BJOG. 2021 Oct 17; doi: 10.1111/1471-0528.16975. Epub 2021 Oct 17.

The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.

BJOG : an international journal of obstetrics and gynaecology

B Frugtniet, S Morgan, A Murray, S Palmer-Smith, R White, R Jones, L Hanna, C Fuller, E Hudson, A Mullard, A E Quinton

PMID: 34657373 DOI: 10.1111/1471-0528.16975

Abstract

OBJECTIVE: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing.

DESIGN: National retrospective audit.

SETTING: The All Wales Medical Genomics Service (AWMGS).

POPULATION: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS.

METHODS: Analysis of NGS data from germline and/or tumour testing.

MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 pathogenic variants.

RESULTS: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone.

CONCLUSIONS: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer.

TWEETABLE ABSTRACT: Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer.

© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.

Keywords: BRCA; germline; mainstreamed; oncology-led; ovarian cancer; pathogenic variant; somatic

References

1. Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 2019;381:2416-28. - PubMed
2. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852-61. - PubMed
3. Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, McNeish IA, Swisher EM, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol 2017;147:267-75. - PubMed
4. Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495-505. - PubMed
5. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-61. - PubMed
6. Mohyuddin GR, Aziz M, Britt A, Wade L, Sun W, Baranda J, et al. Similar response rates and survival with PARP inhibitors for patients with solid tumors harboring somatic versus Germline BRCA mutations: a meta-analysis and systematic review. BMC Cancer 2020;20:507. - PubMed
7. Kuchenbaecker KB, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017;317:2402-16. - PubMed
8. Lewis KE, Lu K, Klimczak A, Mok S. Recommendations and choices for BRCA mutation carriers at risk for ovarian cancer: a complicated decision. Cancers 2018;10:57. - PubMed
9. Rust K, Spiliopoulou P, Tang CY, Bell C, Stirling D, Phang T, et al. Routine germline BRCA1 and BRCA2 testing in patients with ovarian carcinoma: analysis of the Scottish real-life experience. BJOG 2018;125:1451-8. - PubMed
10. Rahman B, Lanceley A, Kristeleit RS, Ledermann JA, Lockley M, McCormack M, et al. Mainstreamed genetic testing for women with ovarian cancer: first-year experience. J Med Genet 2019;56:195-8. - PubMed
11. Rumford M, Lythgoe M, McNeish I, Gabra H, Tookman L, Rahman N, et al. Oncologist-led BRCA 'mainstreaming' in the ovarian cancer clinic: a study of 255 patients and its impact on their management. Sci Rep 2020;10:3390. - PubMed
12. George A, Riddell D, Seal S, Talukdar S, Mahamdallie S, Ruark E, et al. Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients. Sci Rep 2016;6:29506. - PubMed
13. Plaskocinska I, Shipman H, Drummond J, Thompson E, Buchanan V, Newcombe B, et al. New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. J Med Genet 2016;53:655-61. - PubMed
14. Flaum N, Morgan RD, Burghel GJ, Bulman M, Clamp AR, Hasan J, et al. Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England. Eur J Hum Genet 2020;28:1541-7. - PubMed
15. Koczkowska M, Zuk M, Gorczynski A, Ratajska M, Lewandowska M, Biernat W, et al. Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases. Cancer Med 2016;5:1640-6. - PubMed
16. Eoh KJ, Kim HM, Lee J-Y, Kim S, Kim SW, Kim YT, et al. Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer. BMC Cancer 2020;20:204. - PubMed
17. Peixoto A, Pinto P, Guerra J, Pinheiro M, Santos C, Pinto C, et al. Tumor testing for somatic and germline BRCA1/BRCA2 variants in ovarian cancer patients in the context of strong founder effects. Front Oncol 2020;10:1318. - PubMed
18. Kansu B, Gardner J, Price-Tate R, Murch O, Murray A. BRCA gene testing in women with high-grade serous ovarian carcinoma. J Obstet Gynaecol 2020;41:962-5. - PubMed
19. Sundar S, Manchanda R, Gourley C, George A, Wallace A, Balega J, et al. British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for germline and tumor testing for BRCA1/2 variants in ovarian cancer in the United Kingdom. Int J Gynecol Cancer 2021;31:272-8. - PubMed
20. Ellard S, Baple EL, Berry I. ACGS best practice guidelines for variant classification in rare disease 2020. Assoc Clin Genomic Sci (ACGS) 2020:1-33. https://www.acgs.uk.com/quality/best-practice-guidelines/ - PubMed
21. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24. - PubMed
22. Garrett A, Callaway A, Durkie M, Cubuk C, Alikian M, Burghel GJ, et al. Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network. J Med Genet 2020;57:829-34. - PubMed
23. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012;30:2654-63. - PubMed
24. The BRCA Exon Duplication Screening Group. The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. The BRCA1 Exon 13 Duplication Screening Group. Am J Hum Genet 2000;67:207-12. - PubMed
25. Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol 2020;38:1222-45. - PubMed
26. Grellety T, Peyraud F, Sevenet N, Tredan O, Dohollou N, Barouk-Simonet E, et al. Dramatic response to PARP inhibition in a PALB2-mutated breast cancer: moving beyond BRCA. Ann Oncol 2020;31:822-3. - PubMed
27. Kuemmel S, Harrach H, Schmutzler RK, Kostara A, Ziegler-Löhr K, Dyson MH, et al. Olaparib for metastatic breast cancer in a patient with a germline PALB2 variant. NPJ Breast Cancer 2020;6:31. - PubMed

Publication Types

• Journal Article