Quality-adjusted life years for HER2-positive, early-stage breast cancer using trastuzumab-containing regimens in the context of cost-effectiveness studies: a systematic review

Figures & data

Figure 1. Flowchart depicting the process of selecting studies for inclusion in the review.

Table 1. Summary details of the studies included in the review.

No	Author, year	Country	Time horizon	Discounting (%)	Age (years)	Trastuzumab group	Control group	QALYs value (trastuzumab)	QALYs value (control)
1	Garrison et al., 2007 [26]	U.S.A.	Lifetime	3	50	Doxorubicin 60 mg/m2 and cyclophosphamide 600mg/m2 every three weeks for four cycles. This is followed by paclitaxel, either at a dose of 175 mg/m2 every three weeks or 80 mg/m2 weekly for 12 weeks, alongside trastuzumab for the same duration. After the initial 12 weeks, trastuzumab is continued alone on a weekly basis for an additional 40 weeks	Anthracycline/taxane-based chemotherapy	11.78	10.08
2	Aboutorabi et al., 2014 [27]	Iran	20 years	3	50	The AC-T arm involves intravenous administration of 100 mg/m2 docetaxel, 60 mg/m2 doxorubicin, and 600 mg/m2 cyclophosphamide in each session, repeated six times every 3 weeks, extending over approximately 4 months. Trastuzumab is also included in the treatment regimen, but its duration is not specified	Anthracycline/taxane-based chemotherapy	11.98	11.11
3	Hall et al., 2011 [28]	UK	Lifetime	3.5	50	Trastuzumab	Anthracycline/taxane-based chemotherapy	7.71	7.22
4	Pichon-Riviere et al., 2015 [29]	Argentina	Lifetime	5	55	Trastuzumab (12 months)	No trastuzumab (chemotherapy regimen was not explained)	8.70	8.12
5	Gupta et al., 2020 [30]	India	Lifetime	3	>50	Trastuzumab is administered with adjuvant chemotherapy, with an initial infusion at 8 mg/kg for the first cycle, followed by infusions at 6 mg/kg for the remaining 16 cycles	Anthracycline/taxane-based chemotherapy	6.60	5.50
6	Younis et al., 2020 [24]	Canada	Lifetime	1.5	49	Trastuzumab 6 mg/kg every 3 weeks intravenously	T-DM1 3.6 mg/kg every 3 weeks intravenously	16.16	18.32
7	Hajjar et al., 2019 [31]	U.S.A.	Lifetime	3	40 and above 80	Adjuvant paclitaxel 80 mg/m^2 weekly for 3 months and trastuzumab 4 mg/kg on day 1 and then 2 mg intravenously per kg weekly for one year	Anthracycline/taxane-based chemotherapy	16.17	9.57
8	Schwartz et al., 2019 [25]	U.S.A.	Lifetime	3	18 and older	Adjuvant Trastuzumab	Neratinib	15.28	15.67
9	Purmonen et al., 2011 [32]	Finland	Lifetime	3	50	Trastuzumab for 1 year	No trastuzumab (chemotherapy regimen was not explained)	8.37	7.71
10	Gershon et al., 2019 [33]	Congo	Lifetime	3	≥45	Trastuzumab 8mg/kg followed by 16 doses of 6 mg/kg	Anthracycline/taxane-based chemotherapy	9.89	8.88
11	Genuino et al., 2019 [34]	Philippines	Lifetime	3.5	50	Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 are administered on day 1 every 3 weeks for 4 cycles. This is followed by docetaxel 100 mg/m2 on day 1, along with an initial dose of trastuzumab at 8 mg/kg, then 6 mg/kg on day 1 every 3 weeks for 4 cycles. Finally, trastuzumab is continued at a dose of 6 mg/kg on day 1 every 3 weeks for an additional 14 cycles	Anthracycline/taxane-based chemotherapy	8.99	7.99
12	Kongsakon et al., 2019 [35]	Thailand	Lifetime	3	50	An initial dose of trastuzumab at 8 mg/kg intravenously, followed by subsequent doses of 4 mg/kg every 3 weeks for a duration of 1 year. Additionally, paclitaxel is administered intravenously at a dose of 175 mg/m2 every 3 weeks for a total of 6 cycles	Paclitaxel 175/m2 intravenously IV every 3 weeks for 6 cycles	5.01	4.59
13	Buendía et al., 2013 [36]	Colombia	Lifetime	5	50	Trastuzumab	Anthracycline/taxane-based chemotherapy	7.62	6.83
14	Kurian et al., 2007 [37]	U.S.A.	2 years	3	49	Doxorubicin 60 mg/m^2 plus cyclophosphamide 600 mg/m^2 are administered intravenously for four cycles every 3 weeks, followed by paclitaxel administered at 80 mg/m^2, with trastuzumab administered weekly; the initial dose of trastuzumab is 4 mg/kg, with subsequent doses of 2 mg/kg. Trastuzumab treatment continues weekly for a total duration of 1 year	Anthracycline/taxane-based chemotherapy	9.79	9.35
15	Seferina et al., 2017 [38]	The Netherlands	Lifetime	1.5	Not reported	Trastuzumab treatment	No trastuzumab (chemotherapy regimen was not explained)	13.93	13.10
16	Liberato et al., 2007 [39]	Italy	15 years	3	50	During the first quarter of adjuvant treatment, patients receive paclitaxel and trastuzumab at a dosage of 2 mg/kg/week	Anthracycline/taxane-based chemotherapy	11.09	9.55
17	Lang et al., 2016 [40]	Taiwan	20 years	3	50	Trastuzumab was used as an adjuvant treatment and reimbursed for only 1 year pre- or post-operation or after standard chemotherapy	Anthracycline/taxane-based chemotherapy	4.98	3.35
18	Hassett et al., 2020 [41]	U.S.A.	5 years	Not reported	55	Trastuzumab with pertuzumab	Trastuzumab emtansine with pertuzumab	4.67	4.62
19	Skedgel et al., 2009 [42]	Canada	25 years	3	49	12-month adjuvant trastuzumab after adjuvant chemotherapy	No trastuzumab (chemotherapy regimen was not explained)	0.59	0.39
20	Macedo et al., 2010 [43]	Portugal	45 years	3	Not reported	Adjuvant trastuzumab for 1 year	No trastuzumab (chemotherapy regimen was not explained)	11.69	9.68
21	Konishi et al., 2022 [44]	Japan	20 years	2	70	Adjuvant trastuzumab for 1 year	No trastuzumab (chemotherapy regimen was not explained)	13.27	12.91
22	Botelho et al., 2022 [45]	Brazil	50 years	5	49	Adjuvant trastuzumab for 1 year	No trastuzumab (chemotherapy regimen was not explained)	7.31	6.48

Abbreviations: A = doxorubicin; C = cyclophosphamide; QALYs = quality-adjusted life years; T = paclitaxel; T-DM1 = trastuzumab emtansine.

Table 2. Summary of ICERs of the included studies.

No	Author, year	Currency and year	Costs, US$ 2023 (trastuzumab)	Costs, US$ 2023 (comparator)	ICER, US$ 2023 (Cost per QALY)	Threshold, US$ 2023	Most influential factors reported in one-way sensitivity analysis
1	Garrison et al., 2007 [46]	US$ (2006)	107,728	42,039	38,629	54,864–82,296	Discount rate, cost of trastuzumab, and probability of metastatic
2	Aboutorabi et al., 2014 [27]	US$ (2010)	78,160	16,991	70,366	Not reported	Cost of trastuzumab, discount rate for outcomes, and HR in trastuzumab group
3	Hall et al., 2011 [28]	£ (2008)	Not reported	Not reported	52,800	61,388	Cost of trastuzumab, hazard ratio, discount rate for benefits, percentage of local recurrence versus distant recurrence, and relative percentage of distant recurrences that are brain metastatic
4	Pichon-Riviere et al., 2015 [29]	US$ (2012)	57,448	16,092	101,925	12,034	Cost of trastuzumab, hazard ratio of trastuzumab and discount rate
5	Gupta et al., 2020 [30]	US$ (2019)	5,729	Not reported	2,257	Not reported	Cost of trastuzumab, DFS utility after 1 year, and transition probability from a disease-free to metastatic in the chemotherapy group
6	Younis et al., 2020 [24]	CAD$ (2018)	257,717	175,899	Dominate	19,783	Not specified (one-way sensitivity analysis was not performed)
7	Hajjar et al., 2019 [31]	US$ (2016)	222,851	135,754	13,203	62,371	Discount rate, probability of relapse, and cost of adjuvant therapy
8	Schwartz et al., 2019 [25]	US$ (2018)	182,675	379,689	497,424	59,771	DFS HR, annual discount rate, and probability of recurrence between 9 and 10 years
9	Purmonen et al., 2011 [32]	Euro (2008)	101,845	88,784	19,840	49,600	Discount rate and trastuzumab treatment cost
10	Gershon et al., 2019 [33]	US$ (2018)	26,999	3,094	24,530	23,908	Discount rate, HR, cost of trastuzumab
11	Genuino et al., 2019 [34]	PHP (2017)	275,694	247,761	28,018	7,414	HR for DFS, duration of efficacy of trastuzumab, discounting rate for outcomes, cost of trastuzumab therapy, and transition probabilities from DFS to metastatic
12	Kongsakon et al., 2019 [35]	US$ (2012)	56,939	36,416	4,468	4,522	Transition probabilities of metastatic to DFS, cost of trastuzumab, cost of computed tomography scan, and quality of life for metastatic stage
13	Buendía et al., 2013 [36]	US$ (2010)	181,547	103,303	98,058	20,574	Discount rate
14	Kurian et al., 2007 [37]	US$ (2005)	286,541	184,547	60,133	60,295	Discount rate, cost of trastuzumab, median survival after breast cancer recurrence, and cost of treating metastatic breast cancer
15	Seferina et al., 2017 [38]	Euro (2012)	391,049	385,327	21,067	128,626	Duration of the treatment effect
16	Liberato et al., 2007 [39]	Euro (2007)	138,017	61,825	32,086	33,829	Time horizon of the analysis
17	Lang et al., 2016 [40]	US$ (2015)	190,348	73,141	71,862	84,496	Transition probabilities of DFS for both the trastuzumab and non-trastuzumab group, health utility for non-trastuzumab group in disease free state, utility for trastuzumab in metastatic state
18	Hassett et al., 2020 [41]	US$ (2020)	236,417	302,026	254,510	Not reported	Recurrence risk
19	Skedgel et al., 2009 [42]	CAD$ (2007)	Not reported	Not reported	84,273	58,287	Discount rate and cost of trastuzumab
20	Macedo et al., 2010 [43]	Euro (2007)	138,018	111,550	13,176	Not reported	Discount rate, QALY values, and costs not associated with trastuzumab
21	Konishi et al., 2022 [44]	¥ (2020)	36,505	29,058	20,398	56,449	Transition probabilities from DFS to metastatic
22	Botelho et al., 2022 [45]	US$ (2018)	42,224	25,522	23,429	10,102	HR, the cost of trastuzumab, and hospital cost in the DFS, local, regional, and contralateral, metastatic and death states

Abbreviations: DFS = Disease-free survival; HR = Hazard ratio; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year.

Table 3. Methods used and sources of the health state utilities in the included studies.

No	Author, year	Health states	Reference method	Population	Cited sources	Health state utility value
1	Garrison et al., 2007 [46]	Year 1: AC-T including treatment	SG and TTO	General population	Oestreicher et al., 2005 [48]	0.77
		Year 1: AC-TH treatment	SG and TTO	General population	Oestreicher et al., 2005 [48]	0.71
		Year2+ stable disease utility	SG and TTO	General population	Oestreicher et al., 2005 [48]	0.9
		Year2+ recurrence utility	SG and TTO	General population	Hornberger et al., 2002 [49]	0.6
2	Aboutorabi et al., 2014 [27]	Treatment with AC-T	VAS	Patients	Earle et al. 2000 [19]	0.94
		Treatment with AC-TH	VAS	Patients	Earle et al., 2000 [19]	0.94
		Disease free survival	VAS	Patients	Earle et al., 2000 [19]	0.98
		Congestive heart failure	SG and TTO	Patients	Lewis et al., 2001 [50]	0.64
		Local recurrence	TTO, EQ5D	Patients	Lidgren et al., 2007 [51]	0.615
		Distant recurrence	SG	Exploratory interview with expert physicians	Lloyd et al., 2006 [52]	0.615
3	Hall et al., 2011 [28]	Disease free survival	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.77
		Trastuzumab treatment	Assumption	Not reported	Authors’ assumption	0.77
		Asymptomatic cardiac toxicity	Assumption	Not reported	Authors’ assumption	0.77
		Symptomatic cardiac toxicity	EQ-5D	Patients	Calvert et al., 2005 [53]	0.60
		Local recurrence	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.78
		Second primary cancer (first y)	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.70
		Distant recurrence	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.69
		Distant recurrence	EORTC QLQ-C30	Patients	Dinnes et al., 2001 [54]	0.69
4	Pichon-Riviere et al., 2015 [29]	Remission	EQ-5D	General population and patients	Lidgren et al., 2008 [55]	0.97
		Local recurrence	EQ-5D	General population and patients	Lidgren et al., 2008 [55]	0.82
		Distance recurrence	EQ-5D	General population and patients	Lidgren et al., 2008 [55]	0.58
		Cardiac toxicity	EQ-5D	Patients	Calvert et al., 2005 [53]	0.50
5	Gupta et al., 2020 [30]	Disease free survival in first year	Review	Patients	Chen et al., 2009 [56]	0.75
		Disease free survival after first year	Review	Patients	Chen et al., 2009 [56]	0.85
		Local recurrence	Review	Patients	Chen et al., 2009 [56]	0.81
		Metastatic	Review	Patients	Chen et al., 2009 [56]	0.48
6	Younis et al., 2020 [24]	DFS on treatment	KATHERINE EQ-5Db with Canadian tariffs	Patients	Cohort	0.81
		DFS off treatment	KATHERINE EQ-5Db with Canadian tariffs	Patients	Cohort	0.83
		Local recurrence	Assume equal to DFS on treatment	Not reported	Authors’ assumption	0.81
		Remission	Assume equal to DFS on treatment	Not reported	Authors’ assumption	0.83
		First-line (metastatic breast cancer)	SG	General population and patients	Lloyd et al., 2006 [52]	0.76
		Subsequent line (metastatic breast cancer)	SG	General population and patients	Lloyd et al., 2006 [52]	0.51
7	Hajjar et al., 2019 [31]	Therapy (no adjuvant trastuzumab)	SG and TTO	General population	Kurian et al., 2007 [37]; Garrison et al., 2007 [46]	0.81
		Utility due to high toxicity (all trastuzumab arms)	VAS, CEA registry, EQ-5D	General population	Kurian et al., 2007 [37]; Skedgel et al., 2013 [47]	0.56
		Utility due to low toxicity (all trastuzumab arms)	VAS, CEA registry, EQ-5D	General population	Kurian et al., 2007 [37]; Skedgel et al., 2013 [47]	0.85
		Adjuvant therapy (TH)	VAS	Patients	Slamon, 2011 [57]; Kurian et al., 2007 [37]	0.79
		Adjuvant therapy (ACTH and TCH)	Not reported	General population	Kurian et al., 2007 [37]; Garrison et al., 2007 [46]	0.78
		40–49	EQ-5D	General population	Skedgel et al., 2013 [47]	0.84
		50–59	EQ-5D	General population	Skedgel et al., 2013 [47]	0.83
		60–69	EQ-5D	General population	Skedgel et al., 2013 [47]	0.83
		70–79	EQ-5D	General population	Skedgel et al., 2013 [47]	0.81
		>80	EQ-5D	General population	Skedgel et al., 2013 [47]	0.78
		Utility of relapse	SG and VAS	General population	Kurian et al., 2007 [37]	0.55
		Utility after therapy (relapse-free)	SG	General population	Garrison et al., 2007 [46]	0.9
8	Schwartz et al., 2019 [25]	Baseline	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.86
		Month 1–2	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.84
		Month 3–5	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.84
		Month 6–8	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.84
		Month 9–11	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.84
		Month 12	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.85
		Remission, placebo	EQ-5D	Patients	Delaloge et al., 2019 [58]
		Baseline	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.86
		Month 1–2	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.86
		Month 3–5	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.84
		Month 6–8	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.85
		Month 9–11	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.84
		Month 12	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.85
		Remission, no drug (after 12 months)	EQ-5D	Patients	Delaloge et al., 2019 [58]	0.85
		Disease progression	Not reported	Not reported	Hornberger et al., 2002 [49]	0.60
9	Purmonen et al., 2011 [32]	Primary breast cancer, 1st year	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.69
		Primary breast cancer, subsequent years	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.78
		Metastatic breast cancer	EQ-5D	Patients	Lidgren et al., 2007 [51]	0,68
		Dead	EQ-5D	Patients	Lidgren et al., 2007 [51]	0.00
10	Gershon et al., 2019 [33]	Remission	Not reported	General population and patients	Norum et al., 2007 [59]; Garrison et al., 2007 [46]	0.94
		Local recurrence	Not reported	Patients	Piccart-Gebhart et al., 2005 [11]	0.82
		Distant recurrence	Not reported	Patients	Piccart-Gebhart et al., 2005 [11]	0.58
11	Genuino et al., 2019 [34]	Disease free survival	EQ-5D-3L	Patients	Not reported	0.83
		CHF	EQ-5D-3L	Patients	Not reported	0.67
		Recurrence	EQ-5D-3L	Patients	Not reported	0.83
		Metastatic	EQ-5D-3L	Patients	Not reported	0.76
12	Kongsakon et al., 2019 [35]	Non metastatic	Review	General population	Oestreicher et al., 2005 [48]; Hornberger et al., 2002 [49]	0.90
		Metastatic	Review	General population	Oestreicher et al., 2005 [48]; Hornberger et al., 2002 [49]	0.60
13	Buendía et al., 2013 [36]	Disease free survival	Not reported	Not reported	Published literature unknown	0.85
		Local recurrence	Not reported	Not reported	Not reported	0.81
		Metastatic	Not reported	Not reported	Not reported	0.48
		Cardiac events	Not reported	Not reported	Not reported	0.70
14	Kurian et al., 2007 [41]	Symptomatic heart failure	VAS	Patients	Lewis EF et al., 2001 [50]	0.64
		Cardiac toxicity with symptoms	Assumption	Not reported	Assumption	1.00
		Breast cancer recurrence	SG and VAS	Nurses who were acting as proxy patients	Lewis EF et al., 2001 [50]	0.55
		Weighted average, cardiac toxicity utility	VAS	Patients	Lewis EF et al., 2001 [50]	0.91
		Well	TTO	General population	Fryback DG et al., 1993 [60]	1.00
		Well, age 45–54 years	TTO	General population	Fryback DG et al., 1993 [60]	0.90
		Well, age 55–64 years	TTO	General population	Fryback DG et al., 1993 [60]	0.87
		Well, age 65–74 years	TTO	General population	Fryback DG et al., 1993 [60]	0.83
		Well, age >75 years	TTO	General population	Fryback DG et al., 1993 [60]	0.79
15	Seferina et al., 2017 [38]	Disease free survival	EQ-5D with UK tariffs	Patients	Cohort	0.73
		Disease free survival after first year	EQ-5D with UK tariffs	Patients	Cohort	0.81
		Local recurrence first year	EQ-5D with UK tariffs	Patients	Cohort	0.72
		Local recurrence after first year	EQ-5D with UK tariffs	Patients	Cohort	0.71
		Distant metastases in first year	EQ-5D with UK tariffs	Patients	Cohort	0.58
		Distant metastases after first year	EQ-5D with UK tariffs	Patients	Cohort	0.60
		Cardiac toxicity	EQ-5D	Patients	Calvert MJ et al., 2005 [53]	0.6
		Disutility	EQ-5D with UK tariffs	Patients	Cohort	0.13
16	Liberato et al., 2007 [39]	Disease free (in patients without symptomatic cardiac dysfunction)	TTO	Patients	Kirsch J, 2000 [61]	0.97
		Disease free (in patients with symptomatic cardiac dysfunction)	EQ-5D	Patients	Kirsch J, 2000 [61]	0.51
		Disease free after local relapse	Not reported	Patients	Kirsch J, 2000 [61]	0.92
		Local recurrence	Observational study	Patients	Not reported	0.82
		Metastatic disease	Observational study	Patients	Not reported	0.58
17	Lang et al., 2016 [40]	Disease free survival	Not reported	Patients	Not reported	0.83
		Local recurrence to metastatic	Not reported	Patients	Not reported	0.81
		Metastatic to death	Not reported	Patients	Murray CJ et al., 2000 [62]; Hedden L et al., 2012 [63]; Lidgren M et al., 2007 [51]	0.65
18	Hasset et al., 2020 [41]	Recurrence	SG	General population and patients	Lloyd et al., 2006 [52]	0.60
		Post-surgery (off treatment)	VAS	Patients	de Koning et al., 1991 [64]	0.87
19	Skedgel et al., 2009 [42]	Well, off treatment	CEA registry	Not reported	CEA registry	0.90
		Well, on adjuvant trastuzumab	VAS	Patients	Kurian et al., 2007 [37]	0.92
		Cardiotoxicity	CEA registry	Not reported	Gold, 1996 [65]	0.83
		1st local cancer recurrence	CEA registry	Not reported	CEA registry	0.70
		2nd local cancer recurrence	CEA registry	Not reported	CEA registry	0.50
		Well after LCR	CEA registry	Not reported	CEA registry	0.90
		Distant recurrence	CEA registry	Not reported	CEA registry	0.60
20	Macedo et al., 2010 [43]	Disease free survival in first year	TTO	Patients	Tengs and Wallace, 2000 [66]	0.75
		Disease free survival after first year	TTO	Patients	Tengs and Wallace, 2000 [66]	0.84
		Metastatic disease in first year	TTO	Patients	Hayman, 1998 [67]	0.48
		Metastatic disease after first year	Basic reference gamble	Patients	Carter, 1998 [68]	0.48
		Local recurrence	SG	Patients	Tengs and Wallace, 2000 [66]	0.81
21	Konishi et al., 2022 [44]	Disease free survival in first year	FACT-G	Patients	Taira et al., 2021 [69]	0.81
		Disease free survival after first year	FACT-G	Patients	Taira et al., 2021 [69]	0.83
		Recurrence	Observational study	Patients	Liberato et al., 2007 [39]	0.82
		Metastatic	Observational study	Patients	Liberato et al., 2007 [39]	0.58
		Death	Observational study	Patients	Liberato et al., 2007 [39]	0
22	Botelho et al., 2022 [45]	Disease free survival in the first year	TTO	Patients	Macedo et al., 2010 [43]	0.749
		Local, regional, and contralateral	SG	Patients	Macedo et al., 2010 [43]	0.81
		Metastatic	TTO	Patients	Macedo et al., 2010 [43]	0.484

Abbreviations: A = Doxorubicin; C = Cyclophosphamide; CEA = Cost-effectiveness analysis; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30; EQ-5D = EuroQoL-5 Dimensions; EQ-5D-3L = EuroQoL-5 Dimensions-3Levels; T = Paclitaxel; H = Trastuzumab; TTO = Time trade-off; SG = Standard gamble; VAS = Visual Analog Scale.

Figure 2. Bibliometric network of the connections between the selected studies included in this review and those cited as the sources of utilities.

Table 4. Overall survival values in the included studies.

No	Author, year	Overall survival value (%)		Sources and methods	Reference(s)
		Trastuzumab with chemotherapy	Chemotherapy without trastuzumab
1	Garrison et al., 2007 [46]	91	87	The data were projected from the combined analysis of data from the 4-year NSABP B-31 and NCCTG N9831 trials and extrapolated to 20-year and lifetime horizons using a Markov model	[12,71]
2	Aboutorabi et al., 2014 [27]	85	93	Based on data from the BCIRG 006 trial	[57]
3	Hall et al., 2011 [28]	92.40	89.70	Data from the HERA trial; based on the assumption of DFS that predicts the OS	[72]
4	Pichon-Riviere et al., 2015 [29]	97.40	94.20	Data from the HERA trial	[72]
5	Gupta et al., 2020 [30]	Not reported	66.10	Data from the CONCORD study, HERA trial, and calibration of the model for the counterfactual scenario to predict survival based on breast cancer survival from 2 Indian cancer registries	[73]
6	Younis et al., 2020 [24]	Not reported	Not reported	Not reported
7	Hajjar et al., 2019 [31]	Not reported	Not reported	Not reported
8	Schwartz et al., 2019 [25]	Not reported	Not reported	Based on data obtained from ExteNET	[74]
9	Purmonen et al., 2011 [32]	Not reported	Not reported	Data from the FinHer trial	[75]
10	Gershon et al., 2019 [33]	Not reported	Not reported	Not reported
11	Genuino et al., 2019 [34]	Not reported	Not reported	Not reported
12	Kongsakon et al., 2019 [35]	85.70	73.50	Data from a combined analysis extrapolated to a lifetime horizon using a cohort simulation model	[76]
13	Buendía et al., 2013 [36]	Not reported	Not reported	Data from the NCCTG N9831 and NSABP B-31 and HERA trials	[12,72]
14	Kurian et al., 2007 [37]	Not reported	Not reported	Data from a pivotal randomized trial of trastuzumab for metastatic disease	[77]
15	Seferina et al., 2017 [38]	Not reported	Not reported	Data from all patients in cohort studies (in real-world settings) and from the HERA trial	[72,78]
16	Liberato et al., 2007 [39]	Not reported	Not reported	Data from a trial	[77]
17	Lang et al., 2016 [40]	Not reported	Not reported	Not reported
18	Hassett et al., 2020 [41]	Not reported	Not reported	Not reported
19	Skedgel et al., 2009 [42]	Not reported	Not reported	Data from the HERA trial of adjuvant trastuzumab	[72]
20	Macedo et al., 2010 [43]	Not reported	Not reported	Not reported
21	Konishi et al., 2022 [44]	95.3	92.4	Data from a trial	[79]
22	Botelho et al., 2022 [45]	79	73	Data from the HERA trial	[80]

Abbreviations: BCIRG 006 = Breast Cancer International Research Group; DFS = Disease Free Survival; FinHer = The Finland Herceptin; HERA = HERceptin Adjuvant; NSABP B-31 = National Surgical Adjuvant Breast and Bowel Project B-31; NCCTG N9831 = North Central Cancer Treatment Group N9831; OS = Overall survival.

Garrison LP, Lubeck D, Lalla D, et al. Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer. Cancer. 2007 [cited 2024 Apr 15];110(3):489–498. doi: 10.1002/cncr.22806

 PubMed Web of Science ®Google Scholar

Aboutorabi A, Hadian M, Ghaderi H, et al. Cost-effectiveness analysis of trastuzumab in the adjuvant treatment for early breast cancer. Glob J Health Sci. 2015 [cited 2024 Mar 19];7(1):98. doi: 10.5539/gjhs.v7n1p98

 Google Scholar

Hall PS, Hulme C, McCabe C, et al. Updated cost-effectiveness analysis of trastuzumab for early breast cancer: a UK perspective considering duration of benefit, long-term toxicity and pattern of recurrence. PharmacoEconomics. 2011;29(5):415–432. doi: 10.2165/11588340-000000000-00000

 PubMed Web of Science ®Google Scholar

Pichon-Riviere A, Garay OU, Augustovski F, et al. Implications of global pricing policies on access to innovative drugs: the case of trastuzumab in seven Latin American countries. Int J Technol Assess Health Care. 2015 [cited 2022 Mar 14];31:2–11. doi: 10.1017/S0266462315000094

 PubMed Web of Science ®Google Scholar

Gupta N, Verma RK, Gupta S, et al. Cost effectiveness of trastuzumab for management of breast cancer in India. JCO Glob Oncol. 2020 [cited 2022 Mar 14];6(6):205–216. doi: 10.1200/JGO.19.00293

 PubMedGoogle Scholar

Younis T, Lee A, Coombes ME, et al. Economic evaluation of adjuvant trastuzumab emtansine in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment in Canada. Curr Oncol. 2020 [cited 2022 Mar 14];27:578–589. Available from: http://www.current-oncology.com.

 Web of Science ®Google Scholar

Hajjar A, Ergun MA, Alagoz O, et al. Cost-effectiveness of adjuvant paclitaxel and trastuzumab for early-stage node-negative, HER2-positive breast cancer. PLoS One. 2019 [cited 2022 Mar 14];14(6):e0217778. doi: 10.1371/journal.pone.0217778

 PubMed Web of Science ®Google Scholar

Schwartz NRMM, Flanagan MR, Babigumira JB, et al. Cost-effectiveness analysis of adjuvant neratinib following trastuzumab in early-stage HER2-positive breast cancer. J Manag Care Spec Pharm. 2019 [cited 2022 Mar 14];25(10):1133–1139. doi: 10.18553/jmcp.2019.25.10.1133

 PubMed Web of Science ®Google Scholar

Purmonen TT, Pänkäläinen E, Turunen JHO, et al. Short-course adjuvant trastuzumab therapy in early stage breast cancer in Finland: cost-effectiveness and value of information analysis based on the 5-year follow-up results of the FinHer Trial. Acta Oncol (Madr). 2011 [cited 2024 Mar 19];50(3):344–352. doi: 10.3109/0284186X.2011.553841

 PubMed Web of Science ®Google Scholar

Gershon N, Berchenko Y, Hall PS, et al. Cost effectiveness and affordability of trastuzumab in sub-saharan Africa for early stage HER2-positive breast cancer. Cost Eff Resour Alloc. 2019 [cited 2022 Mar 14];17:5. doi: 10.1186/s12962-019-0174-7

 PubMed Web of Science ®Google Scholar

Genuino AJ, Chaikledkaew U, Guerrero AM, et al. Cost-utility analysis of adjuvant trastuzumab therapy for HER2-positive early-stage breast cancer in the Philippines. BMC Health Serv Res. 2019;19(1):874. doi: 10.1186/s12913-019-4715-8

 PubMed Web of Science ®Google Scholar

Kongsakon R, Lochid-Amnuay S, Kapol N, et al. From research to policy implementation: trastuzumab in early-stage breast cancer treatment in Thailand. Value Health Reg Issues. 2019;18:47–53. doi: 10.1016/j.vhri.2018.08.004

 PubMedGoogle Scholar

Buendía JA, Vallejos C, Pichón-Rivière A. Evaluación económica del trastuzumab como tratamiento adyuvante en cáncer de mama HER2-positivo en Colombia. Biomedica. 2013 [cited 2022 May 13];33(3):411–417. Available from: http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-41572013000300010&lng=en&nrm=iso&tlng=en

 PubMed Web of Science ®Google Scholar

Kurian AW, Thompson RN, Gaw AF, et al. A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/ neu –positive breast cancer. J Clin Oncol. 2007;25(6):634–641. doi: 10.1200/JCO.2006.06.3081

 PubMed Web of Science ®Google Scholar

Seferina SC, Ramaekers BLTT, de Boer M, et al. Cost and cost-effectiveness of adjuvant trastuzumab in the real world setting: a study of the southeast Netherlands breast cancer consortium. Oncotarget. 2017 [cited 2022 Mar 14];8:79223–79233. doi: 10.18632/oncotarget.16985.

 PubMedGoogle Scholar

Liberato NL, Marchetti M, Barosi G. Cost effectiveness of adjuvant trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol. 2007;25(6):625–633. doi: 10.1200/JCO.2006.06.4220

 PubMed Web of Science ®Google Scholar

Lang H-C, Chen H-W, Chiou T-J, et al. The real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu-positive early breast cancer in Taiwan. J Med Econ. 2016;19(10):923–927. doi: 10.1080/13696998.2016.1185013

 PubMed Web of Science ®Google Scholar

Hassett MJ, Li H, Burstein HJ, et al. Neoadjuvant treatment strategies for HER2-positive breast cancer: cost-effectiveness and quality of life outcomes. Breast Cancer Res Treat. 2020 [cited 2024 Mar 17];181(1):43–51. doi: 10.1007/s10549-020-05587-5

 PubMed Web of Science ®Google Scholar

Skedgel C, Rayson D, Younis T. The cost-utility of sequential adjuvant trastuzumab in women with Her2/Neu-positive breast cancer: an analysis based on updated results from the HERA trial. Value Health. 2009;12(5):641–648. doi: 10.1111/j.1524-4733.2009.00511.x

 PubMed Web of Science ®Google Scholar

Macedo A, Monteiro I, Andrade S, et al. Cost-effectiveness of trastuzumab in the treatment of early stages breast cancer patients, in Portugal. Acta Med Port. 2010;23(3):475–482.

 PubMed Web of Science ®Google Scholar

Konishi T, Fujiogi M, Michihata N, et al. Cost-effectiveness analysis of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with HER2-positive early breast cancer. Jpn J Clin Oncol. 2022 [cited 2024 Mar 19];52:1115–1123. doi: 10.1093/jjco/hyac107

 PubMed Web of Science ®Google Scholar

Botelho CH, Estevez-Diz MDP, Campolina AG. Cost-effectiveness analysis of trastuzumab for early breast cancer in Brazil. Expert Rev Pharmacoecon Outcomes Res. 2022 [cited 2022 Sep 6];22(1):63–72. doi: 10.1080/14737167.2021.1909478

 PubMed Web of Science ®Google Scholar

Garrison LPJ, Lubeck D, Lalla D, et al. Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer. Cancer. 2007 [cited 2022 Mar 14];110(3):489–498. doi: 10.1002/cncr.22806

 PubMed Web of Science ®Google Scholar

Oestreicher N, Ramsey SD, Linden HM, et al. Gene expression profiling and breast cancer care: what are the potential benefits and policy implications? Genet Med. 2005 [cited 2022 Mar 1];7(6):380–389. doi: 10.1097/01.GIM.0000170776.31248.75

 PubMed Web of Science ®Google Scholar

Hornberger J, Kerrigan M, Foutel V. Cost-effectiveness of trastuzumab (herceptin) for treatment of metastatic breast cancer. Ann Oncol. 2002;13:52.

 PubMedGoogle Scholar

Earle CC, Chapman RH, Baker CS, et al. Systematic overview of cost-utility assessments in oncology. J Clin Oncol. 2000 [cited 2022 Feb 22];18(18):3302–3317. doi: 10.1200/JCO.2000.18.18.3302

 PubMed Web of Science ®Google Scholar

Lewis EF, Johnson PA, Johnson W, et al. Preferences for quality of life or survival expressed by patients with heart failure. J Heart Lung Transplant. 2001;20(9):1016–1024. doi: 10.1016/S1053-2498(01)00298-4

 PubMed Web of Science ®Google Scholar

Lidgren M, Wilking N, Jönsson B, et al. Health related quality of life in different states of breast cancer. Qual Life Res. 2007 [cited 2022 Feb 22];16(6):1073–1081. doi: 10.1007/s11136-007-9202-8.

 PubMed Web of Science ®Google Scholar

Lloyd A, Nafees B, Narewska J, et al. Health state utilities for metastatic breast cancer. Br J Cancer. 2006 [cited 2022 Feb 21];95:683. doi: 10.1038/sj.bjc.6603326

 PubMed Web of Science ®Google Scholar

Calvert MJ, Freemantle N, Cleland JGF. The impact of chronic heart failure on health-related quality of life data acquired in the baseline phase of the CARE-HF study. Eur J Heart Fail. 2005 [cited 2022 Feb 22];7(2):243–251. doi: 10.1016/j.ejheart.2005.01.012

 PubMed Web of Science ®Google Scholar

Dinnes J, Cave C, Huang S, et al. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review. Health Technol Assess (Rockv). 2001;5(13). doi: 10.3310/hta5130

 Google Scholar

Lidgren M, Jönsson B, Rehnberg C, et al. Cost-effectiveness of HER2 testing and 1-year adjuvant trastuzumab therapy for early breast cancer. Ann Oncol. 2008 [cited 2022 Feb 22];19(3):487–495. doi: 10.1093/annonc/mdm488

 PubMed Web of Science ®Google Scholar

Chen W, Jiang Z, Shao Z, et al. An economic evaluation of adjuvant trastuzumab therapy in HER2-positive early breast cancer. Value Health. 2009 [cited 2022 Mar 1];12(Suppl 3):S82–4. Available from: https://pubmed.ncbi.nlm.nih.gov/20586989/

 PubMed Web of Science ®Google Scholar

Skedgel C, Rayson D, Younis T. Is adjuvant trastuzumab a cost-effective therapy for HER-2/neu-positive T1bN0 breast cancer? Ann Oncol. 2013;24(7):1834–1840. doi: 10.1093/annonc/mdt069

 PubMed Web of Science ®Google Scholar

Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 [cited 2022 May 15];365:1273. doi: 10.1056/NEJMoa0910383

 PubMed Web of Science ®Google Scholar

Delaloge S, Cella D, Ye Y, et al. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 [cited 2022 Feb 22];30(4):567–574. doi: 10.1093/annonc/mdz016

 PubMed Web of Science ®Google Scholar

Norum J, Olsen JA, Wist EA, et al. Trastuzumab in adjuvant breast cancer therapy. A model based cost-effectiveness analysis. Acta Oncol. 2007 [cited 2022 Mar 1];46(2):153–164. doi: 10.1080/02841860601096841

 PubMed Web of Science ®Google Scholar

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 [cited 2021 Nov 16];353(16):1659–1672. doi: 10.1056/NEJMoa052306

 PubMed Web of Science ®Google Scholar

Fryback DG, Dasbach EJ, Klein R, et al. The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors. Medical decision making. Med Decis Mak. 1993 [cited 2022 Feb 24];13(2):89–102. doi: 10.1177/0272989X9301300202

 PubMed Web of Science ®Google Scholar

Kirsch J, Mcguire AA. ESTABLISHING HEALTH STATE VALUATIONS for DISEASE SPECIFIC STATES: AN EXAMPLE from HEART DISEASE. Health Econ. 2000;9(2):149–158. doi: 10.1002/(SICI)1099-1050(200003)9:2<149:AID-HEC501>3.0.CO;2-N

 PubMed Web of Science ®Google Scholar

Murray CJL, Evans DB, Acharya A, et al. Development of WHO guidelines on generalized cost-effectiveness analysis. Health Econ. 2000 [cited 2022 Mar 1];9(3):235–251. Available from: http://europepmc.org/article/MED/10790702

 PubMed Web of Science ®Google Scholar

Hedden L, O’Reilly S, Lohrisch C, et al. Assessing the real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu positive breast cancer. Oncology. 2012 [cited 2022 Mar 1];17(2):164–171. doi: 10.1634/theoncologist.2011-0379

 Google Scholar

de Koning HJ, Martin van Ineveld B, van Oortmarssen GJ, et al. Breast cancer screening and cost-effectiveness; policy alternatives, quality of life considerations and the possible impact of uncertain factors. Int J Cancer. 1991 [cited 2022 Feb 22];49(4):531–537. Available from: https://onlinelibrary-wiley-com.proxy-ub.rug.nl/doi/full/10.1002/ijc.2910490410

 PubMed Web of Science ®Google Scholar

Gold M. Panel on cost-effectiveness in health and medicine. Med care. 1996;34(12 Suppl):SDS197–9.

 Web of Science ®Google Scholar

Tengs TO, Wallace A. One thousand health-related quality-of-life estimates. Med care. 2000 [cited 2022 Mar 1];38(6):583–637. doi: 10.1097/00005650-200006000-00004

 PubMed Web of Science ®Google Scholar

Hayman JA, Hillner BE, Harris JR, et al. Cost-effectiveness of routine radiation therapy following conservative surgery for early-stage breast cancer. J Clin Oncol. 1998 [cited 2022 Mar 1];16(3):1022–1029. doi: 10.1200/JCO.1998.16.3.1022

 PubMed Web of Science ®Google Scholar

Carter KJ, Ritchey NP, Castro F, et al. Treatment of early-stage breast cancer in the elderly: a health-outcome-based approach. Med Decis Making. 1998 [cited 2022 Mar 1];18(2):213–219. doi: 10.1177/0272989X9801800210

 PubMed Web of Science ®Google Scholar

Taira N, Sawaki M, Uemura Y, et al. Health-related quality of life with trastuzumab monotherapy versus trastuzumab plus standard chemotherapy as adjuvant therapy in older patients with HER2-positive breast cancer. J Clin Oncol. 2021;39(22):2452–2462. doi: 10.1200/JCO.20.02751

 PubMed Web of Science ®Google Scholar

Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 [cited 2022 May 15];353(16):1673–1684. doi: 10.1056/NEJMoa052122

 PubMed Web of Science ®Google Scholar

Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2–positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 [cited 2022 May 15];29(25):3366. doi: 10.1200/JCO.2011.35.0868

 PubMed Web of Science ®Google Scholar

Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 [cited 2022 May 15];369(9555):29–36. doi: 10.1016/S0140-6736(07)60028-2

 PubMed Web of Science ®Google Scholar

Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018 [cited 2022 May 15];391(10125):1023. doi: 10.1016/S0140-6736(17)33326-3

 PubMed Web of Science ®Google Scholar

Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 [cited 2022 May 15];17(3):367–377. doi: 10.1016/S1470-2045(15)00551-3

 PubMed Web of Science ®Google Scholar

Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2009 [cited 2022 May 15];354(8):809–820. doi: 10.1056/NEJMoa053028

 Google Scholar

Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744–3752. doi: 10.1200/JCO.2014.55.5730

 PubMed Web of Science ®Google Scholar

Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792. doi: 10.1056/NEJM200103153441101

 PubMed Web of Science ®Google Scholar

Seferina SC, Lobbezoo DJA, de Boer M, et al. Real-Life Use and effectiveness of adjuvant trastuzumab in early breast cancer patients: a study of the southeast Netherlands breast cancer consortium. Oncology. 2015 [cited 2022 May 15];20(8):856–863. doi: 10.1634/theoncologist.2015-0006

 Google Scholar

Sawaki M, Taira N, Uemura Y, et al. Randomized Controlled Trial of Trastuzumab with or without chemotherapy for HER2-positive early breast cancer in older patients. J Clin Oncol. 2020;38(32):3743–3752. doi: 10.1200/JCO.20.00184

 PubMed Web of Science ®Google Scholar

Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin adjuvant (HERA) trial. Lancet. 2017 [cited 2022 Sep 6];389(10075):1195–1205. doi: 10.1016/S0140-6736(16)32616-2

 PubMed Web of Science ®Google Scholar