Roberto Moretto1, Salvatore Corallo2, Antonino Belfiore3, Daniele Rossini4, Alessandra Boccaccino4, Sara Lonardi5, Giovanni Centonze3, Federica Morano2, Marco Maria Germani4, Fotios Loupakis5, Luca Morelli6, Lucio Urbani7, Silvia Brich3, Federica Marmorino4, Michele Prisciandaro2, Giuseppe Aprile8, Matteo Fassan9, Umberto Cillo10, Laura Cattaneo3, Gabriella Fontanini11, Filippo De Braud12, Alfredo Falcone4, Massimo Milione3, Filippo Pietrantonio12, Chiara Cremolini13. 1. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 2. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy. 3. Department of Pathology and Laboratory Medicine, First Pathology Division, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy. 4. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy. 5. Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy. 6. Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy; 1st General Surgery Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 7. General Surgery Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 8. Department of Oncology, San Bortolo General Hospital, Vicenza, Italy. 9. Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy. 10. Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncologic and Gastroenterologic Sciences "P.G. Cevese", University Hospital of Padua, Padua, Italy. 11. Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, AOU Pisana, Pisa, Italy. 12. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy. 13. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address: chiaracremolini@gmail.com.
Abstract
BACKGROUND: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. METHODS: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. RESULTS: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. CONCLUSIONS: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.
BACKGROUND: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. METHODS: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. RESULTS: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. CONCLUSIONS: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.