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Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix
  1. Matthew Ryan Carroll1,
  2. Preetha Ramalingam2,
  3. Gloria Salvo3,
  4. Junya Fujimoto4,
  5. Luisa Maren Solis Soto4,
  6. Natacha Phoolcharoen3,
  7. Robert Tyler Hillman3,
  8. Robert Cardnell5,
  9. Lauren Byers6 and
  10. Michael Frumovitz3
  1. 1 Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
  2. 2 Pathology, MD Anderson Cancer Center, Houston, Texas, USA
  3. 3 Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  4. 4 Molecular and Translational Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5 Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6 Thoracic/Head & Neck Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr Michael Frumovitz, Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77057, USA; mfrumovitz{at}mdanderson.org

Abstract

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.

  • neuroendocrine tumors
  • cervical cancer
  • pathology
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Footnotes

  • Twitter @frumovitz

  • Contributors MRC analyzed data and drafted the manuscript. PR was involved in study design, data collection, analysis, and manuscript review. JF, GS, LMSS, NP, RTH and RC were involved with data collection, analysis, and manuscript review. LB and MF were responsible for data collection, analysis, study design, and manuscript review. All authors had approval of the final version of the manuscript.

  • Funding Supported by a grant from the Allyson Whitney Foundation and the NIH/NCI under award numbers R01-CA207295 and P5-CA070907. Supported by a grant from UT Lung SPORE (P50CA070907).

  • Competing interests LB has served as a consultant for Medivation, AbbVie, BioMarin Pharmaceutical, Lilly Humana, LUNGevity. She has served on Scientific Advisory Committees for AstraZeneca Pharmaceuticals, StemCentrx, Astex Therapeutics, GENMAB. MF has served as a consultant for Stryker, Genetench, and Ipsen and as a speaker for Stryker and gets research funding from Tesaro/GSK and Astra Zeneca.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article.

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