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Loss of BRCA1 Protein Expression as Indicator of the BRCAness Phenotype Is Associated With Favorable Overall Survival After Complete Resection of Sporadic Ovarian Cancer
  1. Marc P. Radosa, MD,
  2. Norman Häfner, PhD,
  3. Oumar Camara, MD,
  4. Herbert Diebolder, MD,
  5. Anke Mothes, MD,
  6. Harald Winzer, MD,
  7. Lars Jansen,
  8. Matthias Dürst, PhD and
  9. Ingo B. Runnebaum, MD, MBA
  1. Department of Gynecology and Obstetrics, Jena University Hospital, Jena, Germany.
  1. Address correspondence and reprint requests to Ingo B. Runnebaum, MD, MBA, Department of Gynecology and Obstetrics, Jena University Hospital, Bachstrasse 18, 07743 Jena, Germany. E-mail: ingo.runnebaum{at}med.uni-jena.de.

Abstract

Objective: Hereditary epithelial ovarian cancers (EOCs) not expressing functional BRCA1 protein are characterized by defects in homologous recombination DNA repair, rendering such tumors more sensitive to DNA damaging agents and synthetic lethality, that is, poly-ADP-ribose-polymerase inhibitor treatment. The aim of this study was to evaluate the use of BRCA1 immunohistochemistry (IHC) for EOC prognosis and identification of features of the BRCAness phenotype.

Methods: Twenty-seven patients who were treated for advanced EOC by macroscopic complete surgical tumor resection and first-line carboplatin/paclitaxel treatment were included. Time to recurrence and overall survival time after initial surgery were determined, and patients' samples were evaluated for BRCA1 expression by IHC. BRCA1 messenger RNA expression and promoter methylation was analyzed to elucidate regulatory mechanisms involved in BRCA1 protein loss.

Results: BRCA1 IHC-negative patients had a significantly longer overall survival (crude rate, 1537 days) compared to the BRCA1 IHC-positive group (crude rate, 827 days; P = 0.01). The patients in the BRCA1 IHC-negative group were significantly younger (51 years) compared to BRCA1 IHC-positive patients (61 years; P < 0.01). Importantly, both transcriptional and posttranscriptional mechanisms regulate BRCA1 protein expression. Only protein but not messenger RNA level were associated with longer overall survival.

Conclusion: Epithelial ovarian cancers with negative BRCA1 protein expression were identified in younger patients, showed a significantly better overall survival, prolonged treatment intervals and a tendency for an extended progression free time interval. BRCA1 IHC negativity of sporadic EOC may be predictive of sensitivity to platinum-based chemotherapy and the poly-ADP-ribose-polymerase inhibitor-sensitive BRCAness phenotype.

  • Sporadic epithelial ovarian cancer
  • BRCA1
  • Prognostic marker
  • Gene expression regulation
  • BRCAness

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Footnotes

  • Radosa and Häfner contributed equally to this work.

  • The authors declare that they have no conflicts of interest.

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