Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer

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O-17 A TNM-Immune (TNM-I) classification staging system for predicting survival in colon cancer in a multicenter international SITC study

Background The present study was performed to evaluate the predictive capacity of the TNM-Immune (TNM-I) classification staging system vs. the 8th edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM8) staging system for survival of patients with colon cancer. Methods Data of eligible patients from the Society-for-Immunotherapy-of-Cancer (SITC) international-consortium from 13 countries were evaluated for the consensus Immunoscore in 3539 patients with AJCC/UICC-TNM stages I-III colon cancer. The primary-endpoint time-to-recurrence (TTR) and secondary-endpoint overall-survival (OS) were evaluated for 2650 patients with complete TNM staging and Immunoscore information. The consensus Immunoscore was predefined and previously published (Pages et al. Lancet 2018), and TNM-I categories (IA to IIID) were performed based on TNM8 plus consensus Immunoscore categories. Results A total of 1737 (64.8%) patients presented stage migration, including 1495 (55.8%) migrating to a lower stage and 242 (9.0%) to a higher stage. In TNM8 stage IIIB, patients migrated to all possible TNM-I stages from IA to IIID. A total of 563 Stage IIIB (67.0%) patients presented stage migration, including 181 (32.1%) migrating to a lower stage and 196 (34.8%) to a higher stage. TNM-I Hazard ratio for TTR between TNM-I stage IA and IIID was HR= 16.9 (95%CI 7.75-36.83), in contrast TNM8 TTR between IA and IIIC was only HR= 12.77 (95%CI 7.99-20.4), all P< 0.0001. TNM-I Hazard ratio for OS between TNM-I stage IA and IIID was HR= 5.95 (95%CI 3.17-11.19), in contrast, TNM8 OS between IA and IIIC was only HR= 3.16 (95%CI 2.38-4.18), all P< 0.0001. The TNM8 staging system exhibited prognostic discrepancies in discriminating stage IIB and IIC and between IIC and IIIA on survival curves from TTR and OS, which were improved in the TNM-I staging system. In cox multivariate analysis, the relative contribution of TNM-I was 90.3% in comparison to gender, sidedness, MSI, grade of differentiation, mucinous colloid, VELIPI. The TNM-I had a better predictive capability of survival, as evidenced by higher likelihood ratio scores, and smaller AIC values for TNM-I compared with those for TNM8 edition. Conclusion Therefore, the present study showed the importance of immuno-pathology and demonstrated that the TNM-Immune (TNM-I) classification staging system is superior (log-likelihood ratio test P< 0.0001) to the 8th edition of the AJCC/UICC-TNM staging system in predicting the TTR and OS of patients with colon cancer

Immunoscore predicts significant differences in time to recurrence in stage I colon cancer patients

Immunoscore® is an in vitro diagnostic test that predicts the risk of relapse in patients with Colon Cancer (CC) by measuring the host immune response at the tumor site. It is an immune risk-assessment tool providing independent and superior prognostic value than traditional histopathological risk parameters, and is intended to be used as an adjunct to the TNM classification. Currently, Immunoscore plays a critical role to guide post-surgery decisions in stage II & III CC patients. In stage I, survival rates are high and adjuvant chemotherapy is not typically recommended. However, approximately 10% of stage I CC tumors will recur even after surgical resection. Methods A subgroup analysis was performed on the stage I patients (n = 451) from the Immunoscore international validation study (Pagès et al. The Lancet 2018). Patients were classified by Immunoscore based on pre-defined cutoffs, either in 5 (IS 0-4) or in 3 categories: IS Low (IS0-1), Intermediate (IS 2), High (IS 3-4). Time to recurrence (TTR) was compared between Immunoscore categories. Results Immunoscore Low, Intermediate and High were observed in 14%, 47% and 39% of the cohort, respectively. Immunoscore was positively and significantly correlated with TTR. When adjusting the model with Immunoscore, age, gender, T-stage sidedness and MSI, Immunoscore remained the sole significant parameter (stratified by participating center HRlow vs high=7.82; 95% CI 1.49 − 41.01; p = 0.015). In multivariate analysis, the variable with the most important relative contribution to the risk (Chi2) was Immunoscore. The robust correlation between Immunoscore classification and TTR was further corroborated by a separate analysis of the same cohort distributed into five IS categories. In MSS stage I patients, TTR rates at 5 years were 100%, 98.1%, 93.5%, 85.4%, 87.5% for IS4, IS3, IS2, IS1, IS0, respectively. Conclusions Immunoscore® is a robust prognostic indicator of the risk of recurrence in stage I CC. This risk assessment tool reliably identifies a sub-group of patients with an increased risk of relapse for whom a more intensive surveillance program after curative resection may be recommended

Significant differences in outcome between Immunoscore categories in stage I colon cancer patients.

Introduction: Immunoscore® is an in vitro diagnostic test that predicts the risk of relapse in patients with early-stage Colon Cancer (CC) by measuring the host immune response at the tumor site. It is a risk-assessment tool that provides independent and superior prognostic value than traditional risk parameters and is intended to be used as an adjunct to the TNM classification. Currently, the target population for Immunoscore is stage II & III CC patients, for whom individual risk-assessment plays a critical role to guide post-surgery decisions. In stage I, survival rates are high and adjuvant chemotherapy is not typically recommended. However, approximately 10% of stage I CC tumors will recur even after surgical resection. Methods: A subgroup analysis was performed on the stage I patients (n = 451) from the Immunoscore international validation study (Pagès et al. The Lancet 2018). Patients were classified by Immunoscore based on pre-defined cutoffs, either in 5 (IS 0-4) or in 3 categories: IS Low (IS0-1), Intermediate (IS 2), High (IS 3-4). Time to recurrence (TTR) was compared between Immunoscore categories. Results: Immunoscore High, Intermediate and Low were observed in 39%, 47% and 14% of the cohort, respectively. Immunoscore was positively and significantly correlated with TTR. After 5 years, 97.1% of Immunoscore High patients were event-free (95% CI 94.3-100.0), followed by 94.9% for Immunoscore Intermediate (95% CI 91.7-98.2) and 91.0% for Immunoscore Low patients (95% CI 83.8-98.9) (unadjusted and stratified by participating center HRlow vs high=4.86; 95% CI 1.35 − 17.44; p = 0.0155). When adjusting the model with Immunoscore, age, gender, T-stage sidedness and MSI, Immunoscore remained the sole significant parameter (stratified by participating center HRlow vs high=7.82; 95% CI 1.49 − 41.01; p = 0.015), with the highest relative contribution (chi-squared proportion (χ2) =62%) compared to the other parameters in the model. Similar significant results were found using the Immunoscore percentiles as a numeric continuous parameter. The robust correlation between Immunoscore classification and TTR was further corroborated by a separate analysis of the same cohort distributed into five IS categories (IS 0-4): Immunoscore classification – Events/total number of patients (%) – 5y event-free survival IS4 – 1/27 (6%) – 100% IS3 – 4/149 (33%) – 96.6% IS2 – 13/214 (47%) – 94.9% IS1 – 4/45 (10%) – 90.5% IS0 – 2/16 (4%) – 92.3% Conclusion: Immunoscore® is a robust prognostic indicator of the risk of recurrence in stage I CC. This risk assessment tool reliably identifies a sub-group of patients with an increased risk of relapse for whom a more intensive surveillance program after curative resection may be recommended

79O Clinical performance of Immunoscore® in early colon cancer in the Asian population

Background Immunoscore® is an in vitro diagnostic test predicting the risk of relapse in early-stage Colon Cancer (CC), by measuring the host immune response at the tumor site. This risk-assessment tool provides independent and superior prognostic value than the usual risk parameters and is intended to be used as an adjunct to the TNM classification for clinical decision. In the present study, we investigated Immunoscore® clinical performance in the Asian population from the international SITC-led validation study (Pagès et al. The Lancet 2018). Methods Out of the 2681 eligible stage I-III patients of the international Immunoscore® study, 423 were collected from 4 expert centers in Asia including Japan (n=330), China (n=35), and India (n=58). Patients were classified by Immunoscore® based on pre-defined cutoffs, either in 5 (IS 0-4) or 2 categories: IS Low (IS 0-1) and IS High (IS 2-4). Time to recurrence (TTR) was compared between Immunoscore® categories. Results Immunoscore® Low and High were observed in 37% (n=158) and 63% (n=265) of the Asian cohort, respectively. Immunoscore® was positively and significantly correlated with TTR. After 5 years, 86.9% (95% CI 82.7-91.4), and 77% (95% CI 70,5-84,1) of Immunoscore -High and -Low patients respectively were event free (HR =0.52; 95% CI 0.32-0.86; p=0.0085). When adjusting the model with Immunoscore®, age, gender, T-stage, N-stage, sidedness and MSI, and when stratified by center, Immunoscore® remained a significant parameter (HR=0.45; 95% CI 0.22-0.91; p=0.027). When stratified into 5 Immunoscore® categories, TTR rates at 5 years were 100%, 96%, 84%, 80%, and 73.5% for IS4, IS3, IS2, IS1, IS0, respectively. These results were similar to those found in European and North American patients. Conclusions Immunoscore® is a strong prognostic indicator of the risk of recurrence in stage I-III CC patients who receive standard of care treatment in real-life clinical practice in Asia. This first standardized immune-based assay risk assessment tool can be used reliably to guide clinical decision according to each patient information

Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study

International audienceBackground: The Immunoscore (IS), which prognostically classifies stage I–III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients.Patients and methods: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance.Results: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24–1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23–70.94) for IS Low and 77.14% (95% CI 73.50–80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37–0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6.Conclusions: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. ClinicalTrials.gov registration: NCT03422601; EudraCT Number: 2009-010384-16

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

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