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

Abstract

ObjectivesWomen 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.MethodsSpecimens 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.ResultsForty 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%).ConclusionsPure 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.

PD‐L1, PARP1, and MMRs as potential therapeutic biomarkers for neuroendocrine cervical cancer

“… 33 In another study of PD‐L1 and PARP1 expression of NECC, the positive expression rate of PD‐L1 was only 8%. 34 These results are different from our results. The reason for this result may be that the evaluation criteria of PD‐L1 positive are different, and the small sample size of NECC study is also the reason for this difference that can not be ignored.…”

Expanding Our Impact in Cervical Cancer Treatment: Novel Immunotherapies, Radiation Innovations, and Consideration of Rare Histologies

“…64 A systematic review highlighted the importance of a similar spectrum of mutations including p52, KRAS, PIK3CA, and c-Myc and also identified loss of heterozygosity in 30% of cases. 65,66 Additionally, somatic BRCA mutations have been reported, as well as recent data indicating a high rate of sPARP-1 mutations. 6769 Evaluation for PD-L1 expression and microsatellite instability has been found to be universally negative in these studies.…”

PD-L1, Mismatch Repair Protein, and NTRK Immunohistochemical Expression in Cervical Small Cell Neuroendocrine Carcinoma

“…Cervical SCNC is a rare type of cervical carcinoma; there are only a few reports focusing on the MMR of cervical SCNC. One study found that 3 out of 9 cases were dMMR in cervical SCNC ( 7 ), while the other indicated an MMR stable status in all 28 cases of cervical SCNC ( 8 ). Our results are in line with the latter report and ours is also the largest number of cervical SCNC cases investigated, and therefore improves the reliability of MMR data for such rare tumors.…”