Matteo Fassan1, Massimo Milione2, Giulia Maddalena3, Chiara Cremolini4, Marta Schirripa3, Filippo Pietrantonio5, Nicoletta Pella6, Emanuela Dell'Aquila7, Elisa Sperti8, Clizia Zichi8, Francesca Bergamo3, Marco Volante9, Alessandra Boccaccino4, Federica Morano10, Francesco Cortiula11, Giovanna De Maglio12, Lorenza Rimassa13, Valeria Smiroldo14, Lorenzo Calvetti15, Giuseppe Aprile15, Lisa Salvatore16, Daniele Santini7, Roberta Salmaso17, Giovanni Centonze2, Paola Biason3, Chiara Borga17, Sara Lonardi3, Vittorina Zagonel3, Angelo P Dei Tos17, Massimo Di Maio8, Fotios Loupakis18. 1. Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy. Electronic address: matteo.fassan@unipd.it. 2. 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy. 3. Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 4. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. 5. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy. 6. Department of Oncology, University and General Hospital, Udine, Italy. 7. Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy. 8. Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy. 9. Department of Oncology, University of Turin at San Luigi Hospital, Orbassano (TO), Italy. 10. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 11. Department of Oncology, University and General Hospital, Udine, Italy; Department of Medicine (DAME), University of Udine, Italy. 12. Department of Pathology, University Hospital of Udine, Udine, Italy. 13. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy. 14. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. 15. Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy. 16. U.O.C Oncologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy. 17. Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy. 18. Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. Electronic address: fotios.loupakis@iov.veneto.it.
Abstract
BACKGROUND: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. METHODS: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests. RESULTS: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001). CONCLUSIONS: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
BACKGROUND: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. METHODS: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests. RESULTS: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001). CONCLUSIONS: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.