Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix.

Objectives: Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease.

Methods: Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40-100 moderate, and ≥100 high.

Results: Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%).

Conclusions: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.