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• The molecular landscape of prostate carcinoma is extremely complex, comprising of genetic and epigenetic alterations. • Interrogating the molecular underpinnings of these tumors can help delineate risk profiles and tailor therapeutic options. • Current clinical guidelines optimize the utilization of the available genetic tests in the management of prostate cancer in both treatment personalization and familial risk assessment. Prostate cancer is heterogeneous with varied pathologic features and presents with a wide spectrum of clinical manifestations from indolent to advanced cancer. Interrogation of the molecular landscape of prostate cancer has unveiled the complex genomic alterations in these tumors, which significantly impacts tumor biology. The documented array of chromosomal alterations, gene fusions, and epigenetic changes not only play a crucial role in oncogenesis and disease progression, but also impacts response and resistance to various therapeutic modalities. Various gene expression assays have been developed and are currently recommended in aiding clinical decision making in these clinically and molecularly heterogeneous cancer. In this review, we provide an overview of the molecular underpinnings of prostate cancer, and briefly review the current status of molecular testing and therapeutic options in the management of these tumors. [ABSTRACT FROM AUTHOR]

Mucinous adenocarcinoma of jejunum is a rare tumor of the gastrointestinal tract. Patients usually present after fifth decade of their life with non-specific symptoms. Delayed diagnosis is commonplace and often the reason for advanced disease and poor prognosis. These tumors may masquerade as other common malignancies, with a conclusive diagnosis only after the final histopathological examination. We present a case of jejunal mucinous adenocarcinoma, disguised as cecal malignancy, in an old female patient, managed with radical resection and adjuvant chemotherapy. The report reiterates that the mucinous variant of jejunal adenocarcinoma is a rare pathology with an unusual advanced presentation. [ABSTRACT FROM AUTHOR]

Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HR C2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10–3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HR C2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers. • ChallengES tumor mutation burden (TMB) and MSIsensor for predicting response to immunotherapy in MSI mCRC. • Demonstration that MSI misdiagnoses lead to a false ability of TMB and MSIsensor to predict ICI resistance in MSI mCRC. • Identification and validation of DNA and RNA signatures predictive of response to ICI in these patients with mCRC MSI. • Evidence for a fibrosis signature associated with functional ICI resistance in MSI mCRC. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) is a negative predictive factor for neoadjuvant chemotherapy in resectable oesogastric adenocarcinoma and a crucial determinant for immunotherapy. We aimed to evaluate reliability of dMMR/MSI status screening performed on preoperative endoscopic biopsies. Paired pathological samples from biopsies and surgical specimen of oesogastric adenocarcinoma were retrospectively collected between 2009 and 2019. We compared dMMR status obtained by immunohistochemistry (IHC) and MSI status by PCR. dMMR/MSI status on surgical specimen was considered as reference. PCR and IHC were conclusive on biopsies respectively for 53 (96.4%) and 47 (85.5%) of the 55 patients enrolled. IHC was not contributive for 1 surgical specimen. A third reading of IHC was carried out for 3 biopsies. MSI status was observed in 7 (12.5%) surgical specimens. When analyses were contributive, sensitivity and specificity of biopsies for dMMR/MSI were respectively 85% and 98% for PCR vs. 86% and 98% for IHC. Concordance rate between biopsies and surgical specimen was 96.2% for PCR and 97.8% for IHC. Endoscopic biopsies are a suitable source of tissue for dMMR/MSI status determination in oesogastric adenocarcinoma which should be routinely performed at diagnosis to better adapt neoadjuvant treatment. By comparison of dMMR phenotype obtained by immunohistochemistry and MSI status by PCR between match-paired samples of oesogastric cancer's endoscopic biopsies and surgical specimen, we observed that biopsies are a suitable source of tissue for dMMR/MSI status determination. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes. We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen. We included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8–251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio [aHR] = 4.26, 95% confidence interval [CI]:1.85–9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76–14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949). Patients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination. [Display omitted] • The TMB stratifies the outcomes of dMMR/MSI-H mCRC receiving ICIs. • Patients with a low TMB has poor outcomes regardless of the ICI type. • Patients with the highest TMB have greater benefit from anti-CTLA-4 combos. • TMB could be used to drive future research projects and trials' design. [ABSTRACT FROM AUTHOR]

Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented. Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%–46.0%) in cohort A and 34.9% (95% CI, 23.3%–48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1–8.1) in cohort A and 4.1 months (95% CI, 2.1–18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4–58.0) in cohort A and 47.0 months (95% CI, 19.2–NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response. Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC. ClinicalTrials.gov, NCT02460198 • KEYNOTE-164 evaluated pembro in MSI-H/dMMR unresectable/metastatic colorectal cancer (85/85). • Additional responses were observed, and median DOR was still NR (64/85). • Second-course pembro showed some benefit in patients with progressive disease after initial response (78/85). • OS was lengthy for a population with previously treated CRC (73/85). • Pembro continued to be well tolerated, and no new safety signals were observed (78/85). [ABSTRACT FROM AUTHOR]

Immunotherapy with immune checkpoint inhibitors has significantly improved the survival of patients with MSI/dMMR mCRC. These tumors are associated with a specific metastatic spread, i.e. frequent peritoneal carcinomatosis (PC) that may be treated surgically when there is no other metastatic location. We aimed at evaluating the prognosis of patients treated with immune checkpoint inhibitors for MSI/dMMR mCRC with isolated PC. All consecutive patients with isolated PC from MSI/dMMR mCRC, initially considered as unresectable by multidisciplinary team meeting, treated with immune checkpoint inhibitors were included in this French multicenter cohort study. Among 45 patients included, we observed 11 complete responses and 10 partial responses for an overall response rate iRECIST of 46%. After a median follow-up of 24.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. Seven of the eight patients who underwent cytoreductive surgery after treatment with anti-PD1 ± anti-CTLA-4 were in complete pathologic response. These results demonstrate long-term benefit of immune checkpoint inhibitors for patients with isolated PC from MSI/dMMR mCRC. Such treatment appears as the best therapeutic option for patients with isolated PC from MSI/dMMR mCRC. With a majority of pathological complete responses for patients who underwent surgery for residual lesions, the value of such therapeutic strategy remains unknown. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) due to mismatch repair (MMR) defects accounts for 15–20% of colon cancers (CC). MSI testing is currently standard of care in CC with immunohistochemistry of the four MMR proteins representing the gold standard. Instead, label-free quantum cascade laser (QCL) based infrared (IR) imaging combined with artificial intelligence (AI) may classify MSI/microsatellite stability (MSS) in unstained tissue sections user-independently and tissue preserving. Paraffin-embedded unstained tissue sections of early CC from patients participating in the multicentre AIO ColoPredict Plus (CPP) 2.0 registry were analysed after dividing into three groups (training, test, and validation). IR images of tissue sections using QCL-IR microscopes were classified by AI (convolutional neural networks [CNN]) using a two-step approach. The first CNN (modified U-Net) detected areas of cancer while the second CNN (VGG-Net) classified MSI/MSS. End-points were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). The cancer detection in the first step was based on 629 patients (train n = 273, test n = 138, and validation n = 218). Resulting classification AUROC was 1.0 for the validation dataset. The second step classifying MSI/MSS was performed on 547 patients (train n = 331, test n = 69, and validation n = 147) reaching AUROC and AUPRC of 0.9 and 0.74, respectively, for the validation cohort. Our novel label-free digital pathology approach accurately and rapidly classifies MSI vs. MSS. The tissue sections analysed were not processed leaving the sample unmodified for subsequent analyses. Our approach demonstrates an AI-based decision support tool potentially driving improved patient stratification and precision oncology in the future. [Display omitted] • Testing of microsatellite instability has become standard of care in colon cancer. • Immunohistochemistry may render false negative results in 10% of cases. • An infrared absorption spectrum summarises the biochemistry in the analysed tissue. • Artificial intelligence can use infrared imaging to challenge immunohistochemistry. • Infrared imaging works label-free preserving tissue for further analyses. [ABSTRACT FROM AUTHOR]

Background: Microsatellite instability (MSI) is recognized as a favorable outcome predictor in colorectal cancer. However, its impact on overall survival (OS) of appendiceal carcinoma has not been thoroughly studied. This study aimed to assess the impact of MSI on OS of patients with appendiceal adenocarcinoma, stratified by disease stage, tumor histology, and patients' demographics. Methods: This was a retrospective cohort analysis of the colon cancer National Cancer Database (NCDB) between 2005 and 2019. Patients with appendiceal adenocarcinoma with known MSI status were included and subdivided according to MSI status into positive and negative. Primary outcome was OS stratified by MSI status. Results: The study included 1681 (50.1% male) patients with a mean age of 58.9 ± 14.2 years; 211 (12.5%) had MSI-positive tumors (69 MSI low, 53 MSI high, and 89 not specified). Mean 5-year OS of patients with MSI-positive and MSI-negative carcinomas was similar (81.9 versus 78.6 months, p = 0.747). Patients with stage IV MSI-positive carcinomas had significantly longer OS than patients with MSI-negative carcinomas of the same stage (41.3 vs 26.5 months, p = 0.02). Differences in OS for patients with stages I–III were not statistically significant. Compared to MSI-negative/low carcinomas, MSI-high tumors had more advanced pathologic TNM stage (stage III: 23.9% vs 17.8%—stage IV: 41.3% vs 35.4%, p = 0.003), received more chemotherapy (56% vs 41%, p = 0.04), yet had similar OS (81.9 vs 78.9 months, p = 0.357). Conclusions: MSI status of appendiceal adenocarcinomas did not significantly impact survival, except for stage IV disease in which a survival benefit of MSI was noted. [ABSTRACT FROM AUTHOR]

The use of neoadjuvant chemotherapy (NAC) in patients with mismatch repair (MMR) deficient (dMMR) localized gastric and oeso-gastric junction (OGJ) adenocarcinoma is subject of debate. Histological response assessment might help to better evaluate the impact of dMMR on response to NAC. Patients with localized gastric/OGJ adenocarcinoma resected after NAC were retrospectively identified. MMR protein expression status was assessed by immunohistochemistry. The primary objective was the frequency of histological responders to NAC defined by tumour regression grade (TRG) using Mandard's (TRG1-2) and Becker's (TRG1) classifications, according to the MMR status. In total, 247 patients with 43 dMMR and 204 pMMR gastric/OGJ adenocarcinoma were identified. Among dMMR tumours, 18 (42%) arose from the OGJ. Histological response (Becker TRG1-2) was observed for 28% and 35% of dMMR and pMMR tumours, respectively (p = 0.35). Similar results were observed with Mandard classification. With a median follow-up of 37.5 months, median disease-free and overall survival were not reached for the dMMR group. Histological response after NAC in patients with localized dMMR gastric/OGJ adenocarcinoma is not statistically different to those with pMMR tumours. This study provides additional data for the discussion about avoiding NAC in patients with dMMR gastric/OGJ adenocarcinomas. [ABSTRACT FROM AUTHOR]

Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy. [ABSTRACT FROM AUTHOR]

Neoadjuvant treatment with either chemotherapy or immunotherapy is gaining momentum in colon cancers (CC). To reduce over-treatment, increasing staging accuracy using computed tomography (CT) is of high importance. To assess and compare CT imaging features of CC between mismatch repair-proficient (pMMR) and MMR-deficient (dMMR) tumours and identify CT features that can distinguish high-risk (pT3-4, N+) CC according to MMR status. Primary staging CTs of 266 patients who underwent primary surgical resection of a colon tumour were retrospectively and independently evaluated by two radiologists. Logistic regression analysis was performed to identify significant associations between imaging features and positive lymph node status. Receiver operating characteristic (ROC) curves of significantly associated features were assessed and validated in an external cohort of 104 patients. Among pT3 tumours only, dMMR CC were significantly larger than pMMR CC in both length and thickness (length 59.39 ± 26.28 mm versus 48.70 ± 23.72, respectively, p = 0.031; thickness 20.54 mm ± 11.17 versus 16.34 ± 8.73, respectively, p = 0.027). For pMMR tumours, nodal internal heterogeneity on CT was significantly associated with a positive lymph node status (odds ratio (OR) = 2.66, p = 0.027), while for dMMR tumours, the largest short diameter of the nodes was associated with lymph node status (OR = 2.01, p = 0.049). The best cut-off value of the largest short diameter of involved nodes was 10.4 mm for dMMR and 7.95 mm for pMMR. In the external validation cohort, AUCs for predicting involved nodes based on the largest short diameter was 0.764 for dMMR tumours using 10 mm size cut-off and 0.624 for pMMR tumours using 7 mm cut-off. These data show that CT imaging features of primary CC differ between dMMR and pMMR tumours, suggesting that the assessment of CT-based CC staging should take MMR status into consideration, especially for lymph node status, and thus may help in selecting patients for neoadjuvant treatment. • Radiologic assessment of colon cancer stage differs between dMMR and pMMR tumours. • pMMR tumours: nodal internal heterogeneity is associated with positive lymph nodes. • dMMR tumours: diameter of lymph nodes is associated with positive lymph nodes. [ABSTRACT FROM AUTHOR]

DNA mismatch repair (MMR) deficiency and the associated microsatellite instability (MSI) phenotype has become a subject of enormous interest in recent years due to the demonstrated efficacy of immune checkpoint inhibitors (ICI) in advanced tumours. Assessing MSI in patients with gastrointestinal tract (GI) cancers is useful to exclude Lynch syndrome, but also to predict benefit for ICI. Following review of the relevant literature, this review article aims to outline the clinicopathologic spectrum of MSI and mismatch repair deficiency (dMMR) in the GI tract, hepatobiliary system and pancreas and discuss the therapeutic consideration in this disease. • Defects in DNA mismatch repair can be seen in several GI tumours. • Tissue based immunohistochemistry and next generation sequencing are used to detect microsatellite instability. • Evidence to support the use of immune checkpoint inhibitors in GI cancers including in both early and late stage disease is evolving. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors yielded unprecedented outcomes in patients with mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), but clinical decision-making in this rapidly evolving treatment landscape is challenging. Since performance status (PS) represents a well-established prognostic factor in clinical practice, we investigated whether worse PS, overall or related to either patients' frailty or high tumour burden, could affect the outcomes in this whole patients' population and according to immune checkpoint inhibitor treatment type. We conducted a global study at Tertiary Cancer Centres and collected data of patients with dMMR/MSI-H mCRC treated with anti- programmed-death (ligand)-1 (PD(L)-1) monotherapy or anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination. The cohort included 502 patients. At a median follow-up of 31.2 months, worse PFS and OS were reported in patients with patient-related PS ≥ 1 (adjusted-HRs: 1.73, 95%CI: 1.06–2.83, p = 0.004 and 2.06, 95%CI: 1.13–3.74, p = 0.001, respectively) and cancer-related PS ≥ 1 (adjusted-HRs: 1.61, 95%CI: 1.19–2.17, p = 0.004 and 1.87, 95%CI: 1.32–2.66, p = 0.001, respectively). Anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination did not provide significantly better survival compared to anti-PD(L)-1 monotherapy in PS 0 subgroup (PFS HR = 0.62, 95%CI: 0.37–1.02, p = 0.059; OS HR = 0.59, 95%CI: 0.32–1.11, p = 0.100) and in patient-related PS ≥ 1 (PFS HR 0.93, 95%CI: 0.31–2.83, p = 0.899; OS HR 1.22, 95%CI: 0.34–4.37, p = 0.760), but the difference was significant and clinically meaningful in the subgroup with cancer-related PS ≥ 1 (PFS HR = 0.32, 95%CI: 0.19–0.53, p < 0.001; OS HR = 0.26, 95%CI: 0.14–0.48, p < 0.001). In patients with dMMR/MSI-H mCRC, an extensive evaluation of clinical variables including PS may be implemented in the therapy decision-making. • We investigated Eastern Cooperative Oncology Group performance status in 502 patients with mismatch repair deficient/ microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors. • Eastern Cooperative Oncology Group performance status is independently associated with outcomes of immune checkpoint inhibitors. • Programmed-death 1 blockade alone may be preferred in patients with performance status (PS) 0. • Adding cytotoxic T-lymphocyte antigen 4 blockade seems not beneficial if worse PS is patient-related. • Adding cytotoxic T-lymphocyte antigen 4 blockade yields meaningful benefit if worse PS is cancer-related. [ABSTRACT FROM AUTHOR]

Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain–Barre syndrome, n = 1 each). Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting. • Pembrolizumab showed an ORR of 30.8% across a wide range of advanced MSI-H/dMMR noncolorectal cancers. • Responses were durable with a median duration of response of 47.5 months. • Pembrolizumab had manageable toxicity, consistent with the established safety profile for pembrolizumab monotherapy. • Results support the efficacy of pembrolizumab in previously treated advanced MSI-H/dMMR noncolorectal cancers. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the commonest cancers worldwide, with incidence rates in India being around 4%. It is a heterogeneous disease with multiple established prognostic factors. Ten to fifteen percent originate from microsatellite instability (MSI) pathway, characterized by defect in mismatch repair (MMR) gene. Identification of MMR defective protein is relevant for diagnosis, prognosis, and prediction. Certain clinical and histological features are known to be associated with defective MMR genes. The objectives of this study are to find the prevalence of MSI in CRC to identify features associated with MSI and assess the value of histopathology in predicting MSI. We evaluated various clinical and histological parameters for identifying prognostically favorable colon cancers in a tertiary hospital. One hundred fifty colon cancers were evaluated, and MSI status was correlated with clinicopathologic variables. The prevalence of MSI in CRC was found to be 11.3%. The factors associated with MSI were tumor differentiation, stage, tumor site, tumor size, tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and dirty necrosis. We have defined a "P" score for prediction of MSI using the clinicohistological parameters, which could be used to select patients who are to be tested for MSI. Assessment of clinical and histopathological features will help in patient stratification and selection of patients for MSI testing. The evaluation is economical, reproducible, and easy to apply. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB: somatic mutations per megabase, mut/Mb) predicts the efficacy of immunotherapy. Here, we link TMB levels with the activation of immune pathways and intratumoral immune responses in pancreatic adenocarcinoma (PDAC) to explore immunoarchitectural patterns associated with high TMB. We assessed TMB in 161 resected, microsatellite stable (MSS) PDACs, including 41 long-term survivors (LTS). Five microsatellite instable (MSI-high) cases were also assessed. Cases were classified into TMB-high (≥10 mut/Mb), TMB-intermediate (>5 < 10 mut/Mb), and TMB-low (≤5 mut/Mb) categories. Tumors additionally underwent mRNA in situ hybridization for immune pathway genes and were immunoprofiled by multiplex immunofluorescence followed by automated image analysis. We detected 12 TMB-high, 28 TMB-intermediate, and 121 TMB-low cases. TMB-high tumors comprised ten LTSs (10/41; 24%) and two conventional PDACs (2/120; 1.7%). They exhibited the highest T cell density with significantly increased CD3+CD4+T helper and CD208+dendritic cell (DC) counts, compared to all other cases. CD3+CD8+cytotoxic T cells were significantly closer to tumor cells and T helper cells closer to DCs in TMB-high PDACs. Immune pathways involved in T cell activation, immune cell adhesion/migration, antigen presentation, and cytokine signaling were upregulated in most TMB-high and many TMB-intermediate tumors. ARID1A and ERBB4 alterations were more frequent in TMB-high PDACs. All MSI-high PDACs were TMB-high. TMB-high cases frequently belong to specific PDAC subsets with prolonged survival such as LTSs and MSI-high PDACs. They display strong anti-tumor immune responses fueled by a T helper cell/DC-mediated priming of the cytotoxic T cells. Moreover, they frequently harbor further actionable alterations. [Display omitted] • TMB-high cases frequently belong to specific PDAC subsets with prolonged survival. • They show distinct immuno architectural patterns and "hot" immune microenvironment. • Their anti-tumor response is fueled by a Th/DC priming of the cytotoxic T cells. • TMB-high PDACs frequently harbor further actionable alterations. [ABSTRACT FROM AUTHOR]

In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability−high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K). Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score. At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19–5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36–15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91–9.25]), role (9.88 [3.80–15.97]), emotional (5.62 [1.56–9.68]), and social (8.33 [2.70–13.97]) functioning, and stable cognitive functioning (1.74 [−1.45 to 4.94]). Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours. • Patients with previously treated MSI-H/dMMR cancer received pembrolizumab treatment. • Treatment was associated with improved QLQ-C30 GHS/QoL from baseline to week 9. • Improvements were greatest among patients with a complete or partial response. • Pembrolizumab improved or preserved QoL in previously treated MSI-H/dMMR cancer. [ABSTRACT FROM AUTHOR]

Infertility is associated to multiple types of different genomic instabilities and is a genetic feature of genomic instability syndromes. While the mismatch repair machinery contributes to the maintenance of genome integrity, surprisingly its potential role in infertility is overlooked. Defects in mismatch repair mechanisms contribute to microsatellite instability and genomic instability syndromes, due to the inability to repair newly replicated DNA. This article reviews the literature to date to elucidate the contribution of microsatellite instability to genomic instability syndromes and infertility. The key findings presented reveal microsatellite instability is poorly researched in genomic instability syndromes and infertility. [ABSTRACT FROM AUTHOR]

• MSI or MMR testing is valuable for assessing prognosis and treatment options in CRC patients, but the conventional detection methods such as IHC are limited by not fully consistent results. • TrueMark™ MSI Assay is a novel solution for MSI analysis, but lack of research support in Chinese CRC patients. • Our results suggested that TrueMark™ MSI provides a fast, reliable and highly automated solution to MSI detection in Chinese CRC patients. Microsatellite instability (MSI) and mismatch repair (MMR) detection is valuable in assessing prognosis and treatment options. However, the conventional detection methods such as immunohistochemistry (IHC) are limited by not fully consistent results as well as a long turnaround time. TrueMark™ MSI Assay is a novel solution for MSI analysis, but lack of research support in the Chinese colorectal cancer (CRC) patients. 60 dMMR and 60 pMMR CRC samples identified by IHC were collected and their MSI status were detected using TrueMark™ MSI assay with an expanded panel of 13 markers. The overall performance and diagnostic concordance between TrueMark™ MSI test and MMR IHC analysis were assessed and analyzed. According to the TrueMark™ test, 55 out of the 120 (45.8 %) CRCs were identified as MSI-high (MSI-H) with an instability at ≥ 4/13 markers. Compared with the MMR IHC analysis, an overall percent agreement of 94.2 % and a Kappa of 0.883 were achieved. For the seven inconsistent samples, tumor mutation burden analysis was performed and the results supported the diagnosis by TrueMark™ test. To confirm the robustness of the above findings, a validation was performed in an independent cohort comprising 51 consecutive CRCs. Furthermore, an optimized panel composed of NR-21, NR-24, NR-27, ABI-16, ABI-17 and ABI-20B was developed by multivariate logistic regression model, and showed 100 % agreement with the 13-marker panel for MSI detection in both the derivation and validation sets. TrueMark™ MSI provides a fast, reliable and highly automated solution to MSI detection in Chinese CRC patients, and the new 6-marker panel we established shows promise deserving further evaluation. [ABSTRACT FROM AUTHOR]

• MSI and EBV + GC tumors have a pro-inflammatory immune microenvironment. • Substantial numbers of MSI GC tumors have a less activated antitumor immune response. • Determination of EBV status in large clinical studies is lacking. • Knowledge about immune characteristics within MSI and EBV + subtypes in relation to response to therapy is limited. • Larger patient cohorts and advanced techniques are essential to unravel the intricate complexity and diversity of the immune microenvironment in MSI and EBV + subtypes. Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients. We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated. Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex. This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC. • Role of sex in individual patient data analysis on MSI/MSS resectable gastric cancer. • MSI-high GC patients have better prognosis than MSS/MSI-low ones irrespective of sex. • In MSS/MSI-low GC females had non-significantly improved DFS and OS than males. • MSI-high GC females had a higher trend of detriment from multimodal therapy than males. [ABSTRACT FROM AUTHOR]

One randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. In this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. 133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147–0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. In the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity. • Immunotherapy (IO) has high efficacy in mismatch-repair deficient (dMMR) tumors. • No trial compared chemotherapy (CT) and ICI in non-colorectal dMMR digestive tumors. • ICI has higher progression-free survival, regardless primary tumor site. [ABSTRACT FROM AUTHOR]

• Colorectal carcinoma associated with proficient MLH1 gene are more aggressive cancers. • MLH1 influences the chemoresistance by mediating nuclear autophagy, nucleophagy. • Interaction among MLH1 and autophagy marker LC3 facilitated nucleophagy induction. • MLH1 mediated nucleophagy determined chemoresistance in colorectal cancer cells. [Display omitted] Colorectal Cancer (CRC) with Microsatellite instability (MSI) and mutLhomolog-1 (MLH1) gene deficiency are less aggressive than MLH1 proficient cancers. MLH1 is involved in several cellular processes, but its connection with the autophagy-dependent cellular response towards anticancer drugs remains unclear. In this study, we aimed to investigate the interaction between MLH1 and the autophagy marker LC3, which facilitated nucleophagy induction, and its potential role in determining sensitivity to 5-Fluorouracil (5-FU) induced cell death. To examine the role of MLH1 in DNA-damage-induced nucleophagy in CRC cells, we utilized a panel of MLH1 deficient and MLH1 proficient CRC cell lines. We included a parental HCT116 cell line (MLH1−/−) and its isogenic cell line HCT116 MLH1 +/− in which a single allele of the MLH1 gene was introduced using CRISPR-Cas9 gene editing. We observed that MLH1 proficient cells were less sensitive to the 5-FU-induced cytotoxic effect. The 5-FU induced DNA damage led to LC3 up-regulation, which was dependent on MLH1 overexpression. Moreover, immunofluorescence and immunoprecipitation data showed LC3 and MLH1 were colocalized in CRC cells. Consequently, MLH1 dependent 5-FU-induced DNA damage contributed to the formation of micronuclei. These micronuclei colocalize with autolysosome, indicating a cytoprotective role of MLH1 dependent nucleophagy. Interestingly, siRNA knockdown of MLH1 in HCT116 MLH1 +/− prevented LC3 upregulation and micronuclei formation. These novel data are the first to show an essential role of MLH1 in mediating the chemoresistance and survival of cancer cells by increasing the LC3 expression and inducing nucleophagy in 5-FU treated CRC cells. [ABSTRACT FROM AUTHOR]

Microsatellite instability, programmed death-ligand 1 and tumor-infiltrating leukocytes are prognostic biomarkers in colorectal cancer but unknown toward familial adenomatous polyposis. To investigate the prognostic and clinicopathological roles of microsatellite instability, programmed death-ligand 1 and tumor-infiltrating leukocytes in familial adenomatous polyposis. Clinical data and paraffin embedded tissues from 45 familial adenomatous polyposis patients were collected. Microsatellite instability was detected by immunohistochemistry and polymerase chain reaction. Programmed death-ligand 1 was detected by immunohistochemistry. Tumor-infiltrating leukocytes comprising CD8+ T cells, M1 and M2 tumor associated macrophages, CD56bright and CD56dim natural killer cells were analyzed using multiple fluorescence immunohistochemistry. Microsatellite instability high was noted in 6 samples but not associated with overall survival or progression-free survival. Programmed death-ligand 1 is negative on tumor cells but positive on tumor-infiltrating leukocytes, and positive programmed death-ligand 1 expression on tumor-infiltrating leucocytes is associated with overall survival. Low CD56bright natural killer cell infiltration was associated with longer progression-free survival and was an independent prognostic factor in FAP. For familial adenomatous polyposis, microsatellite instability high can be found but has no correlation with prognosis; programmed death-ligand 1 on tumor-infiltrating leukocytes is related with overall survival; CD56bright natural killer cell is an independent prognostic factor associating with longer progression-free survival. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies have made much headway during the past decades. Techniques including the immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT) have harvested impressive efficacy and provided far-reaching tools for treating cancer patients. However, due to inadequate priming of the immune system, a certain subgroup of patients remains resistant to cancer immunotherapies during or after the treatment. β2-microglobulin (B2M) is an important subunit of major histocompatibility complex (MHC) class I which exerts substantive biological functions in tumorigenesis and immune control. Accumulating evidence has shown that alterations of B2M gene and B2M proteins contribute to poor reaction to cancer immunotherapies by dampening antigen presentation. Here, we discuss the basic biological functions of B2M, its distribution in a spectrum of cancers, and current understanding of its role in ICI, cancer vaccines and chimeric antigen receptor T cell (CAR-T) therapies. Furthermore, we summarize some promising therapeutic strategies to improve the efficacy inhibited by B2M defects. [ABSTRACT FROM AUTHOR]

We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7–16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28–1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity. • Microsatellite testing by next-generation sequencing is higly concordant with immunohistochemistry. • High tumour mutational burden (TMB) defines a clinical and molecular subtype of mCRC. • Alterations in DNA damage repair are rare in microsatellite stable mCRC with high TMB. • Potentially actionable alterations are detectable in a small percentage of mCRC. • Molecular characterisation of mCRC is helpful in adopting personalised treatments. [ABSTRACT FROM AUTHOR]

Background: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. Methods: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. Results: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. Conclusions: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) yielded unprecedented efficacy in patients with microsatellite instability (MSI)–high metastatic colorectal cancer (mCRC). Since the Pan-Immune-Inflammation Value (PIV) is a blood-based biomarker with prognostic usefulness in mCRC, it might predict clinical outcomes and primary resistance to ICIs. We retrospectively analysed the association of PIV and its early modulation at 3/4 weeks after treatment initiation with the outcomes of MSI-high mCRC patients receiving anti-programmed death-(ligand)1 (PD-[L]1) +/− anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. PIV cut-offs were determined using the maximally selected rank statistics. A total of 163 patients were included. In the multivariable models for overall survival (OS) and progression-free survival (PFS), both high (>492) baseline PIV (OS: adjusted [a] HR, 3.00; 95% CI, 1.49–6.04, p = 0.002; PFS: aHR, 1.91; 95% CI, 1.06–3.44, p = 0.031) and early PIV increase ≥+30% (OS: aHR, 3.21; 95% CI, 1.65–6.23, p < 0.001; PFS: aHR, 2.25; 95% CI, 1.30–3.89, p = 0.003) confirmed an independent prognostic impact. After stratifying patients according to baseline PIV and ICI regimen, OS and PFS were significantly worse in subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy. Early PIV increase was an independent predictor of clinical benefit (aOR, 0.23; 95% CI, 0.08–0.66; p = 0.007), whereas a trend was observed for baseline PIV (aOR, 0.33; 95% CI, 0.10–1.07; p = 0.065). PIV is a strong predictor of outcomes in MSI-high mCRC patients receiving ICIs. Prospective validation of these results is required to establish its role as a stratification factor for personalised combination strategies. • PIV is a composite immune-inflammation biomarker with prognostic usefulness in mCRC. • High baseline PIV identifies MSI-high mCRC patients with poorer outcomes upon ICIs. • Early PIV increase ≥+30% at 3/4 weeks independently correlates with poor OS and PFS. • Subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy have worse OS and PFS. • Baseline PIV and early PIV variation correlate with primary ICIs resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Genetic and transcriptional changes in of FRGs in gastric cancer. • Multilayer FRGs changes correlate with patients clinicopathology, prognosis, and TME cell infiltration. • Low FRG-score, due to its MSI-H, high mutational load and immune activation, indicates the possible advantage of OS. • The FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug. Ferroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches. FRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR. In the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC). Low FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug. [ABSTRACT FROM AUTHOR]

The remarkable outcomes achieved with neoadjuvant checkpoint inhibitors for patients diagnosed with MSI colorectal cancer hold the potential to revolutionize the treatment landscape in this context. Specifically, the combination of nivolumab plus ipilimumab in colon cancer and dostarlimab in rectal cancer has led to an unprecedented rate of complete pathological and clinical responses. Notably, these responses have been further substantiated by the absence of relapses, with a 0% relapse rate observed during the first year of follow-up. The significance of these achievements becomes even more apparent when compared to the relatively high relapse rates, ranging from 11% to 28%, observed in MSI colorectal cancer cases treated neoadjuvantly with chemo(radio)therapy. However, it is crucial to exercise caution when interpreting such exceptional responses in oncology, especially within a short follow-up period. The future implications of these findings will depend on how the data mature over time. In this manuscript, we attempt to explore the potential scenarios that may unfold in the near future. • Immunotherapy is impacting the management of MSI colorectal cancer. • Neoadjuvant immunotherapy produced amazing pathological and clinical responses. • 100% DFS rate at 1 year is a relevant achievement of neoadjuvant immunotherapy. • Different scenarios may unfold in the near future as data continue to mature. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel thiophen-2-ylmethylene bis-dimedone derivatives were synthesized. • Thiophen-2-ylmethylene bis-dimedones exhibited inhibitory activity against WRN. • The optimal compound induced DNA damage and apoptotic cell death in MSI cells. • This study provides a new pharmacophore for WRN inhibitors. Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers. [ABSTRACT FROM AUTHOR]

• The top mutational genes of pure PSC were TP53 , KRAS , SMARCA4 , and MET. • 37.9 % of cases had a TMB ≥ 10 mutations/Mb and 12.1 % had a TMB ≥ 20 mutations/Mb. • The median TMB was higher in TP53 -mutant tumors than in wild-type tumors. • The MSI status was in independent of MET exon 14 status. • 45 % of patients had PD-L1-positive tumors and 24 % had high PD-L1-expressing tumors. The distribution of genetic mutations differs between pure pulmonary sarcomatoid carcinoma (PSC) and biphasic PSC; however, most of the enrolled cases in previous studies are biphasic PSC. The current study aimed to investigate the genomic and immunologic profiles of pure PSC in the Chinese population. Next-generation sequencing analysis of a panel of 1021 genes was performed on surgical specimens of 58 pure PSCs. The tumor mutational burden (TMB) was calculated from 0.69 megabases (Mbs) of sequenced DNA. PD-L1 expression was evaluated by immunohistochemistry. Microsatellite instability (MSI) was evaluated by fluorescence-labeled microsatellite marker polymerase chain reaction followed by capillary electrophoresis fragment size analysis. The top mutational genes of pure PSC were TP53 (74 %, 43/58), KRAS (24 %, 14/58), SMARCA4 (14 %, 8/58), MET (12 %, 7/58), EGFR (10 %, 6/58), MLL4 (10 %, 6/58), NF1 (10 %, 6/58), NOTCH4 (10 %, 6/58), and TERT (10 %, 6/58). The median TMB was 8.6 mutations/Mb; 37.9 % of cases (22/58) had a TMB > 10 mutations/Mb and 12.1 % of cases (7/58) had a TMB > 20 mutations/Mb. The median TMB was higher in TP53 -mutant tumors than in wild-type tumors (10.1 versus 7.2 mutations/Mb, p = 0.019). Thirty-five patients had microsatellite-stable pure PSC, and four patients carried MSI-H tumors. The MSI status was independent of MET exon 14 status. Twenty-six patients (45 %) had PD-L1-positive tumors (≥1%) and 14 (24 %) had high PD-L1 expression (≥50 %). In our cohort, 45 % of patients with pure PSC harbored at least one actionable alteration. More importantly, more than 60 % of patients (65.5 %, 38/58) had either MSI-H, PD-L1-positive, or high-TMB tumors, and these might derive survival benefits from immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT 03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018. [ABSTRACT FROM AUTHOR]

Stratification of patients with stage III colon cancer into low (T 1-3 N 1) and high (T 4 and/or N 2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group. Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [ KRAS and BRAF/ mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2. Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAF V600E /pMMR, subgroups. Specifically, BRAF V600E /pMMR (OS: HR = 1.75; 95% CI: 1.36–2.24; P adj <.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31–1.83; P adj <.0001), and SAR (HR = 1.64; 95% CI: 1.37–1.95; P adj <.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF /MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF /MMR for SAR among high risk tumours. Sidedness and BRAF/ MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group. • Sidedness, KRAS, and BRAFV600E are related with poorer survival in high and low risk tumours. • Sidedness and BRAF /MMR contributed the most to survival among high risk tumours. • Age, gender, and KRAS were the top relative contributors to survival in low risk tumours. [ABSTRACT FROM AUTHOR]

The efficacy of immune checkpoint inhibitors (ICIs) in microsatellite instability-high/DNA mismatch repair (MSI/dMMR) metastatic colorectal cancer (mCRC) is well established. ICIs are responsible for pseudoprogression (PSPD) that complicates clinical decisions. We evaluated the PSPD frequency in patients with MSI/dMMR mCRC treated with ICIs. Consecutive patients with MSI/dMMR mCRC treated with ICIs from February 2015 to December 2019 at Saint-Antoine Hospital were included. Imaging was retrospectively and centrally reviewed according to Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1) and immune RECIST (iRECIST). PSPD was defined as an unconfirmed disease progression by iRECIST. One hundred twenty-three patients with MSI/dMMR mCRC were included. Thirty-six patients (29%) had radiological PD according to RECIST 1.1 during the median follow-up of 22.3 months (95% confidence interval [CI], 1.5–62.2), including 22 in the first 3 months (the primary radiological PD). Twenty-nine patients continued ICIs beyond PD. Twelve patients experienced PSPD, representing 10% of the population and 52% of the primary radiological PD. The median time to PSPD was 5.7 weeks (95% CI, 4.1–11.4). No PSPD was observed after 3 months. The PSPD incidence was 14.8% in patients treated with anti-PD1 alone (n = 9/61) and 4.8% in case of anti-PD1 plus anti-CTLA-4 (n = 3/62). Eight patients with PSPD experienced an objective response. The 2-year progression-free survival and overall survival rates for patients with PSPD were 70.0% (95% CI, 32.9–89.2) and 75.0% (95% CI, 29.8–93.4), respectively. Patients with MSI/dMMR mCRC treated with ICIs experienced PSPDs. PSPD occurred within the first 3 months and represented most of the primary radiological PDs. The use of iRECIST criteria should be questioned after 3 months. • Ten percent of patients with microsatellite instability metastatic colorectal cancer experience pseudoprogression. • Pseudoprogressions occur within the first 3 months. • Pseudoprogressions represent 52% (12/22) of primary radiological progressions. • The use of immune RECIST (iRECIST) criteria should be questioned after 3 months. • Majority of patients with pseudoprogression in this study population have favourable outcomes. [ABSTRACT FROM AUTHOR]

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are rare tumors, mainly encountered in the gastroenteropancreatic tract. Based on the limited available data, MiNEN is usually a highly aggressive neoplasm combining a high-grade neuroendocrine and a non-neuroendocrine component, associated with a poor prognostic outlook. Deficient DNA mismatch repair (MMR) results in microsatellite instability, which is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. Little information on MMR status in MiNEN is available in published studies. Therefore, the purpose of this study was to explore the status and putative role of MMR on MiNEN. We investigated the MMR status in 44 cases and characterized their clinicopathological features and prognoses. Immunohistochemistry was performed for four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Mean age at diagnosis was 61 years, and 75% of the patients were male. Lymph node metastases were observed in 14 (35.9%) patients. The most common tumor localizations were gastric (28 patients, 63.6%). Lack of immunohistochemical expression of MMR proteins was shown in 38.6% of cases. The common deletion rates of one or more proteins were 29.4% (5/17) for MLH1/PMS2 and 23.5% (4/17) for MLH1. Correlation between clinicopathological parameters showed that MMR deficiency was significantly associated with early TNM stage and better prognoses in patients with MiNEN. MiNENs showed frequent losses of MMR protein expression, which contributes to the knowledge of the pathological and clinical aspects of MiNEN tumors. [ABSTRACT FROM AUTHOR]

Microcystic, elongated, and fragmented (MELF) pattern of myoinvasion has been related with increased risk of lympho-vascular space invasion (LVSI) and lymph node metastasis. We analysed a cohort of endometrioid endometrial carcinomas (EECs) to examine the relationships between the MELF pattern of invasion and the clinico-pathological and immunohistochemical features of EEC. 129 EECs were evaluated for the presence of MELF pattern and immunohistochemically tested for Mismatch repair (MMR) proteins, p16, p53 and beta-catenin. We observed 28 MELF + EECs and 101 MELF- EECs. LVSI was observed in 20 MELF + cases and in MELF- tumors. Lymph-node metastases were observed in 7 MELF + cases (2 macrometastases, 3 micrometastases and 2 ITCs). None of the MELF- cases showed micrometastases or ITCs, 18 cases had macrometastatic lymph-nodes. Statistical analysis showed that MELF + tumors carry an increased risk of developing nodal metastasis independent of tumor dimension and LVSI. Loss of MMR proteins expression was observed in 11 MELF + cases and 45 MELF- cases, respectively. Our data showed a higher frequency of immunohistochemical MLH1-PMS2 loss in MELF- pattern of invasion (32.67% of MELF- cases vs 21.43% of MELF + cases) but a higher prevalence of MSH2-MSH6 loss in MELF + pattern (7.14% in MELF + population vs 3.96% of MELF- population) The morphological recognition of MELF pattern is more reliable than immunohistochemical and molecular signatures of EEC in predicting the risk of nodal involvement. The observed higher prevalence of MSH2-MSH6 loss in MELF + group and MLH1-PMS2 loss in MELF- group may suggest a different molecular signature. [ABSTRACT FROM AUTHOR]

• CRC is one of the top causes of death in high-income countries. • Colorectal primary tumours mostly disseminate to liver, lungs and peritoneum. • Bone metastases rarely belong to the unique and curable metastases group of patients. • Isolated colorectal cancer bone metastases are rare and usually associated with better prognosis. • Careful study of the behaviour of rare types of colonic tumours is essential to progress in scientific knowledge. Bone metastases of colorectal cancer (CRC) are uncommon and usually occur in the context of a widespread disease. A 77-year-old woman presented with increasing pain in the right shoulder which had started 5 months earlier. On examination, a hard mass arising from the right scapula was found. There were no other abnormal findings on body Computerized Tomography (CT). A biopsy confirmed a metastatic adenocarcinoma. Further colonoscopy revealed a colonic obstructive tumour. Both solitary metastasis and the primary tumour were treated, and patient maintains a progression-free status. This is an unusual form of presentation for a colon cancer. With this report we aimed to discuss the unique clinical and pathological features of this colonic cancer and call attention of the physicians' community for this atypical presentation. Isolated bone metastasis in CRC is a rare entity and there are only a few similar cases reported in the literature. [ABSTRACT FROM AUTHOR]

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection. • The PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib recently received regulatory approval. • Such tumour-agnostic regulatory approvals, based on tumour biomarker status, represent a paradigm shift in cancer therapy. • These recommendations provide guidance on which patients should be selected and tested for tumour MSI and NTRK gene fusions. [ABSTRACT FROM AUTHOR]

• MSI occurs in several solid cancer types and is predictive of response to immunotherapy. • There are some issues with the current gold standard methods from ambiguous data. • We performed MSI-next-generation sequencing (MSI-NGS) combined with MSIcall, a bioinformatics tool, in 76 microsatellite loci in 184 formalin-fixed paraffin-embedded tumor from patients with various solid tumors. • MSIcall predicted MSI scores with a specificity of 91.3%, a sensitivity of 100% and high accuracy (98.9%). • We validated the additional 50 samples to classified MSI status with 100% concordance. Microsatellite instability (MSI) occurs in solid tumors and is a predictive biomarker for remarkable response to immune checkpoint inhibitors. Detection of MSI status has been conventionally conducted by PCR–electrophoresis-based assay (MSI-PCR) and immunohistochemistry (IHC) of mismatch repair proteins. However, these approaches require visual confirmation and involve some difficulties in determining MSI statuses from equivocal results. We performed amplicon-based targeted sequencing of 76 microsatellite loci (MSI-NGS) in 184 formalin-fixed paraffin-embedded (FFPE) tumor tissues and baseline control samples. A bioinformatics tool, MSIcall, was used to calculate the quantitative values based on the aligned sequence reads and evaluated MSI status. Furthermore, we examined the concordance between the results from MSI-NGS and MSI-PCR/IHC. Diagnostic accuracy, sensitivity, and specificity were estimated by receiver operating characteristic (ROC) curve analysis. For validation cohort, we studied additional 50 tumor samples to determine the MSI status. Of 184 tumor samples, MSI-PCR and IHC analysis classified 161 tumors as MSS/pMMR and 23 as MSI-H/dMMR. Using MSI-NGS combined with MSIcall, we predicted MSI status with high accuracy (98.9%), specificity (91.3%), and sensitivity (100%) in 25 types of cancers. This method achieved an area under the ROC curve (AUC) value of 0.9986. Furthermore, we achieved the 100% concordant results using additional 50 samples for validation. We demonstrated newly developed MSI-NGS with MSIcall accurately determines the MSI status of FFPE tumor tissues thorough sequencing of tumor samples alone without patient-matched normal controls. This approach can be applied to all types of solid tumors to determine responders to immune-oncology therapy. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) is one of the promising biomarkers in human colorectal cancers (CRCs), and it is influenced by an intricate gene interaction network. Hence, we aimed to identify and validate hub genes associated with MSI CRC and to illustrate its underlying mechanisms. Weighted gene co-expression network analysis (WGCNA) was used to investigate potential regulatory targets and relationships between key modules and hub genes associated with MSI CRC. In the red module (r = 0.83), SET nuclear proto-oncogene (SET) was selected due to its high intra-modular connectivity and module membership. In the test sets, SET expression was downregulated in MSI CRCs compared to that in microsatellite stability (MSS) CRCs. SET expression level had a good performance in stratifying patients into MSI or MSS CRCs (area under the curve = 0.953). Moreover, the BRAF V600E mutation was highly associated with SET expression, and MSI/HLA- samples showed lower levels of SET mRNA expression than MSS/HLA- samples. Finally, gene set enrichment analysis (GSEA) indicated that patients in the SET low expression group were enriched in base excision repair. SET was identified and validated as a novel potential biomarker in MSI CRCs, and SET probably acts through regulating the base excision repair pathway. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: To investigate whether quantitative radiomics features extracted from computed tomography (CT) can predict microsatellite instability (MSI) status in an Asian cohort of patients with stage Ⅱ colorectal cancer (CRC).Materials and Methods: This retrospective study was approved by our institutional review board, and the informed consent requirement was waived. From March 2016 to March 2018, 119 Chinese patients with pathologically confirmed stage Ⅱ CRC, available MSI status, and preoperative contrast-enhanced CT images were included in this study. Clinical and pathological information was obtained from the institutional database. The radiomics features were extracted from portal venous-phase CT images of segmented volumes of each entire primary tumor by using Matrix Laboratory (MATLAB), and radiomics signatures were generated using the least absolute shrinkage and selection operator logistic regression model. The minority group was balanced via synthetic minority over-sampling technique method. The association between the clinicopathologic characteristics and MSI status was assessed using Student's t test, Chi-square, or Fisher's exact test. The predictive efficacy of MSI status using radiomics features, clinical factors (including age, gender, CT-reported tumor location, differentiation degree of tumor, smoking history, hypertension history, family history of cancer, diabetes history, level of the Ki-67 expression, and laboratory analysis) and the combined models were evaluated, respectively. Predictive performance was evaluated by the area under receiver operating characteristic curve, accuracy, sensitivity, and specificity.Results: MSI status was significantly associated with tumor location (p = 0.043); differentiation degree of tumor (p < 0.0001), hypertension history (p = 0.012), and the level of the Ki-67 expression (p = 0.015). Six radiomics features and 11 clinical characteristics were selected for predicting MSI status. The model that used the combination of clinical factors and radiomics features achieved the overall best performance than using either of the two features alone, yielding the area under the curve, sensitivity, and specificity of 0.752, 0.663, 0.841 for the combined model, 0.598, 0.371, 0.825 for clinical factors alone, and 0.688, 0.517, 0.858 for radiomics features alone, respectively.Conclusion: CT-based radiomic features of stage Ⅱ CRC are associated with MSI status. Combining analysis of clinical features and CT features could improve predictive efficacy and could potentially select the patients for individualized therapy noninvasively. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the third most commonly diagnosed cancer among both men and women. Personalised treatment options remain complex, although there is broad agreement over which patients with colorectal liver metastases (CRLM) should and should not be offered resection. Decisions on an optimal management strategy involves careful assessment of both technical and oncological factors. In this review we aim to summarise current prognostic biomarkers for metastatic colorectal cancers, specifically patients considered for resection. A number of clinico-pathological factors have been identified as prognostically important with good internal validity, but limited external validity. Furthermore, these prognostic scoring systems do not take factor in modern chemotherapeutic agents and the disease modification these agents produce. Histopathological response to chemotherapy is of significant prognostic importance. Molecular markers can help predict the efficacy of a biological agent. An important prognostic factor of liver metastasis is the recognition that location of the primary colorectal cancer impacts on metastatic phenotype and represents difference in genotype, i.e. proximal tumours are more aggressive than distal tumours with an increased likelihood of disease progression. Several mutational molecular markers identified include microsatellite instability, BRAF, and KRAS/NRAS and combination mutations, which confer poorer outcomes. Accurate prognostication in patients with liver limited colorectal metastases remains crucial, as this allows tailoring treatment options to each disease and improving outcomes. Access to tissue before treatment remains a limitation although advances in ability to assess tumour biology by non-invasive methods are promising. [ABSTRACT FROM AUTHOR]

Background It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor–node–metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). Patients and methods We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N  =   1656) and treated (N  =   980), stage II (N  =   1799) and III (N  =   837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). Results In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6–0.9); P  =   0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P  =   0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P  =   0.04). Conclusions Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns. [ABSTRACT FROM AUTHOR]

Gastric adenocarcinoma (GC) and gastroesophageal junction adenocarcinoma represent frequent and severe diseases whose management has radically changed over the last 10 years. With the advent of second- and third-line standard therapies for metastatic GC patients in the 2010s, the molecular dismemberment of the disease and positive trials with immunotherapy and targeted agents will mark the 2020s. New treatment options have emerged in the neoadjuvant, adjuvant, and metastatic setting. In addition to improved multimodal treatment in operable patients, new subgroups have emerged depending on molecular alterations (HER2, Microsatellite instability) or expression of specific proteins in the tumour (PDL1, Claudin 18.2) making immunohistochemistry central in profiling the tumour for an optimal individualised management. The aim of this review is to describe the current standards of management of early and late stage GC and the molecular markers needed today to optimally manage our patients together with future perspectives on this disease. • Gastric cancer is not anymore, a single disease. • Upfront HER2, MSI, CPS-PDL-1 assessment are needed upfront to guide treatment. • 1st line immunotherapy + chemotherapy is a SOC in patients with a CPS >5. • New therapeutic options are emerging for Claudin 18.2 + or FGF-R2 fusion GC. [ABSTRACT FROM AUTHOR]

Neoadjuvant immune checkpoint blockade (IO) is emerging as a therapeutic option for patients with deficient mismatch repair (dMMR) colorectal cancer (CRC) given high pathological response rates. The aim of the study was to characterise imaging and endoscopic response to IO. A retrospective analysis of patients with localised dMMR CRC that received at least one cycle of neoadjuvant anti-PD-1 therapy was conducted. Endoscopy, imaging, and pathological outcomes were reviewed to determine response to treatment according to standardised criteria. Thirty-eight patients had received IO for the treatment of localised CRC (median eight cycles). Among evaluable cases (n = 31 for endoscopy and n = 34 for imaging), the best endoscopic response was complete response (CR) in 45% of cases, and the best radiographic response was CR in 23% of cases. Imaging CR rate after ≤4 cycles of IO (n = 1) was 6% compared to 44% after >4 IO cycles (n = 7). Among 28 patients with imaging and endoscopy available, a discrepancy in best response was noted in 15 (54%) cases. At a median follow-up of 28.2 months from IO start, 18 patients underwent surgical resection of which 11 (61%) had pathological CR (pCR). Despite pCR or no evidence of progression ≥6 months after completion of IO among non-operatively managed patients, 72% and 42% of patients had non-CR on imaging and endoscopy, respectively. Discrepancies between imaging and endoscopy are prevalent, and irregularities identified on these modalities can be identified despite pathological remission. Improved clinical response criteria are warranted. • The response of localised dMMR CRC to neoadjuvant IO needs further characterisation. • Most patients had a discrepancy between the best imaging and endoscopic response. • Imaging and/or endoscopic residual disease was often noted despite pathological CR. • Conventional clinical response assessment may not be optimal for localised dMMR CRC. [ABSTRACT FROM AUTHOR]

Background Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAF V600E complicates the association. Patients and methods Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. Results Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19–85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69–0.98; P  = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58–1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73–2.46; P  < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67–4.21; P  < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. Conclusions In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAF V600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. Trial identification numbers NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918. [ABSTRACT FROM AUTHOR]

Context: Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations.Objective: A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC.Method: A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008.Results: A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability.Conclusion: Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma is the most frequently occurring female genital tract malignancy in developed nations, with a rising annual incidence. Endometrioid endometrial carcinoma (EEC), the most common histological variant, differs in morphologic and molecular characteristics from serous carcinomas but morphological distinction of high-grade EECs from serous carcinomas may prove difficult. Thus, molecular categorization of tumors may allow for better tumor classification with greater insight into the underlying biology of endometrial carcinomas with new therapeutic options. Microsatellite instability (MSI) is a commonly occurring molecular aberration in EECs and has been identified in most Lynch Syndrome (LS) associated tumors. This tumor syndrome predisposes afflicted individuals to a myriad of tumors including endometrial carcinoma. Herein, the molecular signature of endometrial tumors as well as LS, and its clinical manifestations are reviewed. Understanding of the pathogenetic pathways allows for greater comprehension of occurrences at a molecular level which are then appreciated at a cellular and tissue level, by the histopathologist. The molecular classification of endometrial tumors allows for further targeted therapeutic options for affected patients. Screening tests for patients with suspected LS enables surveillance of other tumors in the affected patient and her family with the potential to decrease morbidity and mortality. It is envisioned that this overview will allow for enhanced comprehension of genetic pathways by practicing pathologists, oncologists, gynecologists and other members of the multidisciplinary team, all of whom are involved in the management of the patient with an endometrial malignancy. • Molecular endometrial classification into 4 groups allows for improved targeted therapy. • Microsatellite instability is noted in most tumors associated with Lynch Syndrome. • Lynch Syndrome is diagnosed on molecular evidence of mutation of 1or more of the MMR genes. • Females with MSH6 mutation have a significant risk of developing endometrial cancer. [ABSTRACT FROM AUTHOR]