A review of the cost-effectiveness of genetic testing for germline variants in familial cancer

Figures & data

Figure 1. PRISMA flow chart.

Table 1. Characteristics of economic studies on germline testing for breast and ovarian cancer.

#	Study with publication year (Setting)	Target population for germline testing (Referent strategy)	Testing strategy, genes assessed, variant prob%; cost of test	Cascade testing	Prophylaxis (uptake rate)	Model (perspective), discounting %	ICER*; US$/QALY or LYG (WTP threshold)	Sensitivity analysis, i.e. factors affecting cost-effectiveness
1	Sun et al. (2022)^25 (China)	Women with unselected breast cancer (No testing)	NGS of BRCA 1, BRCA 2 & PALB2, 6.0%, US$ 367	Yes, first & second-degree relatives	CPM (54%), RRSO (57%)	Micro-simulation (Payer & Societal), 3%	Payer: 7,572/QALY, Societal: 4,696/QALY (US$ 10,262; 1x GDP)	None
2	Michaan et al. (2021)^20 (US)	Population-wide of healthy women ≥ 30 years (No testing)	TVA of BRCA 1 & 2 founder mutations; 2.4%; US$ 154	No	RRM (28%), RRSO (65%)	Markov (Payer), 3%	21,278/QALY (US$ 100,000)	Cost of testing, probability of variant positive, prophylaxis uptake, discount rate
3	Manchanda et al. (2020)^32 (UK, USA, Netherlands, China, Brazil, India)	Population-wide of healthy women ≥ 30 years (Testing in high-risk)	NGS of BRCA 1 & 2; 0.7%; $200	No	RRM (47%), RRSO (55%)	Markov (Payer & Societal), 3%	Payer: 18,293/QALY, Societal: dominant (US$ 100,000)	Cost of testing, especially in developing countries
4	Hurry et al. (2020)^33 (Canada)	Women with unselected breast or epithelial ovarian cancer (No testing)	NGS of BRCA 1 & 2; breast: 4.7%, ovarian: 12.5%; US$ 478	Yes, first-degree relatives	RRM (88%), RRM+RRSO (84%)	Microsimulation (Payer), 1.5%	11,665/QALY (US$ 100,000)	Uptake of prophylaxis
5	Guzauskas et al. (2020)^34 (US)	Population-wide of healthy women ≥ 30 years (Testing in high-risk)	NGS of BRCA1, BRCA2, ATM, CHEK2, MSH6, PALB2, RAD51C & TP53; 49.5%; US$200	Yes, first-degree relatives	RRM (46%), RRSO (86%)	Markov (Payer), 3%	91,392/QALY (US$ 100,000)	Cost of testing, prophylaxis uptake, benefits of prophylaxis, cascade testing
6	Sun et al. (2019)^35 (US, UK, Australia)	Women with unselected breast cancer (Testing in high-risk)	NGS of BRCA1, BRCA2 & PALB2; 5.5%; US$330	Yes, first & second-degree relatives	CPM (54%), RRSO (57%)	Microsimulation (Payer & Societal), 3.5%	Payer: 72,566/QALY, Societal: 68,098/QALY (US$ 100,000)	Cost of testing, uptake of prophylaxis
7	Saito et al. (2019)^26 (Japan)	Women with metastatic breast cancer with HER-2 or triple negative status (No testing)	NGS of BRCA 1 & 2; 11.3%; US$2,058	No	PARP Inhibitor vs. standard chemo	Markov (Payer), 2%	158,630/QALY (US$ 129,695, 3× GDP)	Survival rate with PARP therapy
8	Moya-Alarcon et al. (2019)^36 (Spain)	Women with non-mucinous high-grade epithelial ovarian cancer (No testing)	TVA of BRCA 1 & 2; 8.3%; US$716	Yes, first-degree relatives	RRM (20%), RRSO (20–65%)	Microsimulation (Payer), 3%	52,290/QALY (US$ 82,683 or €50,000)	None
9	Tuffaha et al. (2018)^37 (Australia)	Women with breast cancer and with high-risk of mutations (No testing)	NGS of BRCA 1 & 2; 15.0%; US$935	Yes, first & second-degree relatives	RRM (30%), RRSO (54%)	Markov (Payer), 5%	14,730/QALY (US$ 34,770, AU$ 50,000)	None
10	Patel et al. (2018)^38 (UK, US)	Population wide of healthy Sephardi Jewish women ≥ 30 years (Testing in high-risk)	TVA of BRCA 1 founder mutation; 0.7%; US$300	No	RRM (60%), RRSO (66%)	Markov (Payer), 3.5%	344/QALY (US$ 100,000)	None
11	Manchanda et al. (2018)^39 (UK, US)	Population-wide of healthy women ≥ 30 years (Testing in high-risk)	NGS of BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2; 0.7%; US$330	No	RRM (47%), RRSO (55%)	Decision-tree (Payer), 3.5%	61,846/QALY (US$ 100,000)	None
12	Lim et al. (2018)^40 (Malaysia)	Women with early-stage breast cancer (No testing)	NGS of BRCA 1 & 2; 13.7%; US$451	No	RRM (21%), RRSO (48%)	Decision-tree (Payer), 3%	3,012/QALY (US$ 9,500, 1× GDP)	Cost of testing, probability of variant positive, prophylaxis uptake, benefit of prophylaxis, discount rate
13	Manchanda et al. (2017)^41 (UK, US)	Population wide of healthy women ≥ 30 years with Ashkenazi Jewish grandparents (Testing only women with high-risk)	TVA of BRCA 1 & 2 founder mutations; 2.5%; US$300	No	RRM (52%), RRSO (55%)	Decision-tree (Payer), 3.5%	Dominant (US$ 100,000)	None
14	Li et al. (2017)^42 (US)	Multigene testing of women with high-risk of breast or ovarian cancer (BRCA testing)	NGS of BRCA1, BRCA2, TP53, PTEN, CDH1, STK11 & PALB2; 14.9%; US$2,418	No	RRM (42%)	Markov (Payer), 3%	78,118/QALY (US$ 100,000)	Cost of testing, probability of variant positive, prophylaxis uptake
15	Eccleston et al. (2017)^43 (UK)	Women with unselected ovarian cancer (No testing)	NGS of BRCA 1 & 2; 13%; US$440	Yes, first & second-degree relatives	RRM (50%), RRSO (75%)	Microsimulation (Payer), 3.5%	7,167/QALY (US$ 28,736 or £20,000)	None
16	Manchanda et al. (2015)^44 (UK)	Population-wide of healthy Ashkenazi Jewish women ≥ 30 years (Testing in high-risk)	TVA of BRCA 1 & 2 founder mutations; 2.5%; US$71	No	RRM (52%), RRSO (55%)	Decision-tree (Payer), 3.5%	Dominant (US$ 100,000)	None
17	Green et al. (2014)^45 (US)	Women with previous benign breast biopsy (No testing)	TVA of seven SNP mutations; 1.2–1.7%; US$945	No	Tamoxifen (20%)	Microsimulation (Payer), 3%	59,708/QALY (US$ 100,000)	Cost of testing, prophylaxis uptake, utility weights of outcomes
18	Kwon et al. (2010)^46 (US)	Women with unselected ovarian cancer (No testing)	NGS of BRCA 1 & 2; 10%; US$3,000	Yes, first-degree relatives	RRM (30%), RRSO (70%)	Markov (Societal), 3%	39,835/QALY (US$ 50,000)	Cascade testing, prophylaxis uptake
19	Holland et al. (2009)^47 (US)	Healthy women ≥ 35 years with high-risk (No testing)	NGS of BRCA 1& 2; 10%; US$2,542	No	RRM (15%), RRSO (25%)	Semi-Markov (Societal), 3%	11,699/QALY (US$ 50,000)	Prophylaxis uptake, utility weights for outcomes
20	Balmana et al. (2004)^48 (Spain)	Women ≥ 30 years with high-risk (No testing)	TVA of BRCA 1 & 2; 20%; US$546	Yes, first-degree relatives	RRM (9%)	Decision-tree (Not provided), not provided	8,337/QALY (Not provided)	Probability of variant positive
21	Tengs and Berry (2000)^49 (US)	Population-wide of healthy women ≥ 30 years with varying risk of breast or ovarian cancer (No testing)	NGS of BRCA 1 & 2; 0 population-wide: 0.8%; slightly high-risk: 10%; moderately high-risk: 20%; very high-risk: 50%; US$2580	No	RRM (100%), RRSO (100%)	Markov (Societal), 3%	Pop-wide: 2.5 million/QALY; slightly high-risk: 52,875/QALY; moderately high-risk: 23,327/QALY; very high-risk: 5,443–7,620/QALY (US$ 50,000)	None
22	Grann et al. (1999)^50 (US)	Population wide of Ashkenazi Jewish women ≥ 30 years (No testing)	TVA of BRCA 1 & 2 founder mutations; 2.5%; US$450	No	RRM (100%), RRSO (100%)	Markov (Payer), 3%	33,749/LYG (US$ 50,000)	Cost of testing, prophylaxis uptake

Abbreviations. CPM, contralateral prophylactic mastectomy; GDP, gross-domestic product; ICER, incremental cost-effectiveness ratio; LYG, life years gained; MM, mammogram; NGS, next generation sequencing; PARP, poly-adenosine-diphosphate ribose polymerase; QALY, quality-adjusted-life years; RRM, risk-eduction mastectomy; RRS, risk-reduction surgery; RRSO, risk-reduction salpingo-oophorectomy; TVA, targeted variant analysis; WTP: willingness-to-pay.

*Converted to 2021 US $, using the CCEMG-EPPI-Centre Cost Converter³⁰.

Table 2. Characteristics of economic studies on germline testing for colorectal cancer.

#	Study with publication year (Setting)	Target Population for germline testing (Referent strategy)	Test strategy, genes assessed, variant prob%; cost of test	Cascade Testing	Prophylaxis (frequency of surveillance in test positive vs. referent population)	Model (Perspective), discounting %	ICER (WTP threshold) in US$*/QALY or LYG	Sensitivity analysis, i.e. factors affecting cost-effectiveness
1	Guzauskas et al. (2022)^17 (US)	Population- wide of healthy adults (Testing high-risk)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2, 0.3%; US$200	Yes, first-degree relatives	Annual colonoscopy starting at 20 years vs. Decennial colonoscopy staring at 45 years	Markov (Payer), 3%	132,200/QALY (US$ 150,000)	Cost of testing, WTP threshold
2	Salikhanov et al. (2021)^23 (Switzerland)	Newly-diagnosed colorectal cancer patients (Reflex testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 3.0%; US$2,852	Yes, first-degree relatives	In relatives: Biennial colonoscopy starting at 25 years vs. Decennial colonoscopy starting at 50 years	Markov (Payer), 3%	54,122/QALY (US$ 83,190 or CHF 100,000)	Cost of testing, cascade testing
3	Ramzdan et al. (2021)^22 (Malaysia)	Convenience sample of colorectal cancer (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; not provided; US$976	No	In relatives: Biennial colonoscopy vs. FIT ± colonoscopy starting at 50 years	Decision-tree (Payer), 3%	Dominant (Not provided)	None
4	Pastorino et al. (2020)^21 (Italy)	Newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 2.8%; US$348	Yes, first-degree relatives	In relatives: Biennial colonoscopy with Aspirin ± endometrial sampling ± RRSO starting at 25 years vs. colonoscopy every 5 years starting at 45 years	Markov (Payer), 3.5%	2,388/QALY (US$ 42,599 or €30,000)	Probability of variant positive, cascade testing
5	Kang et al. (2020)^18 (Australia)	Newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 2.8%; $832	Yes, first-degree relatives	In relatives: Annual colonoscopy vs. No colonoscopy	Microsimulation (Payer), 5%	46,078/LYG (US$ 34,770 or AU$ 50,000)	Assumed benefits of prophylaxis
6	Pereira et al. (2019)^51 (Portugal)	Healthy adults with high-risk i.e. ≥ 5% (No testing)	SNPs in COX-2, PGE2; 30%; US$49	No	Increased colonoscopy, frequency not provided vs. no colonoscopy	Decision-tree (Societal), 3%	76,750/QALY (US$ 50,000)	Cost of testing, benefits of prophylaxis
7	Chen et al. (2016)^52 (Taiwan)	Newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 2.3%; US$1,000	Yes, first-degree relatives	In relatives: Biennial colonoscopy starting at 20 years vs. FIT ± colonoscopy starting at 50 years	Markov (Payer), 3%	169,887/LYG (US$ 50,000)	None
8	Snowsill et al. (2015)^53 (UK)	Newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 8.4%; US$1,168	Yes, first-degree relatives	In relatives: Biennial colonoscopy starting at 20 years ± endometrial sampling ± RRSO vs. no colonoscopy	Decision-tree (Payer), 3.5%	15,544/QALY (US$28,736 or £20,000)	Cost of testing
9	Severin et al. (2015)^54 (Germany)	Patients with colorectal cancer; stage non-specific (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 2.8%; US$5,985	Yes, first-degree relatives	In relatives: Annual colonoscopy with Aspirin vs. Decennial colonoscopy starting at 55 years	Decision-tree (Payer), 3%	981,494/QALY (US$75,616 or £20,000)	Prophylaxis uptake
10	Gallego et al. (2015)^55 (US)	Patients referred to a genetics clinic for colorectal cancer screening (Reflex testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, BMPR1A, SMAD4, STK11, MUTYH, PTEN, TP53, CDH1; 15.4%; US$2,700	Yes, first, second, & third-degree relatives	In positive individuals: Increased colonoscopy, details not provided vs. no colonoscopy in test negative	Decision-tree (Payer), 3%	41,216/QALY (US$100,000)	Penetrance of tested variants
11	Barzi et al. (2015)^56 (US)	Population-wide of healthy adults & newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 0.2% in general population and 3.0% in colorectal cancer patients; $3,520	Yes, first-degree relatives	Annual colonoscopy starting at 20 years vs. No colonoscopy	Markov (Societal), 3%	1.1 million/QALY (US$50,000)	Cost of testing
12	Wang et al. (2012)^57 (Singapore)	First-degree relatives of hereditary colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 0–2.3%; US$1,962	No	Biennial colonoscopy starting at 21 years vs. Decennial colonoscopy starting at 50 years	Markov (Payer), 3%	Dominant (US$72,069 or 1× GDP)	Prophylaxis uptake
13	Ladabaum et al. (2011)^58 (US)	Newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 3%; US$4,288	Yes, first-degree relatives	In relatives: Annual colonoscopy starting at 21 years ± endometrial sampling at 35 years ± RRSO vs. no colonoscopy	Decision-tree & Markov (Third-party), 3%	61,150/QALY (US$100,000)	Cascade testing
14	Dinh et al. (2011)^59 (US)	Population-wide of healthy adults with varying risk; 0–10% (Testing high-risk)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 5%; US$4,307	Yes, first & second-degree relatives	Annual colonoscopy + endometrial sampling starting at 25 years vs. Decennial colonoscopy starting at 50 years	Microsimulation (Societal), 3%	54,884/QALY (US$50,000)	Probability of variant positive, prophylaxis uptake, discount rate, WTP threshold
15	Mvundura et al. (2010)^60 (US)	Newly-diagnosed colorectal cancer patients (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2; 3%; US$3,457	Yes, first-degree relatives	In relatives: Annual colonoscopy starting at 20 years vs. Decennial colonoscopy staring at 50 years	Decision-tree (Payer), 3%	180,119/LYG (US$50,000)	Cost of testing, probability of variant positive, prophylaxis uptake
16	Olsen et al. (2007)^61 (Denmark)	Families with moderate- to high-risk of HNPCC (No testing)	NGS of Lynch syndrome variants, MLH1 & MSH2; 22%; US$153	No	Biennial colonoscopy starting at 25 years vs. no colonoscopy	Markov (Payer), 5%	353/LYG (Not provided)	Cost of prophylaxis (colonoscopy)
17	Neilsen et al. 2007^62 (Netherlands)	Families of MAP patients (No testing)	NGS of MAP; 1.5%; US$754	No	In family members: Biennial colonoscopy starting at 25 years vs. FOBT ± colonoscopy starting at 50 years	Markov, (Societal), 4%	37,972/QALY (US$93,458 or €80,000)	Cost of testing, probability of variant positive, discount rate
18	Breheny et al. (2006)^63 (Australia)	Healthy first-degree relatives of known FAP & HNPCC mutation carriers (No testing)	NGS of Lynch syndrome variants, MLH1, MSH2, MSH6, PMS2 & FAP; 50%: US$1,580	No	Lynch positive: Annual colonoscopy starting at 25 years and colorectal surgery at 45 years FAP positive: Sigmoidoscopy every 18 months starting at 10 years and colorectal surgery at 21 years	Markov (Payer), 5%	Dominant (Not provided)	Prophylaxis uptake

Abbreviations. FAP, familial adenomatous polyposis; FIT, faecal immunochemical test; GDP, gross-domestic product; ICER, incremental cost-effectiveness ratio; IHC, immunohistochemistry test; iFOBT, immunochemical faecal occult blood test; LYG: life years gained; MAP, MUTYH-associated polyposis; NGS, next generation sequencing; QALY, quality-adjusted-life years; WTP: willingness-to-pay.

*Converted to 2021 US$, using the CCEMG-EPPI-Centre Cost Converter³⁰.

Table 3. Summary of characteristics of economic studies on germline testing for breast or ovarian cancer.

Study characteristics	Breast or ovarian cancer (n = 22 studies)
Population/setting
Multiple countries	5 (22.7%)
US	7 (31.8%)
UK	2 (9.1%)
Asia	3 (13.6%)
Australia	1 (4.6%)
Others	4 (18.2%)
Initial target populations for germline testing
Population-wide	5 (22.7%)
Targeted testing
Healthy women at high-risk	9 (40.9%)
Breast or ovarian cancer patients	8 (36.4%)
Cascade testing
Included in the model	10 (45.4%)
Germline variants tested
BRCA1	1 (4.6%)
BRCA 1 & 2	15 (68.2%)
BRCA & others	6 (27.3%)
Cost of germline testing*
≤ US$200	2 (9.1%)
US$201–500	11 (50.0%)
US$501–1,000	4 (18.2%)
≥ US$1,000	5 (22.7%)
Study perspective
Health payer	15 (68.2%)
Societal	3 (13.6%)
Health payer & societal	3 (13.6%)
Not provided	1 (4.6%)
Modelling design
Decision-tree	5 (22.7%)
Markov	10 (45.4%)
Semi-Markov	1 (4.6%)
Microsimulation	6 (27.3%)
Time horizon
5 years or less	1 (4.6%)
lifetime	21 (95.4%)
Discount rate
≤ 2%	2 (9.1%)
3%	12 (54.6%)
3.5%	6 (27.3%)
4–5%	2 (9.1%)
Willingness-to-pay (WTP) threshold, US$
≤50,000	8 (36.4%)
51,000–100,000	12 (54.6%)
101,000–150,000	1 (4.6%)
Not provided	1 (4.6%)
ICERs, stratified by target population for testing vs. referent strategy in US$*
Population-wide	US$344 − 2.5 million/QALY
Targeted testing
Healthy women with high-risk	Dominant: US$78,118/QALY; 8,337/LYG
Women with previous benign breast biopsy	59,708/LYG
Women with breast or ovarian cancer	US$3,012–72,566/QALY; 39,835/LYG
Metastatic breast cancer	US$158,630/QALY
Results of economic evaluations
Cost-saving	3 (13.6%)
Cost-effective	17 (77.3%)
Not Cost-effective	2 (9.1%)
Factors influencing results (Sensitivity analysis)
Cost of testing	8 (36.4%)
Uptake of prophylaxis	10 (45.5%)
Probability of being variant positive	4 (18.2%)
Assumed benefits of prophylaxis	3 (13.6%)
Cascade testing	2 (9.1%)
Discounting	2 (9.1%)

*Converted to US$ using the CCEMG-EPPI-Centre Cost Converter³⁰.

Table 4. Summary of characteristics of economic studies on germline testing for colorectal cancer.

Study characteristics	Colorectal cancer (n = 18 studies)
Population/setting
US	6 (33.3%)
UK	1 (5.6%)
Asia	3 (16.7%)
Australia	2 (11.1%)
Others	6 (31.6%)
Initial target populations for germline testing
Population-wide	2 (11.1%)
Targeted testing
People with high-risk	7 (38.9%)
Colorectal cancer patients	9 (50.0%)
Cascade testing
Included in the model	12 (66.7%)
Germline variants tested
Lynch	14 (77.8%)
Lynch & others	2 (11.1%)
Other colorectal cancer variants	2 (11.1%)
Cost of germline testing*
≤ US$200 or less	2 (11.1%)
US$201–500	2 (11.1%)
US$501–1,000	4 (21.2%)
US$1,000–2,000	3 (16.7%)
≥US$2,000	7 (38.9%)
Study perspective
Health payer	13 (72.2%)
Societal	4 (22.2%)
Third party	1 (5.6%)
Modelling design
Decision-tree	6 (33.3%)
Markov	9 (50.0%)
Microsimulation	2 (11.1%)
Cross-sectional	1 (5.6%)
Time horizon
lifetime	16 (88.9%)
not provided	2 (11.1%)
Discount rate
3%	12 (66.7%)
3.5%	2 (11.1%)
4–5%	4 (22.2%)
Willingness-to-pay (WTP) threshold in US$/QALY or LYG
≤ 50,000	8 (44.4%)
51,000–100,000	6 (33.3%)
101,000–150,000	1 (5.6%)
not provided	3 (16.7%)
ICERs, by target population for testing vs. referent population in US$*
Population-wide testing	132,000/QALY; 1.1 million/LYG
Targeted testing
Healthy adults with high-risk	32,322 − 76,750/QALY; dominant: 353/LYG
Colorectal cancer patients	dominant: 54,122/QALY; 98,790–6.3 million/LYG
Results of economic evaluations
Cost-saving	3 (16.7%)
Cost-effective	10 (55.6%)
Not cost-effective	5 (27.8%)
Factors influencing results (Sensitivity analysis)
Cost of testing	7 (38.9%)
Compliance with increased surveillance	5 (27.8%)
Probability of being variant positive	5 (27.8%)
Assumed benefits of increased surveillance	2 (11.1%)
Cascade testing	3 (15.8%)
WTP threshold	2 (16.7%)
Discounting	2 (11.1%)

*Converted to US$ using the CCEMG-EPPI-Centre Cost Converter³⁰.

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