Molecular profiling reveals novel targetable biomarkers in neuroendocrine carcinoma of the uterine cervix


Semir Vranic, David Arguello, Elma Contreras, Adela Cimic, Zoran Gatalica


Neuroendocrine carcinoma of the uterine cervix (NEC) is a rare cervical malignancy, accounting for 0.9% of all cervical carcinomas. Cervical NEC is a high-grade cancer with an aggressive clinical course and poor outcome. Given that no target therapy has been approved yet for NEC, we explored novel targetable biomarkers in a large cohort of NEC of the cervix.

Materials and Methods:

Sixty-two NEC of the cervix were profiled for biomarkers of targeted therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), tropomyosin receptor kinases (NTRK1/2/3 gene fusions), and immune checkpoint inhibitors (PD-L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays.


The study included 36 primary and 26 metastatic cervical NEC. The mean patient’s age was 43.6 years (range, 24-82 years). DLL3 expression was observed in 81% of the cases with 49% of cases expressing diffusely (≥50% of positive cancer cells) DLL3 protein. DLL3 expression was inversely correlated with commonly observed mutations: PIK3CA (17%) (p=0.018) and PTEN mutations (10%) (p=0.006). Other frequently seen mutations (TP53 17%, KRAS 11% and CTTNB1 5%) were not associated with DLL3 expression. PD-L1 expression was observed in 10% of the cases while high TMB was seen in a single case. Although NTRK protein expression was observed in 21% of the cases, none of these had confirmatory NTRK gene fusions. TROP-2 was positive in one case while FOLR1 showed no expression in any of the tested cases.


PIK3CA/PTEN pathway genes may be potential therapeutic targets for a substantial proportion of the patients NEC of the cervix. DLL3 protein expression also characterizes the majority of cervical NEC. A therapeutic benefit of DLL3-targeted drugs remains uncertain given the recent suspension of the Rova T trial after it failed to show a therapeutic benefit in SCLC patients. Based on I-O biomarkers status, only minority of the patients with cervical NEC might benefit from immune checkpoint inhibitors.

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