Cost-effectiveness analysis of the Oncotype DX Breast Recurrence Score test in node-positive early breast cancer

Figures & data

Figure 1. Diagram of the decision-tree part of the model. The square node represents the decision whether to use the Oncotype DX test or clinical risk alone to guide chemotherapy decisions. The circle nodes are chance nodes representing the distribution of genomic risk and probability of chemotherapy assignment. The triangle nodes are the terminal nodes for the decision tree and the point at which patients enter the Markov portion of the model.

Figure 2. The long-term impact of distant recurrence of breast cancer and acute myeloid leukemia (AML) as a long-term adverse event of chemotherapy was extrapolated beyond the horizon of the clinical study using a Markov model with four mutually exclusive health states: “distant recurrence-free”, “distant recurrence”, “AML” and “dead”. It was assumed that 10.5% of patients entering the distant recurrence state previously experienced a local recurrence.

Table 1. Grade 3 or 4 adverse event costs based on incidence reported in the RxPONDER trial.

Adverse event	% in CET	% in ET	Unit cost	Cost source^a
Arthralgia	2.2	1.5	£1,409.97	HRG HD23D-J, non-elective short and long stay
Fatigue	2.3	0.4	£200.20	Consultant-led outpatient visit, WF01A medical oncology
Febrile neutropenia	4.0	0.0	£1,785.62	HRG SA35A-E, non-elective short and long stay
Neutrophil count decreased	7.3	0.0	£483.52	See description in footer^b
White blood cell count decreased	3.2	0.0	£483.52	See description in footer^b
Weighted average cost	£157.14	£22.84

^a NHS reference costs 2019–20 by default.

^b Assumed to be managed in inpatient setting in 11.5% of cases and in outpatient for the remaining cases (based on Copley-Merriman et al. Medicine. 2018;97(31):e11736; outpatient cost: NHS reference costs 2019–20: consultant-led outpatient, medical oncology; inpatient cost: NHS reference costs 2019–20: weighted average if JA12D-L, non-elective short and long stay).

Table 2. Scenario analysis results.

Parameter/assumption	Incremental cost	Incremental QALYs	ICER per QALY
Base case	–£989	0.024	Dominant^a
Clinical inputs
Decrease chemotherapy treatment effect for RS 26–100 by 50%	–£967	0.023	Dominant
% assigned to chemotherapy with RS 0–25 increased by 20%	£149	0.017	£8,568
% assigned to chemotherapy with underlying RS 0–25 without Oncotype DX test by 10%	–£426	0.021	Dominant
% assigned to chemotherapy with underlying RS 0–25 without Oncotype DX test by 20%	£143	0.017	£8,224
FEC-T chemotherapy replaced with accelerated EC-P	–£1,387	0.024	Dominant
No reduction in rate of distant recurrence after 10 years^b	–£763	0.016	Dominant
No excess risk of distant recurrence after 15 years^b	–£835	0.020	Dominant
Utility inputs
Recurrence-free utility from Farkkila et al. [1]	–£989	0.024	Dominant
Distant recurrence utility from Farkkila et al.	–£989	0.026	Dominant
Distant recurrence utility from Yousefi et al. [2]	–£989	0.021	Dominant
Distant recurrence utility from Ibarrondo et al. [3]	–£989	0.022	Dominant
Local recurrence disutility from Lidgren et al. [4]	–£989	0.025	Dominant
Chemotherapy utility decrement from Ibarrondo et al.	–£989	0.029	Dominant
Cost inputs
Price discount of 20% for the Oncotype DX test	–£1,505	0.024	Dominant
Cost of distant recurrence applied as a one-off cost	–£1,653	0.024	Dominant
Cost of distant recurrence reduced by 50%	–£1,358	0.024	Dominant
Cost of treating chemotherapy AEs reduced by 50%	–£951	0.024	Dominant
Cost of G-CSF reduced by 50%	–£502	0.024	Dominant

^a The Oncotype DX test is more effective and less costly vs. clinical risk alone.

^b Probability of distant recurrence >10 years after starting adjuvant therapy set to 50% of the probability in years 1–10.

[1] Farkkila et al. Value Health. 2011;14(7):A459; [2] Yousefi et al. Iran Red Crescent Med J. 2016;18(5); [3] Ibarrondo et al. Gac Sanit. 2020;34(1):61–68; [4] Lidgren et al. Qual Life Res. 2007;16(6):1073–1081.

Table 3. Early breast cancer chemo-endocrine therapy cost.

Parameter	Value/unit cost	Cost per model cycle	Source
Body surface area	1.75		Assumption
Vial sharing	0%		Assumption
% with 30 MIU G-CSF dose	19%		Personal communication, Edinburgh Cancer Centre
% with 48 MIU G-CSF dose	81%
Early BC chemotherapy
FEC-T	24%	Acquisition^a: £1,734; admin: £3,848	Distributions: clinical expert opinion; calculations: see Table 4; unit costs: see Table 5
TC	10%	Acquisition: £1,635; admin: £2,611
EC90/T75	29%	Acquisition: £2,308; admin: £5,085
C-D	3%	Acquisition: £2,443; admin: £3,848
TAC	1%	Acquisition: £3,046; admin: £3,848
Accelerated EC/P	24%	Acquisition: £3,537; admin: £5,085
Weekly P	3%	Acquisition: £122; admin: £7,559
EC/weekly P	8%	Acquisition: £882; admin: £10,582
Early BC endocrine therapy
Tamoxifen 20 mg/day	40%	Acquisition + admin: £50.96	Distributions: NICE DG34
Anastrozole 1 mg/day	20%	Acquisition + admin: £6.37
Letrozole 2.5 mg/day	20%	Acquisition + admin: £10.60
Exemestane 25 mg/day	20%	Acquisition + admin: £28.88
Chemotherapy AE cost	See Table 3
Drug unit costs	See Table 5

^a Includes the list price of the chemotherapy regimen and supportive treatments (G-CSF and aprepitant).

Abbreviations. FEC-T, fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m², docetaxel 100 mg/m²; TC, cyclophosphamide 600 mg/m², docetaxel 75 mg/m²; EC90/T75, epirubicin 90 mg/m², cyclophosphamide 600 mg/m², docetaxel 75 mg/m²; C-D, carboplatin AUC 6 (assumed 600 mg), cyclophosphamide 600 mg/ m², docetaxel 75 mg/m²; TAC, docetaxel 75 mg/m², doxorubicin 500 mg/m², cyclophosphamide 500 mg/m²; accelerated EC90/P, epirubicin 90 mg/m², cyclophosphamide 600 mg/m², paclitaxel 175 mg/m²; weekly P, paclitaxel 80 mg/m².

Table 4. Details of chemotherapy regimens in early breast cancer.

Regimen	Dose per admin (mg)	No. of doses	Acquisition cost^b
FEC-T
Fluorouracil 500 mg/m^2	875	3	£15.02
Epirubicin 100 mg/m^2	175	3	£243.92
Cyclophosphamide 500 mg/m^2	875	3	£35.57
Docetaxel 100 mg/m^2	175	3	£57.03
Aprepitant^a	285	6	£53.70
Filgrastim	1.5 or 2.4	6	£2,202.14
TC
Cyclophosphamide 600 mg/m^2	1,050	4	£56.91
Docetaxel 75 mg/m^2	131.25	4	£57.03
Aprepitant	285	4	£35.80
Filgrastim^b	1.5 or 2.4	4	£1,589.19
EC90/T75
Epirubicin 90 mg/m^2	157.50	4	£292.70
Cyclophosphamide 600 mg/m^2	1,050	4	£56.91
Docetaxel 75 mg/m^2	131.25	4	£57.03
Aprepitant	285	8	£71.60
Filgrastim	1.5 or 2.4	8	£2,936.19
C-D
Carboplatin AUC 6 (assumed 600 mg)	600	6	£121.68
Docetaxel 75 mg/m^2	131.25	6	£85.54
Supportive: aprepitant	285.00	6	£53.70
Supportive: filgrastim	1.5 or 2.4	6	£2,202.14
TAC
Docetaxel 75 mg/m^2	131.25	6	£85.54
Doxorubicin 500 mg/m^2	1050.00	6	£630.63
Cyclophosphamide 500 mg/m^2	875.00	6	£71.14
Supportive: aprepitant	285.00	6	£53.70
Supportive: filgrastim	1.5 or 2.4	6	£2,202.14
Accelerated EC90/P
Epirubicin 90 mg/m^2	157.50	4	£292.70
Cyclophosphamide 600 mg/m^2	1,050	4	£56.91
Paclitaxel 175 mg/m^2	306.25	4	£82.89
Aprepitant	285	8	£71.60
Filgrastim	1.5 or 2.4	8	£2,936.19
Weekly P
Paclitaxel 80 mg/m^2	140	12	£113.68

^aAprepitant used in 20% of all anthracycline and taxane cycles; filgrastim 5 units per cycle used in 20% of anthracycline cycles and with every taxane cycle and all cycles of accelerated EC90/P.

^b Cost for each regimen per 6-month model cycle. Final cost adjusted according to % used.

Abbreviations. FEC-T, fluorouracil 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m², docetaxel 100 mg/m²; TC, cyclophosphamide 600 mg/m², docetaxel 75 mg/m²; EC90/T75, epirubicin 90 mg/m², cyclophosphamide 600 mg/m², docetaxel 75 mg/m²; C-D, carboplatin AUC 6 (assumed 600 mg), cyclophosphamide 600 mg/m², docetaxel 75 mg/m²; TAC, docetaxel 75 mg/m², doxorubicin 500 mg/m², cyclophosphamide 500 mg/m²; accelerated EC90/P, epirubicin 90 mg/m², cyclophosphamide 600 mg/m², paclitaxel 175 mg/m²; weekly P, paclitaxel 80 mg/m².

Table 5. Drug unit costs.

Drug costs	Cost per vial/pack	Source
Fluorouracil 500 mg/10 ml	£2.83	eMIT^a
Epirubicin 50 mg/25 ml	£23.23
Cyclophosphamide 1 g	£13.55
Cyclophosphamide 500 mg	£8.23
Docetaxel 160 mg/8 ml	£17.38
Docetaxel 20 mg/1 ml	£3.56
Paclitaxel 150 mg/25 ml	£10.15
Carboplatin 600 mg/60 ml	£20.28
Doxorubicin 200 mg/100 ml solution for infusion vials	£20.02
Doxorubicin 50 mg/25 ml solution for injection vials	£7.09
Capecitabine 300 mg	£7.77
Capecitabine 500 mg	£26.30
Pegylated liposomal doxorubicin 50 mg/25 ml infusion vials	£360.23	BNF^b
Eribulin 0.88 mg/2 ml solution for injection vials	£361.00
Tamoxifen 20 mg	£4.20	eMIT
Anastrozole 1 mg	£0.98
Letrozole 2.5 mg	£1.63
Exemestane 25 mg	£4.76
Fulvestrant 250 mg/5 ml solution for injection	£522.41	BNF
Everolimus with exemestane 5 mg tablets	£2,200.00
Everolimus with exemestane 10 mg tablets	£2,673.00
Abemaciclib 150 mg capsule	£1,475.00
Palbociclib 125 mg capsule	£2,950.00
Ribociclib 200 mg tablet	£983.33
Aprepitant pre-made pack	£8.95	eMIT
Filgrastim 300 mcg/0.5 ml solution for injection pre-filled syringes	£246.50	BNF
Filgrastim 480 mcg/0.5 ml solution for injection pre-filled syringes	£395.25

^a Drugs and pharmaceutical electronic market information tool (eMIT) (31).

^b British National Formulary [32].

Table 6. Cost of treatment regimens in metastatic breast cancer.

Drug/dosage	1st line^a	2nd line^a	3rd line^a	Acquisition cost per model cycle	Admin cost per model cycle	Total per cycle cost
Chemotherapy
Paclitaxel 175 mg/m^2 monthly	40%	26%	0%	£2,399.74	£4,533.90	£6,933.64
Docetaxel 75 mg/m^2 monthly	27%	17%	0%	£2,321.32	£4,533.90	£6,855.22
Capecitabine 1,250 mg/m^2 daily	18%	47%	82%	£169.04	£0.00	£169.04
Epirubicin 90 mg/m^2+cyclophosphamide 600 mg/m^2 monthly	15%	0%	0%	£1,140.20	£4,533.90	£5,674.10
Caelyx 50 mg/m^2 monthly	0%	10%	0%	£4,322.76	£4,533.90	£8,856.66
Eribulin 1.23 mg/m^2 twice/month	0%	0%	18%	£12,996.00	£8,244.84	£21,240.84
CDK4/6 inhibitors
Abemaciclib 150 mg × 56 per month	33.3%^2	0%	0%	£17,715.66	£0.00	£17,715.66
Palbociclib 125 mg × 21 per month	33.3%^2	0%	0%	£17,709.78	£0.00	£17,709.78
Ribociclib 125 mg × 21 per month	33.3%^b	0%	0%	£17,709.72	£0.00	£17,709.72
Endocrine therapy
Tamoxifen 20 mg/day	18%	15%	29%	£50.96	£0.00	£50.96
Anastrozole 1 mg/day	31%	9%	14%	£6.37	£0.00	£6.37
Letrozole 2.5 mg/day	39%	18%	14%	£10.60	£0.00	£10.60
Exemestane 25 mg daily	7%	18%	14%	£28.88	£0.00	£28.88
Everolimus 10 mg and exemestane 25 mg daily	0%	16%	29%	£16,245.08	£0.00	£16,245.08
Fulvestrant 500 mg × 2 doses in first month and 1 dose in  months 2–6	4%	23%	0%	£3,895.70	£238.83	£4,134.53

^a Treatment distributions from Kurosky et al. (33) and NICE TA563 (34).

^b Assumption.

Table 7. Base case parameter values, ranges and distributions.

Parameter	Base case	DSA range	PSA SE and distribution		Source
RS distribution, N1 population
0–13	38%	Not varied	Dirichlet (2147,2871,554)		RxPONDER^16
14–25	51%
26–100	11%
Probability of chemotherapy, by RS result
0–13	5%	1%, 9%	Beta (α = 6; β = 109)		CHS^6
14–25	18%	14%, 22%	Beta (α = 83; β = 379)
26–100	77%	70%, 85%	Beta (α = 102; β = 30)
DRFI with ET (by RS result)
RS 0–25, premenopausal (5-year distant  recurrence-free)	93.9%	93%, 95%	Beta (α = 1387; β = 90)		RxPONDER^16
RS 0–25, postmenopausal (5-year distant  recurrence-free)	96.6%	96%, 97%	Beta (α = 2635; β = 93)
RS 26–100, all patients (10-year DRFS)	68.6%	45%, 84%	Beta (α = 14; β = 6)		TransATAC bespoke analysis^22
DRFI with CET (by RS result)
RS 0–25, premenopausal (5-year distant  recurrence-free)	96.3%	96%, 97%	Beta (α = 2406; β = 92)		RxPONDER^16
RS 0–25, postmenopausal (5-year distant  recurrence-free)	95.8%	95%, 97%	Beta (α = 2098; β = 92)
RS 0–25, premenopausal hazard ratio  with chemotherapy	0.64	0.43, 0.95	Gamma (k = 23, θ = 0.03)
RS 0–25, postmenopausal hazard ratio  with chemotherapy	1.12	0.82, 1.52	Gamma (k = 39, θ = 0.03)
RS 26–100, hazard ratio with  chemotherapy	0.59	0.35, 1.00	Gamma (k = 13; θ = 0)		SWOG-8814^4
Other transition probabilities
Probability of local recurrence prior to  distant recurrence	10.5%	8.8%, 12.3%	Beta (α = 129; β = 1095)		De Bock et al.^17
Reduction in DR rate in years >10	50%	Not varied	Not varied		Assumption in NICE DG34^22
6-month probability of AML	0.28%	0.21%, 0.35%	Beta (α = 70; β = 24,945)		Petrelli et al.^18
Probability of death, recurrence-free	See Table A1	Not varied	Not varied		UK life tables^19
Median overall survival, distant  recurrence (months)	46.7	37.4,56.0	Lognormal (µ=46.7; σ = 0.1)		MONARCH 2 trial^21
Median overall survival, AML (months)	9.6	7.6, 11.5	Lognormal (µ=9.6; σ = 0.1)		NICE TA552^10
Health state utility values
Recurrence-free	0.824	0.785, 0.857	Beta (α = 353; β = 75)		Lidgren et al.^23
Distant recurrence	0.685	0.620, 0.735	Beta (α = 171; β = 79)
AML	0.550	0.504, 0.596	Beta (α = 257; β = 210)		NICE TA552^10
Utility decrements
Local recurrence	0.108	0.028, 0.188	Beta (α = 6; β = 53)		Campbell et al.^24
Chemotherapy	0.038	0.030, 0.046	Beta (α = 92; β = 2338)		Lidgren et al.^23
Unit costs
Test cost Oncotype DX	£2,580	Not varied	Not varied		Assumption in NICE DG34^22
Early BC chemotherapy	See Table 4	Not varied	Not varied		N/A
Early BC endocrine therapy	See Table 4	Not varied	Not varied		N/A
Drug admin pharmacy cost	£45	£36, £54	Gamma (k = 96; θ = 0.5)		Ward et al.^13
First admin IV	£478	£383, £574	Gamma (k = 96; θ = 5.0)		NHS reference costs 2019/20: SB13Z
Subsequent admin IV	£341	£273, £410	Gamma (k = 96; θ = 3.6)		NHS reference costs 2019/20: SB15Z
Intramuscular admin	£239	£191, £287	Gamma (k = 96; θ = 2.5)		NICE TA563^34^,^35
Oral admin	£0.00	Not varied	Not varied		Assumption
Recurrence-free 1st year	£228	Individual parameters varied			Assumption in NICE DG34: 2x outpatient visits in first year, yearly outpatient visit in years 2–5, annual mammogram in years 1–5^22
Recurrence-free years 2–5	£128
Recurrence-free years 6+	£0	Not varied	Not varied
Local recurrence	£23,099	£12,372, £33,826	Gamma (k = 18; θ = 1297)		Karnon et al.^37
Distant recurrence disease management	£3,900	£3,120, £4,680	Gamma (k = 96; θ = 41)		NICE TA563^34^,^35
Distant recurrence metastatic BC chemo-  endocrine therapy	£8,828	Not varied	Not varied		See Table 6
AML one-off cost	£42,852	£34,782, £51,422	Gamma (k = 96; θ = 446)		Zeidan et al.^38
AML ongoing cost	£4,210	£3,368, £5,052	Gamma (k = 96; θ = 44)
Terminal care	£4,916	£3,933, £5,899	Gamma (k = 79; θ = 57)		Hinde et al.^39
Outpatient visit	£200	£160, £240	Gamma (k = 96; θ = 2.1)		NHS reference costs 2019/20: service code 370
LFT	£1.10	Varied in “Total drug admin tests”			NHS reference costs 2019/20: DAPS04
U&E	£1.10	Varied in “Total drug admin tests”
FBC	£2.79	Varied in “Total drug admin tests”			NHS reference costs 2019/20: DAPS05
ECG (in 25% of patients)	£49	Varied in “Total drug admin tests”			NHS reference costs 2019/20: EY51Z
Mammogram	£56	£45, £67	Gamma (k = 96; θ = 1)		Campbell et al.^24
Total drug admin tests	£17	£14, £21	Gamma (k = 96; θ = 0.2)		Sum of test unit costs

Table 8. Incremental cost-effectiveness of the Oncotype DX test compared to clinical risk alone.

Comparator	Oncotype DX	Clinical risk alone
Absolute values
Total cost	£23,138	£24,127
Total QALYs	12.69	12.66
Total life-years	16.41	16.40
Incremental values vs. clinical risk alone
Total cost	–£989	–
QALYs	0.02	–
Life-years	0.01	–
ICER per QALY	Dominant	–
ICER per life-year	Dominant	–

Table 9. Breakdown of cost for the Oncotype DX test compared to clinical risk alone.

	Oncotype DX	Clinical risk alone	Incremental cost
MGA cost	£2,580	£0	£2,580
Chemo-endocrine therapy	£1,704	£5,692	–£3,989
Short-term AEs	£49	£123	–£74
Recurrence-free	£1,327	£1,328	£0
Local recurrence	£297	£283	£14
Distant recurrence	£15,078	£14,340	£739
AML	£88	£345	–£257
Terminal care	£2,015	£2,017	–£1

Table 10. Comparison of model results to NICE DG34, Oncotype DX vs. clinical risk alone.

Scenario	Endpoint		Updated model			NICE model
		New RS cut-points (ongoing DR cost)	New RS cut-points (one-off DR cost)	Old RS cut-points (ongoing DR cost)	Old RS cut-points (one-time DR cost)	Old RS cut-points (one-time DR cost)
Oncotype DX predictive	Incr. cost	–£989	–£1,653	–£547	–£629	–£68
	Incr. QALYs	0.024	0.024	0.046	0.046	0.090
	ICER per QALY	Dominant^a	Dominant^a	Dominant^a	Dominant^a	Dominant^a
Oncotype DX not predictive	Incr. cost	–£36	–£1,530	£1,905	–£315	£647
	Incr. QALYs	–0.033	–0.033	–0.108	–0.108	–0.070
	ICER per QALY	£1,104	£46,637	Dominated^b	£2,921	Dominated^b

^a Dominant: the Oncotype DX test is more effective and less costly.

^b Dominated: the Oncotype DX test is less effective and more costly.

Figure 3. Tornado diagram representing the 10 parameters which had the largest impact on the model results. The diagram displays the effect of varying the value of each parameter across a pre-determined range which reflects the confidence interval reported in the original published source or the assumed distribution. The results are presented in terms of net monetary benefit assuming the NICE ceiling willingness-to-pay of £20,000 per QALY: NMB=£20,000 × incremental QALYs – incremental cost.

Figure 4. Scatter diagram from the probabilistic sensitivity analysis. The PSA was conducted using Monte Carlo simulation with 5,000 random draws from pre-defined probability distributions for all uncertain parameters. In the probabilistic analysis, the Oncotype DX test generated 0.02 QALYs with a cost saving of £1,017 per patient compared to clinical risk alone, which was consistent with the results of the deterministic cost-effectiveness analysis. Sixty-eight percent of the points in the scatter diagram were in the dominant south-east quadrant. The ellipse represents the area which contains 95% of the simulated points. The line from the origin corresponds to the £20,000 per QALY willingness-to-pay threshold for cost-effectiveness set by NICE.

Figure 5. Cost-effectiveness acceptability curve. The Oncotype DX test had probability of cost-effectiveness vs. clinical risk alone of 80% at a willingness-to-pay of £20,000 per QALY, and remained above 70% over the whole range of willingness-to-pay thresholds.

Table A1 UK life tables, 2016–18.

Age	Annual rate
18	0.000218
19	0.000196
20	0.000197
21	0.000224
22	0.000219
23	0.000220
24	0.000226
25	0.000260
26	0.000252
27	0.000286
28	0.000330
29	0.000314
30	0.000374
31	0.000394
32	0.000482
33	0.000500
34	0.000545
35	0.000586
36	0.000655
37	0.000738
38	0.000720
39	0.000846
40	0.000883
41	0.000993
42	0.001052
43	0.001183
44	0.001329
45	0.001437
46	0.001541
47	0.001701
48	0.001825
49	0.001937
50	0.002138
51	0.002366
52	0.002584
53	0.002759
54	0.002956
55	0.003270
56	0.003627
57	0.003903
58	0.004334
59	0.004741
60	0.005117
61	0.005615
62	0.006323
63	0.006856
64	0.007373
65	0.008027
66	0.008899
67	0.009568
68	0.010433
69	0.011426
70	0.012681
71	0.013877
72	0.016044
73	0.017700
74	0.019486
75	0.022255
76	0.025369
77	0.028178
78	0.031865
79	0.035010
80	0.039695
81	0.044925
82	0.051057
83	0.059202
84	0.067236
85	0.076619
86	0.087955
87	0.100071
88	0.114565
89	0.129490
90	0.147050
91	0.165974
92	0.185106
93	0.206525
94	0.230003
95	0.260357
96	0.284553
97	0.313245
98	0.339652
99	0.375917
100	0.409183

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Data availability statement

The parameter inputs used in the model were identified from sources in the open domain or peer-reviewed journal articles. All parameter values and their sources are reported in the article and appendix. The Excel data traces used to generate the results of the cost-effectiveness model can be obtained upon written request to the corresponding author.