Evolution of Metastases in Space and Time under Immune Selection.

We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.

Circulating DNA in the neoadjuvant setting of early stage colon cancer.

BACKGROUND: While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/- adjuvant FOLFOX in the PePiTA trial. MATERIAL AND METHODS: Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS). RESULTS: After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15-9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94-7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker ≥11%, or mean ctDNA change of NPY and WIF1 ≥ 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81-16.44, p = .09). CONCLUSION: This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.

Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study.

BACKGROUND: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here. METHODS: Pa tients with mGC/mGEJC treated with ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC). RESULTS: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI. CONCLUSION: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.

CTCs as a prognostic and predictive biomarker for stage II/III Colon Cancer: a companion study to the PePiTA trial.

BACKGROUND: Adjuvant therapy improves the prognosis of stage II & III colon cancer patients. Unfortunately, most patients do not benefit from this treatment. PePITA (NCT00994864) is a prospective, multicenter, non-randomized study whose primary objective is to predict the outcome of adjuvant therapy in colon cancer. METHODS: The primary objective was to determine the prognostic and predictive value of circulating tumor cell (CTC) detection before therapy and after one course of preoperative FOLFOX. RESULTS: Out of the 58 first patients accrued in PePiTA trial, 36 patients participated in the CTC companion study, of whom 32 had at least one evaluable sample. Only 5 patients (14, 95% CI = 5-30%) had ≥1 CTC/22.5 ml blood in at least one of the two timepoints with 2 patients having ≥1 CTC/22.5 ml at baseline (6, 95% CI: 1-19%). The detection rate of patients with CTCs at baseline being lower than expected, the inclusion of patients in the PePiTA CTC substudy was stopped. The limited sample size did not allow us to investigate the prognostic and predictive value of CTCs in locally advanced colon cancer. CONCLUSIONS: Our data illustrate the need for further standardized studies in order to find the most reliable prognostic/predictive biomarker in early-stage colon cancer. TRIAL REGISTRATION: This trial was prospectively registered at Jules Bordet institute ( NCT00994864 ) on the October 14, 2009.

Surgical Treatment of Colorectal Cancer with Peritoneal and Liver Metastases Using Combined Liver and Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Report from a Single-Centre Experience.

BACKGROUND: Chemotherapeutic advances have enabled successful cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) expansion in treating metastatic colorectal cancer. OBJECTIVES: The aims of this study were to evaluate the safety of combining liver surgery (LS) with HIPEC and CRS (which remains controversial) and its impact on overall survival (OS) rates. METHODS: From 2007 to 2015, a total of 77 patients underwent CRS/HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. Twenty-five of these patients underwent concomitant LS for suspicion of liver metastases (LM; group 2), and were compared with patients who underwent CRS/HIPEC only (group 1). Demographic and clinical data were reviewed retrospectively. RESULTS: Among the group 2 patients, two underwent major hepatectomies, six underwent multiple wedge resections, 16 underwent single wedge resections (one with radiofrequency ablation), and one underwent radiofrequency ablation alone. For groups 1 and 2, median peritoneal cancer index was 6 and 10 (range 0-26; p = 0.08), complication rates were 15.4 and 32.0 % (Dindo-Clavien ≥3; p = 0.15), and median follow-up was 34.2 and 25.5 months (range 0-75 and 3-97), respectively. One group 2 patient died of septic shock after 66 days. Pathology confirmed LM in 21 patients in group 2 (four with benign hepatic lesions were excluded from long-term outcome analysis). Two-year OS rates were 89.5 and 70.2 % (p = 0.04), and 2-year recurrence-free survival rates were 38.3 and 13.4 % (p = 0.01) in groups 1 and 2, respectively. CONCLUSIONS: Simultaneous surgery for colorectal LM and PC is both feasible and safe, with low postoperative morbidity. Further longer-term studies would help determine its impact on patient survival.

Monitoring metabolic response using FDG PET-CT during targeted therapy for metastatic colorectal cancer.

INTRODUCTION: The introduction of targeted drugs has had a significant impact on the approach to assessing tumour response. These drugs often induce a rapid cytostatic effect associated with a less pronounced and slower tumoural volume reduction, thereby impairing the correlation between the absence of tumour shrinkage and the patient's unlikelihood of benefit. The aim of the study was to assess the predictive value of early metabolic response (mR) evaluation after one cycle, and its interlesional heterogeneity to a later metabolic and morphological response assessment performed after three cycles in metastatic colorectal cancer (mCRC) patients treated with combined sorafenib and capecitabine. METHODS: This substudy was performed within the framework of a wider prospective multicenter study on the predictive value of early FDG PET-CT response assessment (SoMore study). A lesion-based response analysis was performed, including all measurable lesions identified on the baseline PET. On a per-patient basis, a descriptive 4-class response categorization was applied based upon the presence and proportion of non-responding lesions. For dichotomic response comparison, all patients with at least one resistant lesion were classified as non-responding. RESULTS: On baseline FDG PET-CT, 124 measurable "target" lesions were identified in 38 patients. Early mR assessments showed 18 patients (47 %) without treatment resistant lesions and 12 patients (32 %) with interlesional response heterogeneity. The NPV and PPV of early mR were 85 % (35/41) and 84 % (70/83), respectively, on a per-lesion basis and 95 % (19/20) and 72 % (13/18), respectively, on a dichotomized per-patient basis. CONCLUSIONS: Early mR assessment performed after one cycle of sorafenib-capecitabine in mCRC is highly predictive of non-response at a standard response assessment time. The high NPV (95 %) of early mR could be useful as the basis for early treatment discontinuation or adaptation to spare patients from exposure to non-effective drugs.

Regorafenib induced severe toxic hepatitis: characterization and discussion.

BACKGROUND: Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS: Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS: Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION: This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.

Bacteria in metastatic sites: Unveiling hidden players in cancer progression.

Bacteria exhibit key features of cancer metastasis, such as motility, invasion, and modulation of the tumor microenvironment. They migrate through lymphatic and blood systems, invade metastatic tissues, and alter local microenvironments to support metastatic growth. Bacteria also shape the tumor microenvironment, affecting immune responses and inflammation, which influence tumor progression and therapy response. While they hold therapeutic potential, challenges like contamination and complex characterization persist, necessitating advanced sequencing and research for clinical application.

Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: factors predictive of severe SOS lesions and protective effect of bevacizumab.

OBJECTIVES: The most frequent presentation of chemotherapy-related toxicity in colorectal liver metastases (CRLM) is sinusoidal obstruction syndrome (SOS). The purpose of the present study was to identify preoperative factors predictive of SOS and to establish associations between type of chemotherapy and severity of SOS. METHODS: A retrospective study was carried out in a tertiary academic referral hospital. Patients suffering from CRLM who had undergone resection of at least one liver segment were included. Grading of SOS on the non-tumoral liver parenchyma was accomplished according to the Rubbia-Brandt criteria. A total of 151 patients were enrolled and divided into four groups according to the severity of SOS (grades 0-3). RESULTS: Multivariate analysis identified oxaliplatin and 5-fluorouracil as chemotherapeutic agents responsible for severe SOS lesions (P < 0.001 and P = 0.005, respectively). Bevacizumab was identified as having a protective effect against the occurrence of SOS lesions (P = 0.005). Univariate analysis identified the score on the aspartate aminotransferase : platelets ratio index (APRI) as the most significant biological factor predictive of severe SOS lesions. Splenomegaly is also significantly associated with the occurrence of severe SOS lesions. CONCLUSIONS: The APRI score and splenomegaly are effective as factors predictive of SOS. Bevacizumab has a protective effect against SOS.

Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting.

With the development of immune checkpoint inhibitors (ICIs), the tumour immune microenvironment (TIME) has been increasingly considered to improve cancer management. The TIME of metastatic lesions is strongly influenced by the underlying immune contexture of the organ in which they are located. The metastatic location itself appears to be an important prognostic factor in predicting outcomes after ICI treatment in cancer patients. Patients with liver metastases are less likely to respond to ICIs than patients with metastases in other organs, likely due to variations in the metastatic TIME. Combining additional treatment modalities is an option to overcome this resistance. Radiotherapy (RT) and ICIs have been investigated together as an option to treat various metastatic cancers. RT can induce a local and systemic immune reaction, which can promote the patient's response to ICIs. Here, we review the differential impact of the TIME according to metastatic location. We also explore how RT-induced TIME modifications could be modulated to improve outcomes of RT-ICI combinations.

Cone-beam computed tomography-guided online-adaptive radiotherapy for inoperable right colon cancer: First in human.

We report the case of a medically inoperable patient with localised colon cancer. Due to symptomatic bleeding, definitive radiotherapy (5 daily fractions of 5 Gy) has been performed using cone-beam computed tomography-based online-adaptive radiotherapy (ART). Online-ART enables compensation of interfraction motion of abdominal organs by performing daily delineation of organs at risk (OARs) and target volumes. Daily treatment replanning maximised target volume coverage while lowering the dose to OARs. Intrafraction variation of the tumour was still significant and had to be incorporated in the planning target volume margin computation. After the treatment, the patient did not develop any acute radiotherapy-induced adverse events and had no further rectal bleeding either at the end of the radiotherapy or at oncological follow-up 4 months later. Online-ART for colon cancer is feasible and is a valuable alternative when surgery is not an option.

Multiplex Immunofluorescence Combined with Spatial Image Analysis for the Clinical and Biological Assessment of the Tumor Microenvironment.

The tumor microenvironment (TME) is composed of a plethora of different cell types, such as cytotoxic immune cells and immunomodulatory cells. Depending on its composition and the interactions between cancer cells and peri-tumoral cells, the TME may affect cancer progression. The characterization of tumors and their complex microenvironment could improve the understanding of cancer diseases and may help scientists and clinicians to discover new biomarkers. We recently developed several multiplex immunofluorescence (mIF) panels based on tyramide signal amplification (TSA) for the characterization of the TME in colorectal cancer, head and neck squamous cell carcinoma, melanoma, and lung cancer. Once the staining and scanning of the corresponding panels are completed, the samples are analyzed on an image analysis software. The spatial position and the staining of each cell are then exported from this quantification software into R. We developed R scripts that allow us not only to analyze the density of each cell type in several tumor compartments (e.g. the center of the tumor, the margin of the tumor, and the stroma) but also to perform distance-based analyses between different cell types. This particular workflow adds a spatial dimension to the classical density analysis already routinely performed for several markers. mIF analysis could allow scientists to have a better understanding of the complex interaction between cancer cells and the TME and to discover new predictive biomarkers of response to treatments, such as immune checkpoint inhibitors, and targeted therapies.

Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial.

BACKGROUND: Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. METHODS: The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. RESULTS: The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. CONCLUSION: No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.

Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore.

BACKGROUND: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. METHODS: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists' T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. RESULTS: Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). CONCLUSIONS: The standardized IS assay outperformed expert pathologists' T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes.

An integrated tumor, immune and microbiome atlas of colon cancer.

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer.

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient's gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

Biomarkers of Response and Resistance to Immunotherapy in Microsatellite Stable Colorectal Cancer: Toward a New Personalized Medicine.

Immune Checkpoint Inhibitors (ICIs) are well recognized as a major immune treatment modality for multiple types of solid cancers. However, for colorectal cancer (CRC), ICIs are only approved for the treatment of Mismatch-Repair-Deficient and Microsatellite Instability-High (dMMR/MSI-H) tumors. For the vast majority of CRC, that are not dMMR/MSI-H, ICIs alone provide limited to no clinical benefit. This discrepancy of response between CRC and other solid cancers suggests that CRC may be inherently resistant to ICIs alone. In translational research, efforts are underway to thoroughly characterize the immune microenvironment of CRC to better understand the mechanisms behind this resistance and to find new biomarkers of response. In the clinic, trials are being set up to study biomarkers along with treatments targeting newly discovered immune checkpoint molecules or treatments combining ICIs with other existing therapies to improve response in MSS CRC. In this review, we will focus on the characteristics of response and resistance to ICIs in CRC, and discuss promising biomarkers studied in recent clinical trials combining ICIs with other therapies.

Hypersensitivity reactions to folinic acid: mechanisms involved based on two case reports and a literature review.

BACKGROUND: Hypersensitivity reactions (HSR) to antineoplastic agents are an increasing problem, especially when they lead to treatment discontinuation, sometimes without any equivalent therapeutic option. HSR to folinic acid (FA), used particularly for the treatment of digestive carcinoma along with oxaliplatin and 5-fluorouracil, are rare. Only seven publications report HSR to FA, mainly confirmed by the disappearance of symptoms after the withdrawal of FA from chemotherapy. Only two papers describe allergy testing. Due to the difficult diagnosis, patients usually receive several further cycles of chemotherapy with progressively more intense symptoms before the withdrawal of FA. CASE PRESENTATION: Here we document two cases of HSR to FA, initially misattributed to oxaliplatin. The first patient described successive cycles with first back muscle pain, then chills and facial oedema and finally diffuse erythema with labial edema despite premedication. The allergy assessment highlighted high acute tryptase levels and intradermal tests positive for FA, pointing to an immunoglobulin E (IgE)-mediated mechanism. The second patient also had lower back muscle pain and chills in addition to tachycardia and desaturation during the administration of FA. Skin tests were negative and tryptase levels normal. After withdrawing FA, the symptoms did not recur, thus allowing the patient to continue chemotherapy. The mechanism of FA hypersensitivity is still unclear. The chronology of symptoms suggests an IgE-mediated mechanism that was not documented in the allergy assessment. A non-IgE-mediated mast cell/basophil activation could be involved, through complement activation or through Mas-related G protein-coupled receptors X2 (MRGPRX2) particularly. CONCLUSIONS: These two cases of anaphylaxis to FA document the clinical manifestations associated with two different mechanisms of HSR. This paper provided the opportunity to review the limited literature on HSR to FA. Through these cases, we hope to draw the practitioner's attention to FA as a potential agent of severe hypersensitivity, especially if symptoms remain after withdrawing the most suspected chemotherapeutic agents. We want also to stress the importance of allergy testing.