PMID- 34579737 OWN - NLM STAT- MEDLINE DCOM- 20211101 LR - 20220531 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 19 IP - 1 DP - 2021 Sep 27 TI - Nuclear HER3 expression improves the prognostic stratification of patients with HER1 positive advanced laryngeal squamous cell carcinoma. PG - 408 LID - 10.1186/s12967-021-03081-0 [doi] LID - 408 AB - BACKGROUND: Compared to the other members of human epidermal growth factor family receptors (HER), the role of HER3 has not been well defined in laryngeal cancer. The predictive and prognostic role of HER3 has been the focus of clinical attention but the research findings are contradictory, especially in laryngeal squamous cell carcinoma (LSCC). The variable localization of HER3 within cancer cells and the role of HER3 in primary and acquired resistance to HER1-targeted therapies remain unclear. METHODS: We performed a retrospective analysis of two cohorts of 66 homogeneous consecutive untreated primary advanced LSCC patients, in which co-expression of HER1, HER2 and HER3 receptors was investigated by semi-quantitative immunohistochemistry. The association of their pattern of expression with survival was evaluated by Kaplan-Meier and Cox's proportional hazard analyses. Multivariable Cox proportional hazards models were developed to predict median 2- and 3-year RFS and 2.5- and 5-year OS. The Akaike information criterion technique and backwards stepwise procedure were used for model selections. The performance of the final Cox models was assessed with respect to calibration and discrimination. RESULTS: Immunohistochemical labeling for HER1 and HER2 was localized both in the cell membrane and in the cytoplasm, while HER3 labeling was observed both in the cell cytoplasm and in the nucleus. HER3 expression was inversely correlated with HER1 positivity. The expression patterns of HERs were associated with tumor differentiation. In both cohorts of patients, HER1 expression was associated with reduced relapse-free (RFS) and overall survival (OS). In HER1 positive tumors, the co-expression with nuclear HER3 was associated with better RFS and OS, compared with HER3 negative tumors or tumors expressing HER3 at cytoplasmic level. HER3 expressing tumors had a higher Geminin/MCM7 ratio than HER3 negative ones, regardless of HER1 co-expression. Multivariable analyses identified age at diagnosis, tumor site, HER1, HER3 and age at diagnosis, tumor stage, HER1, HER3, as covariates significantly associated with RFS and OS, respectively. Bootstrapping verified the good fitness of these models for predicting survivals and the optimism-corrected C-indices were 0.76 and 0.77 for RFS and OS, respectively. CONCLUSIONS: Nuclear HER3 expression was strongly associated with favourable prognosis and allows to improve the prognostic stratification of patients with HER1 positive advanced LSCC carcinoma. CI - (c) 2021. The Author(s). FAU - Almadori, Giovanni AU - Almadori G AUID- ORCID: 0000-0002-4605-2442 AD - Unit of Head and Neck Oncology, "A. Gemelli" University Hospital Foundation IRCCS-Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168, Rome, Italy. almgio@yahoo.it. AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. almgio@yahoo.it. AD - Universita Cattolica del Sacro Cuore, Roma, Italy. almgio@yahoo.it. FAU - Coli, Antonella AU - Coli A AD - Universita Cattolica del Sacro Cuore, Roma, Italy. AD - Unit of Anatomic Pathology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - De Corso, Eugenio AU - De Corso E AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Mele, Dario Antonio AU - Mele DA AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Settimi, Stefano AU - Settimi S AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Di Cintio, Giovanni AU - Di Cintio G AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Brigato, Francesca AU - Brigato F AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Scannone, Domenico AU - Scannone D AD - Unit of Anatomic Pathology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Carey, Thomas E AU - Carey TE AD - Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Paludetti, Gaetano AU - Paludetti G AD - Unit of Otorhinolaryngology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. AD - Universita Cattolica del Sacro Cuore, Roma, Italy. FAU - Lauriola, Libero AU - Lauriola L AD - Universita Cattolica del Sacro Cuore, Roma, Italy. AD - Unit of Anatomic Pathology, "A. Gemelli" University Hospital Foundation IRCCS, Roma, Italy. FAU - Ranelletti, Franco Oreste AU - Ranelletti FO AD - Department of Histology, Universita Cattolica del Sacro Cuore, Roma, Italy. LA - eng PT - Journal Article DEP - 20210927 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (Biomarkers, Tumor) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-3) SB - IM MH - Biomarkers, Tumor MH - *Head and Neck Neoplasms MH - Humans MH - *Laryngeal Neoplasms MH - Neoplasm Recurrence, Local MH - Prognosis MH - Receptor, ErbB-3/genetics MH - Retrospective Studies MH - Squamous Cell Carcinoma of Head and Neck PMC - PMC8477517 OTO - NOTNLM OT - HER family receptors OT - HER phenotypes OT - HER1 OT - HER1-HER3 co-expression OT - Laryngeal squamous cell carcinoma OT - Nuclear HER3 OT - Prognostic role OT - Tumor differentiation COIS- The authors declare that they have no competing interests. EDAT- 2021/09/29 06:00 MHDA- 2021/11/03 06:00 PMCR- 2021/09/27 CRDT- 2021/09/28 05:36 PHST- 2021/07/02 00:00 [received] PHST- 2021/09/14 00:00 [accepted] PHST- 2021/09/28 05:36 [entrez] PHST- 2021/09/29 06:00 [pubmed] PHST- 2021/11/03 06:00 [medline] PHST- 2021/09/27 00:00 [pmc-release] AID - 10.1186/s12967-021-03081-0 [pii] AID - 3081 [pii] AID - 10.1186/s12967-021-03081-0 [doi] PST - epublish SO - J Transl Med. 2021 Sep 27;19(1):408. doi: 10.1186/s12967-021-03081-0.