Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

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Fig. 1: Kaplan–Meier curve.

References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Google Scholar 

  2. 2.

    Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumours of female reproductive organs. 4th ed. International Agency for Research on Cancer (IARC); 2014.

  3. 3.

    Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393:1240–53.

    Article  Google Scholar 

  4. 4.

    NCCN. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in ovarian cancer. 2020. https://www.nccn.org/.

  5. 5.

    Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi24–32.

    Article  Google Scholar 

  6. 6.

    Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;385:2403–15.

    Article  Google Scholar 

  7. 7.

    Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl J Med. 2019;381:2391–402.

    CAS  Article  Google Scholar 

  8. 8.

    Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505.

    CAS  Article  Google Scholar 

  9. 9.

    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.

    CAS  Article  Google Scholar 

  10. 10.

    Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154–64.

    CAS  Article  Google Scholar 

  11. 11.

    Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–84.

    CAS  Article  Google Scholar 

  12. 12.

    Penson RT, Valencia RV, Cibula D, Colombo N, Leath CA III, Bidzinski M, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol. 2020;38:1164–74.

    CAS  Article  Google Scholar 

  13. 13.

    Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18:75–87.

    CAS  Article  Google Scholar 

  14. 14.

    Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20:636–48.

    CAS  Article  Google Scholar 

  15. 15.

    Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, et al. Pathogenic germline variants in 10,389 adult cancers. Cell. 2018;173:355–70.e14.

    CAS  Article  Google Scholar 

  16. 16.

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.

    Article  Google Scholar 

  17. 17.

    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.

    Article  Google Scholar 

  18. 18.

    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.

    Article  Google Scholar 

  19. 19.

    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.

    CAS  Article  Google Scholar 

  20. 20.

    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.

    Article  Google Scholar 

  21. 21.

    Colombo N, Huang G, Scambia G, Chalas E, Pignata S, Fiorica J, et al. Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer. J Clin Oncol. 2018;36:1300–7.

    Article  Google Scholar 

  22. 22.

    Kentwell M, Dow E, Antill Y, Wrede CD, McNally O, Higgs E, et al. Mainstreaming cancer genetics: a model integrating germline BRCA testing into routine ovarian cancer clinics. Gynecol Oncol. 2017;145:130–6.

    Article  Google Scholar 

  23. 23.

    Morgan RD, Burghel GJ, Flaum N, Bulman M, Clamp AR, Hasan J, et al. Prevalence of germline pathogenic BRCA1/2 variants in sequential epithelial ovarian cancer cases. J Med Genet. 2019;56:301–7.

    CAS  Article  Google Scholar 

  24. 24.

    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.

    Article  Google Scholar 

  25. 25.

    Evans DG, Harkness EF, Plaskocinska I, Wallace AJ, Clancy T, Woodward ER, et al. Pathology update to the Manchester Scoring System based on testing in over 4000 families. J Med Genet. 2017;54:674–81.

    CAS  Article  Google Scholar 

  26. 26.

    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002;30:e57.

    Article  Google Scholar 

  27. 27.

    Evans DG, Harkness EF, Plaskocinska I, Wallace AJ, Clancy T, Woodward ER, et al. Pathology update to the Manchester Scoring System based on testing in over 4000 families. J Med Genet. 2017;54:674–81.

    CAS  Article  Google Scholar 

  28. 28.

    Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E, et al. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41:474–80.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    CAS  Article  Google Scholar 

  30. 30.

    Song H, Cicek MS, Dicks E, Harrington P, Ramus SJ, Cunningham JM, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014;23:4703–9.

    CAS  Article  Google Scholar 

  31. 31.

    Flaum N, Crosbie EJ, Woodward ER, Lalloo F, Evans DGR. Challenging the believed proportion of ovarian cancer attributable to BRCA2 versus BRCA1 pathogenic variants. Eur J Cancer. 2020;124:88–90.

    CAS  Article  Google Scholar 

  32. 32.

    Wright S, Porteous M, Stirling D, Lawton J, Young O, Gourley C, et al. Patients’ views of treatment-focused genetic testing (TFGT): some lessons for the mainstreaming of BRCA1 and BRCA2 testing. J Genet Couns. 2018;27:1459–72.

    Article  Google Scholar 

Download references

Acknowledgements

ERW, EJC, EFH, and DGRE are supported by the all Manchester National Institute for Health Research Manchester Biomedical Research Centre (IS-BRC-1215-20007).

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Correspondence to D. Gareth R. Evans.

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The authors declare that they have no conflict of interest.

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The germline BRCA1/2 database is approved by North Manchester Research Ethics Committee (08/H1006/77). All women included in this study provided informed verbal and/or written consent to undergo germline BRCA1/2 testing.

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Flaum, N., Morgan, R.D., Burghel, G.J. et al. Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England. Eur J Hum Genet 28, 1541–1547 (2020). https://doi.org/10.1038/s41431-020-0692-y

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