The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer Journal Article


Authors: Meisel, J. L.; Hyman, D. M.; Garg, K.; Zhou, Q.; Dao, F.; Bisogna, M.; Gao, J.; Schultz, N. D.; Grisham, R. N.; Phillips, M.; Iasonos, A.; Kauff, N. D.; Levine, D. A.; Soslow, R. A.; Spriggs, D. R.
Article Title: The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer
Abstract: Background: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. Patients and methods: Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. Results: Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). Conclusions: BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.
Keywords: immunohistochemistry; survival; protein expression; ovarian cancer; biomarkers; carcinoma; brca1; genetic testing; resistance; olaparib; mutations; breast-cancer; cells; sensitivity; hypermethylation
Journal Title: Annals of Oncology
Volume: 25
Issue: 12
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2014-12-01
Start Page: 2372
End Page: 2378
Language: English
ACCESSION: WOS:000345825800010
DOI: 10.1093/annonc/mdu461
PROVIDER: wos
PMCID: PMC4271017
PUBMED: 25281711
Notes: Article -- Source: Wos
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MSK Authors
  1. Noah Kauff
    122 Kauff
  2. Douglas A Levine
    356 Levine
  3. Qin Zhou
    120 Zhou
  4. Alexia Elia Iasonos
    179 Iasonos
  5. Rachel Nicole Grisham
    35 Grisham
  6. Robert Soslow
    643 Soslow
  7. David Hyman
    187 Hyman
  8. David R Spriggs
    314 Spriggs
  9. Karuna Garg
    74 Garg
  10. Jianjiong Gao
    62 Gao
  11. Fanny Dao
    56 Dao
  12. Nikolaus D Schultz
    202 Schultz
  13. Jane Lowe Meisel
    9 Meisel