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

Cancer Med. 2021 Jul;10(14):4743-4751. doi: 10.1002/cam4.4034. Epub 2021 Jun 2.

Abstract

Objective: Neuroendocrine cervical cancer (NECC) is a rare cervical cancer with high aggressivity that causes poor prognosis even in the early stage. Given other neuroendocrine carcinomas and other types of cervical cancer have been proved to have expression of programmed cell death protein 1 ligand 1(PD-L1) and poly ADP-ribose polymerase-1(PARP1), we would measure and analyze these proteins in this invasive cancer. The purpose of this study is to investigate the application value of PD-1/PD-L1 and PARP1 inhibitors in NECC.

Methods: The NECC cases in our center with formalin-fixed paraffin-embedded tissue blocks were collected, and immunohistochemical (IHC) staining of PD-L1, PARP1, Mismatch repair proteins (MMRs), and P53 was performed. Chi-square test was used to analyze associations between various protein expressions. We analyzed the efficacy of immunotherapy in a recent patient with secondary recurrence after two courses of chemotherapy.

Results: After rigorous screening, 20 cases were finally included. Three cases did not undergo surgical treatment because of their advanced stage. Twelve (60%) developed distant metastases or relapsed within five years, and most of them within two years. The positive rate of PD-L1 and PARP1 were 70% and 75% respectively. Among all the cases, microsatellite instability (MSI) was seen in six cases (30%) and abnormal p53 expression was in 15 patients (75%). PD-L1 was associated with PARP1 expression in the MSI subgroup. The patient treated with chemotherapy + VEGF inhibitor (VEGFi) + programmed cell death protein 1(PD-1) inhibitor had an excellent improvement in clinical symptoms, tumor markers, and mass size.

Conclusion: The IHC results of PD-L1, PARP1, and MMRs suggested that NECC was the target of immunotargeted therapy. Our case confirmed that immune checkpoint therapy was effective in patients with PD-L1 positive and MMRs loss. Considering the clinical practicability, more cases should be collected, and effective biomarkers still need to be further searched.

Keywords: PARP1; PD-L1; immunotherapy; mismatch repair proteins; neuroendocrine cervical cancer; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B7-H1 Antigen / analysis*
  • Biomarkers, Tumor / analysis
  • Carcinoma, Neuroendocrine / chemistry*
  • Carcinoma, Neuroendocrine / secondary
  • Carcinoma, Neuroendocrine / therapy
  • DNA-Binding Proteins / analysis*
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy / methods
  • Microsatellite Instability
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2 / analysis
  • Molecular Targeted Therapy / methods
  • MutL Protein Homolog 1 / analysis
  • MutS Homolog 2 Protein / analysis
  • Neoplasm Recurrence, Local / therapy
  • Poly (ADP-Ribose) Polymerase-1 / analysis*
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / analysis
  • Uterine Cervical Neoplasms / chemistry*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / therapy

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Immune Checkpoint Inhibitors
  • MLH1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein