Ann Lab Med.  2023 Jan;43(1):73-81. 10.3343/alm.2023.43.1.73.

Cost-Effectiveness Analysis of Germline and Somatic BRCA Testing in Patients With Advanced Ovarian Cancer

• Jang J
• Kim Y
• Kim JH
• Cho SM
• Lee KA

• KMID: 2551588
• DOI: http://doi.org/10.3343/alm.2023.43.1.73

Abstract

Background
BRCA testing is necessary for establishing a management strategy for ovarian cancer. Several BRCA testing strategies, including germline and somatic testing, are implemented in clinical practice in Korea. We aimed to comparatively evaluate their cost-effectiveness from patients’ perspective.
Methods
We developed a decision model comprising five BRCA testing strategies implemented in Korea: (1) germline testing first, followed by somatic tumor testing for patients without a germline variant; (2) somatic testing first, followed by germline testing for patients with a variant detected by somatic testing; (3) both germline and somatic testing; (4) germline testing alone; and (5) somatic testing alone, with no testing as the comparator. One-way sensitivity analysis was conducted to test the uncertainty of key parameters.
Results
Assuming a willingness-to-pay of $20,000 per progression-free life-year gain (PF-LYG), all five strategies were considered cost-effective. Strategy 4 was the most cost-effective option, with an incremental cost-effectiveness ratio (ICER) of $2,547.7 per PF-LYG, followed by strategy 1, with an ICER of $3,978.4 per PF-LYG. Even when the parameter values were varied within the possible range, the ICERs of all strategies did not exceed the willingness-to-pay threshold.
Conclusions
Considering the importance of knowing a patient’s BRCA gene status, germline testing first, followed by somatic testing, may be a reasonable option.

Keyword

BRCA testing; Cost-effectiveness analysis; Advanced ovarian cancer

Figure

• 

  Fig. 1 Schematic representation of the model.

• 

  Fig. 2 Results of one-way sensitivity analysis and incremental cost-effectiveness ratio. Abbreviations: PF-LYG, progression-free life-year gain; ICER, incremental cost-effectiveness ratio.

Reference

1. Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, et al. 2021; Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 19:77–102. DOI: 10.6004/jnccn.2021.0001. PMID: 33406487.

2. Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, et al. 2020; Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol. 38:1222–45. DOI: 10.1200/JCO.19.02960. PMID: 31986064. PMCID: PMC8842911.

3. Armstrong DK, Alvarez RD, Bakkum-Gamez JN, Barroilhet L, Behbakht K, Berchuck A, et al. 2021; Ovarian cancer, version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 19:191–226. DOI: 10.6004/jnccn.2021.0007. PMID: 33545690.

4. Owens DK, Davidson KW, Krist AH, Barry MJ, Cabana M, et al. US Preventive Services Task Force. 2019; Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 322:652–65. DOI: 10.1001/jama.2019.10987. PMID: 31429903.

5. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. 2009; Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 361:123–34. DOI: 10.1056/NEJMoa0900212. PMID: 19553641.

6. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. 2018; Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 379:2495–505. DOI: 10.1056/NEJMoa1810858. PMID: 30345884.

7. Banerjee S, Moore KN, Colombo N, Scambia G, Kim BG, Oaknin A, et al. 2020; Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1. Ann Oncol. 31:S613. DOI: 10.1016/j.annonc.2020.08.950.

8. González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. 2019; Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 381:2391–402. DOI: 10.1056/NEJMoa1910962. PMID: 31562799.

9. Korea Central Cancer Registry National Cancer Center. Annual report of cancer statistics in Korea in 2018. Ministry of Health and Welfare;2020.

10. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. 2012; 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. 30:2654–63. DOI: 10.1200/JCO.2011.39.8545. PMID: 22711857. PMCID: PMC3413277.

11. Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. 2016; Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2:482–90. DOI: 10.1001/jamaoncol.2015.5495. PMID: 26720728. PMCID: PMC4845939.

12. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. 2014; Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 20:764–75. DOI: 10.1158/1078-0432.CCR-13-2287. PMID: 24240112. PMCID: PMC3944197.

13. Cunningham JM, Cicek MS, Larson NB, Davila J, Wang C, Larson MC, et al. 2014; Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 4:4026. DOI: 10.1038/srep04026. PMID: 24504028. PMCID: PMC4168524.

14. Yoo J, Lee GD, Kim JH, Lee SN, Chae H, Han E, et al. 2020; Clinical validity of next-generation sequencing multi-gene panel testing for detecting pathogenic variants in patients with hereditary breast-ovarian cancer syndrome. Ann Lab Med. 40:148–54. DOI: 10.3343/alm.2020.40.2.148. PMID: 31650731. PMCID: PMC6822011.

15. Health Insurance Review and Assessment Service, Health insurance benefit cost (2022.02). https://repository.hira.or.kr/handle/2019.oak/2964. Updated on Feb 2022.

16. World Health Organization. 2015; Regional Office for the Western Pacific. Republic of Korea health system review: WHO Regional Office for the Western Pacific. xviii:102.

17. Muennig P, Bounthavong M. 2016. Cost-effectiveness analysis in health: a practical approach. 3rd ed. Jossey-Bass;p. 199–222.

18. Song HJ, Lee EK. 2018; Evaluation of willingness to pay per quality-adjusted life year for a cure: A contingent valuation method using a scenario-based survey. Medicine (Baltimore). 97:e12453. DOI: 10.1097/MD.0000000000012453. PMID: 30235732. PMCID: PMC6160178.

19. Moya-Alarcón C, González-Domínguez A, Simon S, Pérez-Román I, González-Martín A, Bayo-Lozano E, et al. 2019; Cost-utility analysis of germline BRCA1/2 testing in women with high-grade epithelial ovarian cancer in Spain. Clin Transl Oncol. 21:1076–84. DOI: 10.1007/s12094-018-02026-2. PMID: 30617925.

20. Eccleston A, Bentley A, Dyer M, Strydom A, Vereecken W, George A, et al. 2017; A cost-effectiveness evaluation of germline BRCA1 and BRCA2 testing in UK women with ovarian cancer. Value Health. 20:567–76. DOI: 10.1016/j.jval.2017.01.004. PMID: 28407998. PMCID: PMC5406158.

21. Kwon JS, Tinker AV, Hanley GE, Pansegrau G, Sun S, Carey MS, et al. 2019; BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer. Gynecol Oncol. 152:459–64. DOI: 10.1016/j.ygyno.2018.10.014. PMID: 30876489.

22. Zhong L, Tran AT, Tomasino T, Nugent E, Smith JA. 2018; Cost-effectiveness of niraparib and olaparib as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer. J Manag Care Spec Pharm. 24:1219–28. DOI: 10.18553/jmcp.2018.24.12.1219. PMID: 30479195.

23. Gonzalez R, Havrilesky LJ, Myers ER, Secord AA, Dottino JA, Berchuck A, et al. 2020; Cost-effectiveness analysis comparing 'PARP inhibitors-for-all' to the biomarker-directed use of PARP inhibitor maintenance therapy for newly diagnosed advanced stage ovarian cancer. Gynecol Oncol. 159:483–90. DOI: 10.1016/j.ygyno.2020.08.003. PMID: 32863036. PMCID: PMC8086124.

24. Penn CA, Wong MS, Walsh CS. 2020; Cost-effectiveness of maintenance therapy based on molecular classification following treatment of primary epithelial ovarian cancer in the United States. JAMA Netw Open. 3:e2028620. DOI: 10.1001/jamanetworkopen.2020.28620. PMID: 33295974. PMCID: PMC7726632.

25. Muston D, Hettle R, Monberg M, McLaurin KK, Gao W, Swallow E, et al. 2020; Cost-effectiveness of olaparib as a maintenance treatment for women with newly diagnosed advanced ovarian cancer and BRCA1/2 mutations in the United States. Gynecol Oncol. 159:491–7. DOI: 10.1016/j.ygyno.2020.08.013. PMID: 32951894.

26. Tan DS, Chan JJ, Hettle R, Ghosh W, Viswambaram A, Yu CC. 2021; Cost-effectiveness of olaparib versus routine surveillance in the maintenance setting for patients with BRCA-mutated advanced ovarian cancer after response to first-line platinum-based chemotherapy in Singapore. J Gynecol Oncol. 32:e27. DOI: 10.3802/jgo.2021.32.e27. PMID: 33559410. PMCID: PMC7930440.

27. Vos JR, Fakkert IE, de Hullu JA, van Altena AM, Sie AS, Ouchene H, et al. 2020; Universal tumor DNA BRCA1/2 testing of ovarian cancer: prescreening PARPi treatment and genetic predisposition. J Natl Cancer Inst. 112:161–9. DOI: 10.1093/jnci/djz080. PMID: 31076742. PMCID: PMC7019087.

28. Mafficini A, Simbolo M, Parisi A, Rusev B, Luchini C, Cataldo I, et al. 2016; BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing. Oncotarget. 7:1076–83. DOI: 10.18632/oncotarget.6834. PMID: 26745875. PMCID: PMC4811444.

29. de Jonge MM, Ruano D, van Eijk R, van der Stoep N, Nielsen M, Wijnen JT, et al. 2018; Validation and implementation of BRCA1/2 variant screening in ovarian tumor tissue. J Mol Diagn. 20:600–11. DOI: 10.1016/j.jmoldx.2018.05.005. PMID: 29936257.

30. Fumagalli C, Tomao F, Betella I, Rappa A, Calvello M, Bonanni B, et al. 2019; Tumor BRCA test for patients with epithelial ovarian cancer: the role of molecular pathology in the era of PARP inhibitor therapy. Cancers. 11:1641. DOI: 10.3390/cancers11111641. PMID: 31653094. PMCID: PMC6896171.

31. Rivera D, Paudice M, Gismondi V, Anselmi G, Vellone VG, Varesco L, et al. 2021; Implementing NGS-based BRCA tumour tissue testing in FFPE ovarian carcinoma specimens: hints from a real-life experience within the framework of expert recommendations. J Clin Pathol. 74:596–603. DOI: 10.1136/jclinpath-2020-206840. PMID: 32895300.

32. Kofanova O, Bellora C, Garcia Frasquilho S, Antunes L, Hamot G, Mathay C, et al. 2020; Standardization of the preanalytical phase of DNA extraction from fixed tissue for next-generation sequencing analyses. N Biotechnol. 54:52–61. DOI: 10.1016/j.nbt.2019.07.005. PMID: 31398512.

33. Hofreiter M, Jaenicke V, Serre D, von Haeseler A, Pääbo S. 2001; DNA sequences from multiple amplifications reveal artifacts induced by cytosine deamination in ancient DNA. Nucleic Acids Res. 29:4793–9. DOI: 10.1093/nar/29.23.4793. PMID: 11726688. PMCID: PMC96698.

34. Do H, Dobrovic A. 2012; Dramatic reduction of sequence artefacts from DNA isolated from formalin-fixed cancer biopsies by treatment with uracil-DNA glycosylase. Oncotarget. 3:546–58. DOI: 10.18632/oncotarget.503. PMID: 22643842. PMCID: PMC3388184.

35. Wong SQ, Li J, Tan AY, Vedururu R, Pang JM, Do H, et al. 2014; Sequence artefacts in a prospective series of formalin-fixed tumours tested for mutations in hotspot regions by massively parallel sequencing. BMC Med Genomics. 7:23. DOI: 10.1186/1755-8794-7-23. PMID: 24885028. PMCID: PMC4032349.

36. Kim Y, Cho CH, Ha JS, Kim DH, Kwon SY, Oh SC, et al. 2020; An optimized BRCA1/2 next-generation sequencing for different clinical sample types. J Gynecol Oncol. 31:e9. DOI: 10.3802/jgo.2020.31.e9. PMID: 31788999. PMCID: PMC6918881.

37. Jung SM, Ryu JM, Park HS, Park JS, Kang E, Lee S, et al. 2020; Trends in risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in Korean carriers of the BRCA1/2 mutation. J Breast Cancer. 23:647–55. DOI: 10.4048/jbc.2020.23.e61. PMID: 33408890. PMCID: PMC7779723.