Clinical and Health Economic Outcomes of Alternative HER2 Test Strategies for Guiding Adjuvant Trastuzumab Therapy

James A Lee; Megan Shaheen; Thomas Walke; Matt Daly

Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(3):325-341.

Five-year View

While there are clinical trials to evaluate alternative biomarkers and diagnostics to target anti-HER2 therapy, it is not clear to what degree these trials will result in improved diagnostics and, ultimately, clinical outcomes. To get a sense of the breadth of studies, a search of clinicaltrials.gov listed 314 distinct open studies regarding breast cancer and HER2 status throughout the world.^[102]

Regarding anti-HER2 therapy, there are numerous investigations and several promising regimens. Recent studies and clinical trials have provided insight into reasons for resistance to trastuzumab therapy and suggest that combinations of two or more anti-HER2 agents (e.g., bevacizumab, pertuzumab and TDM1) will improve patient outcomes. There are also ongoing Phase II clinical trials for anti-HER2 vaccines targeting patients with HER2-positive breast cancer. Clinically appropriate and cost-effective application of these new regimens is highly dependent on accurate HER2 testing.

Of equal importance are the subset of these trials regarding therapies directed towards the approximately 80% of breast cancer patients who are HER2-negative and unlikely to benefit from anti-HER2 therapies. As these therapies advance, the clinical and economic consequences of a false-negative test increase. Thus, in the next 5 years, the therapy options and concomitant benefits and costs are likely to increase dramatically and demand even greater accuracy in HER2 testing and related breast cancer biomarkers.

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Acknowledgement
The authors thank Michael Press for review and comments in the preparation of this article. The views expressed, however, are solely those of the authors.

Financial & competing interests disclosure
This study was funded in part by Abbott Laboratories (Abbott Park, IL, USA). The authors have served as paid consultants through Altarum Institute to Abbott Molecular Diagnostics, which funded this study. The authors retained full control and final say over the study methods, results, conclusions and manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Cite this: Clinical and Health Economic Outcomes of Alternative HER2 Test Strategies for Guiding Adjuvant Trastuzumab Therapy - Medscape - Jun 01, 2011.

Table 1. Baseline and Monte Carlo model inputs.
Variable/parameter	Baseline estimate	Range tested		Ref.
Therapy benefit
Additional benefit with AT	1.18 QALY^†	0.47–1.91		[27]
Diagnostic effectiveness
Sensitivity of alternative test	Varies by study		See Table 2
Specificity of alternative test	Varies by study		See Table 2
Cost data
Additional therapy cost with AT (US$)	27,446^†	5691–32,210		[40]
IHC test cost (US$)	119			[103]
FISH test cost (US$)	418			[103]
CISH test cost, dual probe (US$)	418		Same as FISH
CISH test cost, single probe (US$)	209		Same as FISH, one probe only
SISH test cost, dual probe	418		Same as FISH

^†The additional therapy benefit and therapy cost were obtained from [27] without modification and were based on a 15-year study horizon with costs and QALYs discounted by 3% per year.
AT: Adjuvant trastuzumab; CISH: Chromogenic in situ hybridization; FISH: Fluorescence in situ hybridization; IHC: Immunohistochemistry; QALY: Quality-adjusted life-year; SISH: Silver-enhanced in situ hybridization.

Table 2. Comparison of immunohistochemistry and fluorescence *in situ* hybridization test performance and cost–effectiveness.
Sample size (n)	IHC 0/1⁺ when FISH⁻ (negative concordance) (%)	IHC 3⁺ when FISH⁺ (positive concordance) (%)	Confirm IHC 2⁺ sensitivity (%)	Pass ASCO/CAP guidelines	Confirm IHC 2⁺ specificity (%)	Cost–effectiveness of primary FISH versus confirm IHC 2^+†	Cost– effectiveness of primary FISH versus confirm IHC 2⁺, 3^+†	Cost–effectiveness of confirm IHC 2⁺, 3⁺ versus confirm IHC 2^+†	Ref.
65	99.2	47.8	99.2	No	65.7	US$24,421	US$26,005	Confirm IHC 2⁺, 3⁺ dominant	[40]
210	99.4	42.9	99.4	No	70.0	US$25,135	US$26,778	Confirm IHC 2⁺, 3⁺ dominant	[41]
108	51.2	91.7	75.3	No	92.6	Primary FISH dominant	US$21,889	Confirm IHC 2⁺, 3⁺ dominant	[42]
2601	91.5	91.1	93.1	No	92.1	Primary FISH dominant	US$27,462	Confirm IHC 2⁺, 3⁺ dominant	[22]
998	98.2	86.1	98.2	No	90.7	US$19,431	US$29,641	Confirm IHC 2⁺, 3⁺ dominant	[10]
129	82.4	100.0	95.7	No	100.0	Primary FISH dominant	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	[43]
426	97.8	98.0	98.0	Yes	98.4	Primary FISH dominant	US$49,600	Confirm IHC 2⁺, 3⁺ dominant	[33]
529	91.8	95.1	93.5	No	95.6	Primary FISH dominant	US$26,930	Confirm IHC 2⁺, 3⁺ dominant	[44]
1527	98.0	89.4	98.3	No	92.0	US$18,918	US$28,736	Confirm IHC 2⁺, 3⁺ dominant	[45]
112	97.1	78.3	97.6	No	83.3	US$18,143	US$26,030	Confirm IHC 2⁺, 3⁺ dominant	[46]
167	96.5	97.4	97.5	Yes	97.8	Primary FISH dominant	US$36,204	Confirm IHC 2⁺, 3⁺ dominant	[19]
254	94.5	100.0	97.6	No	100.0	Primary FISH dominant	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	[47]
100	91.4	100.0	91.6	No	100.0	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	Confirm IHC 2⁺, 3⁺ dominant	[48]
289	91.7	100.0	95.0	No	100.0	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	Confirm IHC 2⁺, 3⁺ dominant	[49]
112	97.5	93.3	97.9	No	93.8	Primary FISH dominant	US$39,971	Confirm IHC 2⁺, 3⁺ dominant	[50]
2279	98.6	86.5	98.8	No	89.9	US$20,489	US$34,880	Confirm IHC 2⁺, 3⁺ dominant	[51]
78	100.0	100.0	100.0	Yes	100.0	Confirm IHC 2⁺ dominant	Confirm IHC 2⁺, 3⁺ dominant	Confirm IHC 2⁺ dominant	[32]
164	93.9	100.0	97.1	No	100.0	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	Confirm IHC 2⁺, 3⁺ dominant	[18]
110	93.9	100.0	95.2	No	100.0	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	Confirm IHC 2⁺, 3⁺ dominant	[18]
215	100.0	84.6	100.0	No	87.9	US$34,655	US$32,707	Confirm IHC 2⁺ dominant	[18]
198	95.5	83.7	96.7	No	84.4	US$11,535	US$26,073	Confirm IHC 2⁺, 3⁺ dominant	[52]
189	93.8	98.1	95.6	No	98.7	US$7906	US$31,138	Confirm IHC 2⁺, 3⁺ dominant	[68]
189	93.0	88.0		No		Primary FISH dominant	ACIS did not provide IHC 0, 1⁺, 2⁺ and 3⁺ scoring	ACIS did not provide IHC 0, 1⁺, 2⁺ and 3⁺ scoring	[69]
42	92.3	83.3	95.5	No	85.0	US$17,756	US$23,620	Confirm IHC 2⁺, 3⁺ dominant	[70]
2913	98.0	88.4	98.8	No	92.6	US$15,241	US$28,567	Confirm IHC 2⁺, 3⁺ dominant	[6]

^†The economic analysis results are the incremental cost per quality-adjusted life-year to use the first listed strategy versus the second (e.g., primary FISH vs confirmation of IHC 2⁺ with FISH). Dominant means the strategy has lower cost and higher quality-adjusted life-years.
ACIS: Automated cellular imaging system; ASCO: American Society of Clinical Oncology; CAP: College of American Pathologists; FISH: Fluorescence in situ hybridization; IHC: Immunohistochemistry.

Table 3. Comparison of *in situ* hybridization test performance and cost–effectiveness.
Sample size (n)	CISH/SISH⁻when FISH⁻ (negative concordance) (%)	CISH/SISH⁺ when FISH⁺ (positive concordance) (%)	Pass ASCO/CAP guidelines	Cost–effectiveness of FISH versus CISH/SISH (dual probe) (all priced at US$418)^†	Cost–effectiveness of FISH versus CISH (single probe) (FISH US$418, CISH US$209)^†	Ref.
74	97.4	97.1	Yes	Performed single only	US$14,859	[15]
102	100.0	100.0	Yes	Equal	Performed dual only	[16]
49	90.5	89.3	No	Performed single only	US$11,033	[5]
24	100.0	100.0	Yes	Mixed single and double	CISH dominant (performed dual-probe CISH for 19 of 24)	[34]
167	100.0	100.0	Yes	Equal	Performed dual only	[19]
194	99.4	96.8	Yes	Performed single only	US$38,916	[71]
215	98.9	100.0	Yes	Performed single only	FISH dominant	[71]
31	76.2	100.0	No	Performed single only	FISH dominant	[17]
254	94.5	96.6	No	Performed single only	FISH dominant	[47]
38	100.0	100.0	Yes	Performed single only	CISH dominant	[72]
192	91.7	95.8	No	Mixed single and double	FISH dominant (performed dual-probe CISH for seven samples)	[73]
32	95.5	100.0	Yes	FISH dominant	Performed dual only	[74]
93	98.4	100.0	Yes	FISH dominant	Performed dual only	[18]
72	100.0	96.0	Yes	US$23,258	Performed dual only	[20]
88	100.0	100.0	Yes	Mixed single and double	CISH dominant (performed dual-probe CISH for some samples)	[57]
174	94.0	97.5	No	Performed single only	FISH dominant	[62]
157	100.0	73.0	No	Performed single only	US$26,412	[64]
50	100.0	100.0	Yes	FISH dominant (performed three-probe CISH only)	Performed three-probe CISH only	[31]
208	96.9	83.8	No	Performed single only	US$21,705	[75]
33	96.0	100.0	Yes	Performed single only	FISH dominant	[76]
62	100.0	100.0	Yes	Mixed single and double	CISH dominant (performed dual-probe CISH for 34 samples)	[77]
SISH and FISH comparison
96	97.6	81.8	No	FISH dominant	SISH is a two-probe assay	[29]
136	99.1	100.0	Yes	FISH dominant	SISH is a two-probe assay	[78]
290	98.8	100.0	Yes	FISH dominant	SISH is a two-probe assay	[21]
298	96.2	100.0	Yes	FISH dominant	SISH is a two-probe assay	[21]
53	97.5	84.6	No	US$11,632	SISH is a two-probe assay	[30]

^†The economic analysis results are the incremental cost per quality-adjusted life-year to use the first listed strategy versus the second (e.g., primary FISH vs primary CISH). Dominant means the strategy has lower cost and higher quality-adjusted life-years.
ASCO: American Society of Clinical Oncology; CAP: College of American Pathologists; CISH: Chromogenic in situ hybridization; FISH: Fluorescence in situ hybridization; SISH: Silver-enhanced in situ hybridization

Table 4. Observed error rate in 46 studies comparing immunohistochemistry and fluorescence *in situ* hybridization using a confirm immunohistochemistry 2+ protocol.
Error rate observed in study (per 1000 tests performed)	False-negative	False-positive
Zero	10	6
1–9.9	5	9
10–19.9	11	8
20–29.9	7	9
30–39.9	4	5
40+	9	9
Total studies	46	46

Table 5. Economic analysis of range of assumptions for primary fluorescence *in situ* hybridization and confirmation of immunohistochemistry.
Sample size (n)	Pass ASCO/CAP guidelines	% HER2 positive by FISH	Sensitivity (confirm IHC 2⁺) (%)	Specificity (confirm IHC 2⁺) (%)	Sensitivity (confirm IHC 2⁺ and 3⁺) (%)	Specificity (confirm IHC 2⁺ and 3⁺) (%)	Cost– effectiveness of primary FISH versus confirm IHC 2^+†	Cost– effectiveness of primary FISH versus confirm IHC 2⁺ and 3^+†	Ref.
426	Yes	29.1	98.4	98.0	98.4	100.0	US$2661 (99.9%)	US$50,968 (56.4%)	[33]
687	Yes	11.4	100.0	96.9	100.0	100.0	Primary FISH dominant	Confirm IHC 2⁺, 3⁺ dominant	[67]
167	Yes	25.1	95.2	96.0	95.2	100.0	Primary FISH dominant	US$34,470 (90.0%)	[62]
116	Yes	31.0	97.2	100.0	97.2	100.0	US$38,892 (83.1%)	US$31,037 (94.2%)	[61]
998	No	26.0	90.7	98.2	90.7	100.0	US$19,372 (99.9%)	US$28,994 (96.0%)	[10]
2601	No	28.8	92.1	93.1	92.1	100.0	Primary FISH dominant	US$27,159 (97.2%)	[22]
842	No	29.0	92.2	90.5	92.2	100.0	Primary FISH dominant	US$27,253 (97.1%)	[14]

^†The economic analysis results are the average, incremental cost per quality-adjusted life-year to use the first listed strategy versus the second (e.g., primary FISH vs confirmation of IHC 2+ with FISH) over 10,000 model runs. The percentage value in parentheses is the percentage of model runs that result in primary FISH having a cost–effectiveness of less than US$50,000 per QALY. Dominant means the strategy has lower cost and higher quality-adjusted life-years.
ASCO: American Society of Clinical Oncology; CAP: College of American Pathologists; FISH: Fluorescence in situ hybridization; HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry.

Table 6. Comparison of hypothetical alternative and reference assays.
Price differential (US$)	Population HER2 positivity (%)	95% certainty cut-off (sensitivity, specificity) (%)
50	20	(100, 99)
100	20	(100, 99)
200	15	(98, 99)
200	20	(98, 99)
200	25	(98, 99)
300	20	(98, 98)
400	20	(97, 98)

Price differential: price of reference assay minus alternative assay. Population HER2 positivity: share of population that is HER2-positive using reference assay. If the sensitivity or specificity is less than the cut-off, then a 95% or greater proportion of model runs resulted in the reference assay having a cost per quality-adjusted life-year of less than US$50,000. HER2: Human epidermal growth factor receptor 2.

Appendix. Example Concordance & Baseline Economic Calculations

Article: Dowsett M, Bartlett J, Ellis IO et al. Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J. Pathol. 199, 418–423 (2003).
Data: Table 2b, Page 420

Table 2b from Dowsett et al. [33].
FISH result	IHC result			Total
FISH result	0 and 1⁺	2⁺	3⁺	Total
FISH⁺	2	26	96	124
FISH⁻	268	28	6	302
Reproduced with permission from [31].

Concordance Calculations

Assuming FISH serves as the reference assay, and excluding IHC equivocal results (IHC 2+):

Again assuming FISH serves as the reference assay, but including IHC equivocal results as concordant with the reference assay to reflect common practice of confirming equivocal results with the reference assay:

Health Economic Calculations

Based on the price and benefit assumptions presented in Table 1 of this article:

Where FISH serves as the reference assay, and confirming IHC equivocal results as concordant with FISH:

Confirming immunohistochemistry equivocal results as concordant with fluorescence in situ hybridization.
Category	Confirm IHC 2+	Primary FISH	Difference
Test price	426 primary tests @ US$119 54 equivocals confirmed @ US$418 Total = US$73,266	426 primary tests @ US$418 Total = US $178,068	+US$104,802
Therapy price	26 + 96 + 6 = 128 positive patients @ US$27,446 (IHC 2+ with FISH+ or IHC 3+) Total = US$3,513,088	96 + 26 + 2 = 124 positive patients @ US$27,446 (all FISH+) Total = US$3,403,304	-US$109,784
Total	US$3,586,354	US$3,581,372	-US$4,982
Therapy benefit	96 + 26 = 122 FISH+ patients @ 1.18 QALYs (IHC 3+ or IHC 2+ with FISH+) Total = 143.96	96 + 26 + 2 = 124 FISH+ patients @ 1.18 QALYs (all FISH+) Total = 146.32	+2.36 QALYs
FISH: Fluorescence in situ hybridization; IHC: Immunohistochemistry; QALY: Quality-adjusted life-year.

Since the total price is US$4,982 less and the QALYs increase by 2.36 with primary FISH, primary FISH is dominant (i.e., lower price, higher quality) over confirm IHC 2+ with FISH.

The calculations are similar for confirming IHC 2+ and IHC 3+ patients:

Calculations for confirming immunohistochemistry 2+ and 3+ patients.
Category	Confirm IHC 2+ and 3+	Primary FISH	Difference
Test price	426 primary tests @ US$119 156 confirmed @ US$418 Total = US$115,902	426 primary tests @ $418 Total = US$178,068	+US$62,166
Therapy price	96 + 26 = 122 positive patients @ US$27,446 (IHC 3+ with FISH+ or IHC 2+ with FISH+) Total = US$3,348,412	96 + 26 + 2 = 124 positive patients @ US$27,446 Total = US$3,403,304	+US$54,892
Total	US$3,464,314	US$3,581,372	+US$117,058
Therapy benefit	96 + 26 = 122 FISH+ patients @ 1.18 QALYs (only IHC 3+ and IHC 2+ patients who test FISH+) Total = 143.96	96 + 26 + 2 = 124 FISH+ patients @ 1.18 QALYs (all FISH+ patients) Total = 146.32	+2.36 QALYs
FISH: Fluorescence in situ hybridization; IHC: Immunohistochemistry; QALY: Quality-adjusted life-year.

The price difference is US$117,058 to achieve 2.36 additional QALYs or US$49,600 per QALY.

Even when selecting a study where IHC compares very favorably with FISH and meets the ASCO/CAP guidelines for concordance, primary FISH is observed to be lower price and higher quality than confirming IHC 2+ only. Relative to confirming both IHC 2+ and 3+, primary FISH results in increased price and increased quality, but with a favorable cost–effectiveness ratio of less than US$50,000 per QALY.

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