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.
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.
Authors: Karuna Garg; Douglas A Levine; Narciso Olvera; Fanny Dao; Maria Bisogna; Angeles Alvarez Secord; Andrew Berchuck; Ethan Cerami; Nikolaus Schultz; Robert A Soslow Journal: Am J Surg Pathol Date: 2013-01 Impact factor: 6.394
Authors: J L Meisel; D M Hyman; K Garg; Q Zhou; F Dao; M Bisogna; J Gao; N D Schultz; R N Grisham; M Phillips; A Iasonos; N D Kauff; D A Levine; R A Soslow; D R Spriggs Journal: Ann Oncol Date: 2014-10-03 Impact factor: 32.976
Authors: Roshni D Kalachand; Britta Stordal; Stephen Madden; Benjamin Chandler; Julie Cunningham; Ellen L Goode; Ilary Ruscito; Elena I Braicu; Jalid Sehouli; Atanas Ignatov; Herbert Yu; Dionyssios Katsaros; Gordon B Mills; Karen H Lu; Mark S Carey; Kirsten M Timms; Jolanta Kupryjanczyk; Iwona K Rzepecka; Agnieszka Podgorska; Jessica N McAlpine; Elizabeth M Swisher; Sarah S Bernards; Ciaran O'Riain; Sharon O'Toole; John J O'Leary; David D Bowtell; David M Thomas; Katharina Prieske; Simon A Joosse; Linn Woelber; Parvesh Chaudhry; Norman Häfner; Ingo B Runnebaum; Bryan T Hennessy Journal: J Natl Cancer Inst Date: 2020-12-14 Impact factor: 13.506