Nuclear HER3 expression improves the prognostic stratification of patients with HER1 positive advanced laryngeal squamous cell carcinoma

Abstract

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.

Recent findings on the impact of ErbB receptors status on prognosis and therapy of head and neck squamous cell carcinoma

“…Evidence in this respect comes from studies on laryngeal HNSCC in which ErbB3 was primarily observed in the nuclear compartment of tumor cells in association with variable cytoplasmic staining, and low expression levels of the receptor were associated with high proliferative indices, and with shorter relapse-free and overall survival (88,91). Further, EGFR-positive laryngeal tumors co-expressing nuclear ErbB3 had a better prognosis as compared to those that expressed EGFR without ErbB3 or in association with cytoplasmic ErbB3 (87). Moreover, based on the observation that ErbB3 was never expressed alone, but always co-expressed with ErbB2, both in the presence and absence of EGFR, the authors of these studies speculated that ErbB3 nuclear localization may play a favorable role by preventing the formation of ErbB heterodimers at the cell membrane and the ensuing activation of pro-tumoral downstream signaling pathways (87).…”

Bioradiotherapy with Cetuximab May Reduce the Risk of Neck Node Relapse in Locoregionally Advanced Laryngeal Glottic Carcinoma: May HER1-Profile Be Useful in the Bioselection of Patients?

“…In our previous studies, a close correlation was observed between the presence of high HER1 expression and a lower MFS; moreover, analysis of logarithmically transformed HER1 values showed that the risk of neck node relapse increased significantly with higher HER1 values, resulting in HER1 expression as an independent predictor of higher metastatic propensity [34,39]. The latter, in fact, is a prognostic factor of the clinical outcome [42], a biomarker of resistance to RT [45], and a target of cetuximab action [26,46].…”

“…Subsequently, lower progression-free survival (PFS) was documented in HNSCC overexpressing EGFR [40,41]. Overexpression of other receptor tyrosine kinases, including HER2, HER3, MPM7, and coexpression of all four HER family member (HER1, HER2, HER3, HER4) receptors, also may contribute to tumor resistance to EGFR-targeting agents [26,[42][43][44].…”

“…HER1 expression in tumor cells was evaluated by immunohistochemistry (IHC) on formalin-fixed and paraffin-embedded tumor tissues, according to standard procedures. Tumor samples from both groups of patients were processed by the same standardized IHC procedures, utilizing anti-HER1 (clone H11, dilution 1:150; Dako, Milano, Italy) monoclonal antibody; the procedure for quantizing the results was previously reported [26].…”

“…Effective personalized medicine approaches, including the evaluation of biomarker-driven targeted therapies, are lacking in this disease. Detailed molecular characterization, as well as immune profiling of LSCC, suggests that the incorporation of new prognostic and predictive biomarkers into clinical management may overcome obstacles to targeted therapies and enable prolonged survival [26]. Additional studies are needed to identify more homogeneous subgroups of tumors with the molecular characterization that may benefit from concomitant cetuximab treatment.…”