Delta-Like Protein 3 Expression and Targeting in Merkel Cell Carcinoma

Abstract

Purpose: Delta-like protein 3 (DLL3) is being developed as a predictive biomarker for DLL3-targeting antibody-drug conjugate and other therapies. Given the neuroendocrine features of Merkel cell carcinoma (MCC), we sought to evaluate DLL3 expression and its role in MCC.

Experimental design: Formalin-fixed and paraffin-embedded MCC cases were consecutively selected. Immunohistochemistry was performed for DLL3 (SC16.65 antibody) and polyomavirus large T-antigen (sc-136172 antibody). Slides were read out for percentage of positive tumor cells. Cox proportional hazards model was applied to assess the association between DLL3 expression and overall survival (OS). A patient with a DLL3-expressing MCC was treated with rovalpituzumab tesirine (Rova-T) in the "other tumor" cohort of NCT02709889 and assessed for response.

Results: The median H-score of DLL3 expression of 65 patients included was 60 (interquartile range, 30-100). Fifty-eight cases (89%) had ≥1% tumor cells positive for DLL3 expression with any intensity, of which the median DLL3 expression was 50% (interquartile range, 25%-70%). Thirty-four cases (52%) had ≥50% tumor cells positive for DLL3 expression with any intensity. Higher H-score of DLL3 expression was associated with higher polyomavirus nuclear expression (p = .003) when it was dichotomized to negative versus positive. H-score of DLL3 expression did not predict OS of patients with MCC (p = .4) after being adjusted for common clinicopathological factors. A patient treated with Rova-T for refractory metastatic MCC achieved partial response.

Conclusions: DLL3 overexpression is very common in MCC by immunohistochemistry. The response to treatment suggests that DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC.

Implications for practice: Delta-like protein 3 (DLL3) is being developed as a predictive biomarker to identify patients for treatment with DLL3-targeting agents. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. It was found that DLL3 overexpression is very common in MCC by immunohistochemistry and significantly associated with Merkel cell polyomavirus expression. Despite the lack of prognostic significance in this cohort, DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. The high levels of DLL3 expression in a subset of MCC may potentially be used to select patients to receive DLL3-targeting therapies.

Keywords: Biomarker; DLL3; Merkel cell carcinoma; Rovalpituzumab tesirine.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

© AlphaMed Press 2020.

Figures

Figure 1

Merkel cell polyomavirus immunohistochemistry. (A): H&E section. (B): Tumor positive for Merkel cell polyomavirus (MCPyV). (C): H&E section. (D): Tumor negative for MCPyV. Original magnification 400× for all images.

Figure 2

DLL3 prevalence in Merkel cell carcinoma. (A): DLL3 expression by immunohistochemisty with magnification 20× and its prevalence in Merkel cell carcinoma (MCC). (B): Higher DLL3 expression is associated with positive MCPyV expression in MCC. Abbreviations: DLL3, Delta‐like protein 3; MCPyV, Merkel cell polyomavirus.

Figure 3

The Kaplan‐Meier curve for overall survival stratified by DLL3 expression in patients with Merkel cell carcinoma. Patients were censored at the time of last follow‐up if they were alive. Abbreviation: DLL3, Delta‐like protein 3.

Figure 4

A patient with Delta‐like protein 3 (DLL3)–positive metastatic Merkel cell carcinoma achieved radiographic partial response to rovalpituzumab tesirine based on RECIST criteria. The changes of three largest target lesions were shown in computed tomography scans prior to cycle 1, cycle 2, and cycle 3 rovalpituzumab tesirine, respectively.