High-frequency Microsatellite Instability Research Articles

Microsatellite instability: A 2024 update.

Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China

BackgroundPembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H.MethodsThis retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS).ResultsThe top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6–21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9–7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events.ConclusionOur study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Efficiency of CT radiomics model in assessing the microsatellite instability of colorectal cancer liver metastasis.

This study aims to investigate the efficiency of a radiomics model in identifying high-frequency microsatellite instability (MSI-H) and microsatellite stability (MSS) of colorectal liver metastasis (CRLM) according to machine learning radiomics features of enhanced CT liver images. A total of 12 patients with MSI-H CRLM and 96 patients with MSS CRLM were randomly divided into the training group and internal validation group according to the ratio of 7: 3 (training: 75 cases, validation: 33 cases). From the enhanced CT (portal phase) image data of patients, 788 radiomics features were extracted, and a random forest model was established with the optimal features selected. The receiver operating characteristics (ROC) curve analysis was performed to assess the model's diagnostic efficacy. The training group comprised 8 patients with MSI-H CRLM and 67 patients with MSS CRLM, and the internal validation group included 4 patients with MSI-H CRLM and 29 patients with MSS CRLM. After feature selection, 7 radiomics features good for distinguishing MSI-H CRLM and MSS CRLM were screened out. The ROC curve analysis demonstrated that the random forest model had the AUC (area under the ROC curve) value 0.88, accuracy 0.85, sensitivity 0.85, specificity 0.92, and F1 score 0.88 in the training group. The model had an AUC value of 0.75, accuracy of 0.74, sensitivity of 0.81, specificity of 0.85, and F1_score of 0.78 in the internal validation group in identifying the MSI-H from the MSS CRLM. In order to evaluate the robustness of the overall model, the 788 features obtained were all applied to the 5-fold cross-validation, with the model being built on the random forest and analyzed with the ROC curve analysis. The AUC value of the model was 0.86 (P＜0.05), accuracy value 0.91, sensitivity 0.60, and specificity 0.95. The random forest prediction model built on the radiometric features extracted from enhanced CT images can be used to identify the MSI-H from the MSS CRLM and may provide effective guidance for clinical immunotherapy of CRLM patients with unknown MSI status.

Discordant microsatellite instability findings in two samples from a patient with biliary cancer that responded to pembrolizumab.

Microsatellite instability (MSI) is a key marker to predict response to immune checkpoint inhibitors; however, only 1-2% of biliary cancers have this genomic feature. In a patient with hilar biliary cancer, MSI was examined in two cancer specimens (forceps biopsy from the biliary stricture and endoscopic ultrasound-guided fine-needle aspiration biopsy [EUS-FNAB] from the adjacent lymph node). We observed discordant results, as high frequency of MSI was found only in the forceps biopsy. Although the FNAB sample was 10 times larger than that of the forceps biopsy, the tumor concentration was much lower, which is a possible reason for the discordance. Besides, immunohistochemistry of four mismatch-repair (MMR) proteins showed proficient MMR expressions. The tumor became refractory to gemcitabine, cisplatin, and S-1 but responded well to pembrolizumab. Caution is needed for sample selection and for interpretation of the test's results, to avoid missing rare chance for effective molecular target agents.

Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens

BackgroundIdentifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME).MethodsWe evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets.ResultsWe identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types.ConclusionsWe propose a novel concept of “paradoxical neoantigenic mutations” that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations.

High Frequency of Microsatellite Instability among Non-Metastatic Gastric Cancer.

Background: Microsatellite instability (MSI) is considered a key factor in carcinogenesis and a genetic alteration pattern in many types of cancers such as gastric cancer (GC). Although the role of MSI in colorectal cancer (CRC) is well known, its prognostic impact on GC has not been clearly defined. The assessment of MSI in GC has notbeen documented in the Iranian population yet. Therefore, this study analyzed the association of MSI status with GC in Iranian patients. Materials and Methods: We compared the frequency of MSI at 5 loci from formalin-fixed paraffin-embedded (FFPE) gastrectomy specimens, between metastatic and non-metastatic cases of GC (N = 60). A panel of five quasi-monomorphic markers and a single dinucleotide marker with linker-based fluorescent primers was used. Results: MSI was observed in 46.6% of cases, including MSI-high (H) (33.3%) and MSI-Low (L) (13.3%). Moreover, the most unstable and stable markers in our study were NR-21 and BAT-26 accordingly. MSI-H and MSI were seen more frequently in non-metastatic tumors (p= 0.028 and p= 0.019, respectively). Conclusion: The current study showed MSI status more frequently in non-metastatic GC which may reflect a good prognostic factor in GC like CRC. Although, larger and more comprehensive studies are needed to confirm this statement. A panel consisting of NR-21, BAT-25, and NR-27 mononucleotide markers appears to be reliable and useful markers for detecting MSI in GC in Iranian patients.

Emerging Immune-Monitoring System for Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have a major impact on cancer treatment. However, the therapeutic efficacy of ICIs is only effective in some patients. Programmed death ligand 1 (PD-L1), tumor mutation burden (TMB), and high-frequency microsatellite instability (MSI-high) are markers that predict the efficacy of ICIs but are not universally used in many carcinomas. The gut microbiota has received much attention recently because of its potential to have a significant impact on immune cells in the cancer microenvironment. Metabolites of the gut microbiota modulate immunity and have a strong influence on the therapeutic efficacy of ICI. It has been suggested that the gut microbiota may serve as a novel marker to predict the therapeutic efficacy of ICI. Therefore, there is an urgent need to develop biomarkers that can predict anti-tumor effects and adverse events, and the study of the gut microbiota is essential in this regard.

Clinical Investigation of Immune Checkpoint Inhibitor-Associated Kidney Injury in Patients with Urologic Cancers

We investigated the clinical characteristics of patients who developed kidney injury after starting treatment with immune checkpoint inhibitors (ICI) for urologic malignancies. The study included 118 patients who were treated with ICI at our hospital. They consisted of 65 with renal cell carcinoma, 52 with urothelial carcinomas and 1 with adrenocortical carcinoma with high-frequency microsatellite instability. Immune-related kidney injury was observed in 13 patients (11.0%), including stage 1, 2 and 3 kidney injuries in 9, 0 and 4 patients, respectively. In univariate analyses, ≥stage 4 chronic kidney disease (CKD) before ICI treatment and proton pump inhibitor use were significantly associated with all stages of kidney injury, whereas ≥stage 4 CKD and ICI combination therapy were significantly associated with kidney injury at ≥ stage 2. Of the 4 patients who developed ≥stage 2 kidney injury, histological examination was done only for 2 because renal biopsy was contraindicated in the other 2 due to prior nephrectomy. Steroid pulse therapy was performed for 3 patients but provided complete recovery only in 1. We should be aware of the risk for immune-related kidney injury in patients with baseline CKD (≥stage 4) and receiving ICI combination therapy. Precise diagnosis by histological examination can often be challenging due to a history of nephrectomy.

N6-Methyladenosine Modification Patterns and Tumor Microenvironment Immune Characteristics Associated With Clinical Prognosis Analysis in Stomach Adenocarcinoma.

Background: N6-methyladenosine (m6A) modification is a part of epigenetic research that has gained increasing attention in recent years. m6A modification is widely involved in many biological behaviors of intracellular RNA by regulating mRNA, thus affecting disease progression and tumor occurrence. However, the effects of m6A modification on immune cell infiltration of the tumor microenvironment (TME) are uncertain in stomach adenocarcinoma (STAD). Methods: The Cancer Genome Map (TCGA) database was used to download transcriptome data, clinicopathological data, and survival data for m6A-regulated genes in 433 STAD tissues that meet the requirements of this study. GSE84437 data were obtained from the Gene Expression Omnibus (GEO) database. The correlation between 23 m6A regulated genes was analyzed using R software. Sample clustering analysis was carried out on the genes of the m6A regulatory factor, and survival analysis and differentiation comparison were made for patients in clustering grouping. Then, the Gene Set Enrichment Analysis (GSEA), the single-sample GSEA (ssGSEA), and other methods were conducted to assess the correlation among m6A modification patterns, TME cell infiltration characteristics, and immune infiltration markers. The m6A modification pattern of individual tumors was quantitatively evaluated using the m6A score scheme of the principal component analysis (PCA). Results: From the TCGA database, 94/433 (21.71%) samples were somatic cell mutations, and ZC3H13 mutations are the most common. Based on the consensus, matrix k-3 is an optimal clustering stability value to identify three different clusters. Three types of m6A methylation modification patterns were significantly different in immune infiltration. Thus, 1028 differentially expressed genes (DEGs) were identified. The survival analysis of the m6A score found that patients in the high m6A score group had a better prognosis than those in the low m6A score group. Further analysis of the survival curve combining tumor mutation burden (TMB) and m6A scores revealed that patients had a significantly lower prognosis in the low tumor mutant group and the low m6A score group (p = 0.003). The results showed that PD-L1 was significantly higher in the high m6A score group than in the low score group (p < 2.22e-16). The high-frequency microsatellite instability (MSI-H) subtype score was significantly different from the other two groups. Conclusions: This study systematically evaluated the modification patterns of 23 m6A regulatory factors in STAD. The m6A modification pattern may be a critical factor leading to inhibitory changes and heterogeneity in TME. This elucidated the TME infiltration characteristics in patients with STAD through the evaluation of the m6A modification pattern.

MMR profile and microsatellite instability status in colorectal mucinous adenocarcinoma with synchronous metastasis: a new clue for the clinical practice

AimsMucinous adenocarcinoma (MA) is associated with a high frequency of microsatellite instability (MSI). In the metastatic setting, it is crucial to establish mismatch repair (MMR) and/or MSI status. However, genetic...

Treatment patterns and outcomes of patients with metastatic colorectal cancer in third-line and beyond systemic therapy: Real-world data from a setting with limited resources.

58 Background: Regorafenib and trifluridine/tipiracil (TAS-102) are the only therapeutic options for patients with chemorefractory metastatic colorectal cancer (mCRC) with demonstrated benefit in overall survival (OS). However, they are not accessible worldwide. In Brazil, they have been recently approved, but they have not yet been provided by public health system or private health insurances. We aimed to describe the treatment patterns and clinical outcomes of that population in a setting with limited access to those drugs. Methods: Retrospective study evaluating 510 patients with mCRC who were treated at five Oncoclinicas centers in Brazil from January 2011 to December 2019. Demographic and clinical data were retrieved from electronic medical records. The median OS was calculated by Kaplan-Meier method and prognostic factors were evaluated via multivariable Cox Regression, calculating the Hazard Ratio (HR) and the confidence interval (CI95%). Results: A total of 163 patients (33% of the overall population) received third-line and 73 (15%) fourth-line systemic therapy. Median age was 62 years, 59% were male. Tumors were right-sided in 19%, RAS mutated 44%, BRAF mutated 3%, and high-frequency microsatellite instability 3%. Metastasectomy prior to third-line was performed in 62% of the patients. From the start of third-line therapy, median follow-up was 9.0 months, with 67% of deaths, and median OS was 13.7 months (CI95% 11.8m–20.0m). Most adopted regimens in third-and fourth-line were (1) rechallenge with oxaliplatin-based therapy (39% and 26%, respectively); (2) rechallenge with irinotecan-based therapy (32% and 34%); (3) rechallenge with anti-EGFR monoclonal antibodies (20% and 29%); (4) regorafenib (13% and 25%); and (5) TAS-102 (2% and 4%). In multivariable model including clinical and molecular variables, prior metastasectomy was the only significant prognostic factor for OS (HR 0.51, CI95% 0.31–0.83, p=0.007). Conclusions: In real-world, a meaningful proportion of patients with mCRC are eligible for third and later lines of therapy. Rechallenge with chemotherapy and anti-EGFR agents is overused in a setting of limited access to therapies with demonstrated OS benefit, such as regorafenib and TAS-102. Barriers to drug access impair the adoption of the best evidence-based continuum of care and strategies to overcome them are urgently needed. Refractory patients in later lines of therapy derive survival benefit from prior metastasectomy.

Myxofibrosarcoma harboring an MLH1 pathogenic germline variant associated with Muir-Torre syndrome: a case report

BackgroundMuir–Torre syndrome (MTS), which accounts for a small subset (1–3 %) of Lynch syndrome (LS), is an autosomal dominant genetic disorder characterized by sebaceous gland or keratoacanthoma associated with visceral malignancies. Most families with MTS have pathogenic germline variants (PGV) in MSH2. Sarcomas are not common on the LS tumor spectrum, and sarcomas associated with MTS are extremely rare.Case presentationHere we report a myxofibrosarcoma of the abdominal wall in a 73-year-old man with a sebaceoma that occurred synchronically, leading to a diagnosis of MTS. The loss of MLH1 and PMS2 protein expression was detected in immunohistochemistry, and high-frequency microsatellite instability (MSI-H) was also confirmed. A germline genetic analysis revealed that he harbored the MLH1 PGV.ConclusionsThis is the first case of MSI-H myxofibrosarcoma with MTS in an MLH1 PGV carrier. Although rare, we should recognize that sarcomas can be part of the spectrum of LS and MTS.

Cutaneous metastasis of cecum cancer with MSI-high and BRAFV600E mutation: a case report

BackgroundCutaneous metastases of colorectal cancer (CRC) are rare, occurring in 0.7% to 5% of cancer patients. Furthermore, the molecular subtypes of cutaneous metastasis of CRC are unclear. Here, we present a rare case of cutaneous metastasis of high-frequency microsatellite instability (MSI-high)/BRAFV600E-mutant cecum cancer.Case presentationA 77-year-old woman presented at the outpatient clinic with a subcutaneous mass on her left back. An excisional biopsy was performed and metastatic cutaneous adenocarcinoma was diagnosed. A computed tomography scan of the thorax and abdomen showed thickening of the cecum wall, the presence of pericolic lymph nodes, multiple masses in the liver, and a single nodule in the right lung. Right colectomy with D2 lymphadenectomy and functional end-to-end anastomosis was performed because of the almost-complete intestinal obstruction. The expression of KRAS wild type, BRAFV600E mutation, and MSI-high was detected in the cecum cancer using molecular pathological examination. She received chemotherapy with XELOX + BEV regimen (capecitabine + oxaliplatin + bevacizumab). After four administrations, a computed tomography scan showed reduction of distant metastases, which suggested partial response.ConclusionsWe encountered a rare case of cutaneous metastasis of MSI-high and BRAFV600E-mutant cecum cancer. In the future, it will be necessary to accumulate more cases to identify clinical features and more effective treatments for CRCs with cutaneous metastasis.

Determination of therapeutic agents efficiencies of microsatellite instability high colon cancer cells in post‐metastatic liver biochip modeling

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.

Can hypoxia-inducible factor-1α overexpression discriminate human colorectal cancers with different microsatellite instability?

Clinicopathological features of high-frequency microsatellite instability (MSI-H) colorectal cancers (CRCs) are different from low-frequency MSI (MSI-L) and microsatellite stable (MSS) CRCs. The clinical features of MSI-L cases are unknown, and although the tumors usually show instability for dinucleotide markers, evaluation based on dinucleotides alone could lead to the misclassification of MSI-L or MSS as MSI-H. In this research, we investigated the usefulness of hypoxia-inducible factor-1α (HIF-1α) expression to discriminate MSI-L from MSS and MSI-H in human CRC. Tumor tissue from 94 CRC patients was used to determine the expression level of HIF-1α mRNA and HIF-1α protein using quantitative real-time PCR and immunohistochemistry analyses, respectively. The results indicated that HIF-1α mRNA and HIF-1α protein levels were upregulated in CRC patients compared with controls (P < 0.0001). Average HIF-1α expression in tissues with advanced stages and grades was also higher than that in earlier stages and grades. Expression of HIF-1α mRNA varied between CRC patients with different types of microsatellite instability (MSS, MSI-L and MSI-H). Taken together, our findings provide preliminary evidence that HIF-1α expression level in CRC tumors correlates with different MSI categories. HIF-1α expression may therefore represent a novel marker to separate the MSI-L group from the MSS and MSI-H groups.

MO10-4 The efficacy of pembrolizumab in patients with high-frequency microsatellite instability (MSI-H) solid tumors

MO10-4 The efficacy of pembrolizumab in patients with high-frequency microsatellite instability (MSI-H) solid tumors

NTRK fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.

3544 Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( &lt; 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.

Emerging and Experimental Agents for Anal Cancer: What is New?

Squamous cell carcinoma of the anal canal (SCCA) is an HPV-related malignancy with rising incidence in the past few decades in the US, characterized by high rates of complete response to chemoradiotherapy with curative intent. However, in a long-term follow-up, a meaningful subgroup of patients with locally advanced disease presents disease recurrence, which demands treatments with high morbidity and important impact in the quality of life. In metastatic or unresectable disease, palliative chemotherapy is the standard of care, but it is still associated with a dismal prognosis. Novel agents are urgently needed in the systemic therapy of SCCA. From a translational standpoint, there are many hurdles to overcome, since PI3KCA mutation is the most frequent genetic abnormality and actionable mutations are rarely found in SCCA, as well as it is characterized by low tumor mutational burden and low rates of high-frequency microsatellite instability. But the latest studies of immunotherapeutic approaches have produced promising findings and this therapeutic strategy is the major path being followed in the ongoing clinical trials. The latest advances in the systemic therapy of SCCA have provided the framework for the conception of new clinical trials. Therefore, carboplatin plus paclitaxel have become the backbone for novel agents. Immune checkpoint inhibitors (ICIs), mainly anti-PD-1 monoclonal antibodies, such as retifanlimab, nivolumab, and atezolizumab have been studied in Phase III trials with chemotherapy in first-line therapy. Likewise, ICIs have been evaluated in locally advanced and refractory disease. Novel technologies, such as bispecific antibodies, and immunotherapeutic approaches, such as vaccines and adoptive T-cell therapies, have also been tested in ongoing clinical trials. Immunotherapy may bring practice-changing advances in the systemic therapy of SCCA in the next few years and it might play a larger role in the therapeutic management of this challenging disease.

Microsatellite instability in colorectal cancer: An analysis of the National Cancer Database.

134 Background: High-frequency microsatellite instability (MSI-H) accounts for roughly 15% of all cases of colorectal cancer (CRC). Studies suggest a significant non-adherence to routine MSI testing in patients diagnosed with CRC despite universal guidelines. Methods: We used the NCDB to identify adults with MSI-H status CRC from 2010-2015 with the following histologic subtypes: mucinous and not otherwise specified adenocarcinoma, and medullary carcinoma. The primary site was localized to the right colon, left colon, and rectum; demographic factors, clinicopathologic features, and treatments were identified. Patients were stratified by site and discrete and continuous variable comparisons were made using the chi-square and Mann-Whitney test, respectively. Survival was examined with the Kaplan-Meier method and a Cox proportional hazards regression model. A logistic regression model was used to examine MSI status. All analyses were conducted with SAS version 9.4. Results: A total of 5364 patients were identified and stratified by site into 3 groups: right colon (n = 4004, 74.6%), left colon (n = 890, 16.59%) and rectum (n = 470, 8.76%). Compared to the left colon and rectum, right colon patients were more likely to be older females with larger tumors and less likely to receive chemoradiation. After adjusting for all else, we found statistical evidence that female vs. male gender (OR = 1.47; 95% CI: 1.24 to 1.73), Black vs. White race (OR = 0.61; 0.45 to 0.83), left vs. right colon (OR = 0.33, 0.27 to 0.41), rectum vs. right colon (OR = 0.08, 0.05 to 0.13), mucinous adenocarcinoma vs. adenocarcinoma (OR = 2.37, 1.92 to 2.93), medullary carcinoma vs. adenocarcinoma (OR = 8.86, 4.56 to 17.22), positive vs. negative k-RAS mutation (OR = 0.49, 0.41 to 0.59), and positive vs. negative CEA status (OR = 0.79, 0.66 to 0.94) were factors associated with MSI-H status. Improved survival was associated were Hispanic white race, stage 1, and free surgical margins within a multivariable context. Factors associated with poor survival: increased Charlson/Deyo score, advanced stage, lymphovascular invasion, and positive CEA status. Conclusions: In settings where resources are scarce and universal testing is not possible, there is a benefit from MSI testing in female patients, those with right-sided colon cancer, mucinous adenocarcinoma, and medullary carcinoma.

A case of pembrolizumab responding to recurrent small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome

An advanced small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome was resected, and we started capecitabine plus oxaliplatin (CapeOX) as adjuvant therapy. However, local recurrence was noted, and the tumor increased even after CapeOX plus bevacizumab and fluorouracil plus leucovorin plus irinotecan plus panitumumab (FOLFIRI plus panitumumab). Pembrolizumab was administered after confirming high-frequency microsatellite instability, and the tumor shrank markedly and remained shrunk for 20 months.