an unmet clinical need to obtain predictors of response to immunotherapy and rational immunotherapy-based combination therapies for this entity. In this review, we present the efforts that have been made to date in the clinical setting to develop immunotherapy-based combinations for MSS mCRC and the rationale that lies behind each strategy. In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC. [ABSTRACT FROM AUTHOR]

Simple Summary: More emerging studies are exploring immunotherapy for solid cancers, including colorectal cancer. Besides, checkpoint blockade immunotherapy and chimeric antigen receptor (CAR) -based immune cell therapy have being examined in clinical trials for colorectal cancer patients. However, immunosuppression that leads to the blockage of normal immunosurveillance often leads to cancer development and relapse. In this study, we systematically reviewed the mechanism of immunosuppression, specifically in colorectal cancer, from different perspectives, including the natural or induced immunosuppressive cells, cell surface protein, cytokines/chemokines, transcriptional factors, metabolic alteration, phosphatase, and tissue hypoxia in the tumor microenvironment. We also discussed the progress of immunotherapies in clinical trials/studies for colorectal cancer and highlighted how different strategies for cancer therapy targeted the immunosuppression reviewed above. Our review provides some timely implications for restoring immunosurveillance to improve treatment efficacy in colorectal cancer (CRC). CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC. [ABSTRACT FROM AUTHOR]

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of "immune-competent" TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer. [ABSTRACT FROM AUTHOR]