Accuracy of HER2 Status Determination on Breast Core-needle Biopsies (Immunohistochemistry, FISH, CISH and SISH vs FISH)

Laurent Arnould; Pascal Roger; Gaëtan MacGrogan; Marie-Pierre Chenard; André Balaton; Sophie Beauclair; Frederique Penault-Llorca

Disclosures

Mod Pathol. 2012;25(5):675-682.

Discussion

Several studies compared HER2 status by immunohistochemistry and FISH on breast core-needle and excisional biopsies^[17–27] and showed generally a very good concordance between these samplings (average ~90%), suggesting that core-needle biopsies can be used with confidence for HER2 status determination. However, most of these studies assessed only a small number of samples with a limited statistical power to detect discordances, leading to considerable differences between their results (range of concordance rate: 64–100%). More recent studies^{[28– 30]} assessing higher samples (n = 500, 332 and 225 paired samples of core-needle biopsies and subsequent surgical specimens, respectively) showed excellent concordance rates (90, 99 and 89%, respectively). This is confirmed in our hands. Thus, when comparing the results of each test on core-needle biopsies to these obtained on surgical specimens, no significant difference was observed between discordance rates, sensitivity, specificity, false positive and false negative rates for immunohistochemistry, irrespective of the guidelines used, or for ISH methods (FISH, CISH and SISH). Whatever the test performed, concordance between core-needle biopsies and surgical specimens on the same tissue sample remained excellent, k coefficients of correlation ranging from 0.97 (for immunohistochemistry interpreted using GEFPICS guidelines) to 0.99 (for immunohistochemistry interpreted using pathologists' scoring and ASCO guidelines or FISH, and SISH). These results, in accordance with previous findings,^{[19,20,24,31,32]} suggest that intratumoral heterogeneity of HER2 is not a significant confounding factor when analyzing small sized samples, if ISH is used. In spite of excellent concordance between core-needle biopsies and surgical specimens, some pathologists retest for HER2 status on surgical specimens in case of rare heterogeneous cases.^[32]

Furthermore, we have shown that the nonfluorescent immunohistochemistry techniques on core-needle biopsies can generally be used with confidence, an excellent concordance rate between immunohistochemistry on core-needle biopsies and FISH on surgical specimens (k: 0.92–0.97) being observed whatever the immunohistochemistry interpretation guideline used. Likewise, CISH and SISH on core-needle biopsies showed a strong correlation with FISH on surgical specimens (k: 0.96 and 0.94, respectively). These results are consistent with previous data available on surgical specimens.^[12–14,33]

In conclusion and based on our results, immunohistochemistry status assessed on cores biopsy is highly concordant with FISH in cores and surgical specimens. Furthermore, CISH and/or SISH even represents a safe alternative method to determine HER2 status on these cores biopsies to confirm any ambiguous immunohistochemistry results (2+) or to perform HER2 status screening, if ISH is used as first-line screening method. CISH or SISH may also be used for calibration or quality controls of immunohistochemistry, either on cores biopsies or on surgical specimens.

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Acknowledgements
This study was sponsored by Roche. Many thanks to all pathologists for their participation in the study: Algros Marie-Paule, Hôpital Jean Minjoz, Besançon; Antoine Martine, CHU Tenon, Paris; Arbion Sylvie, Hôpital Bretonneau, Tours; Arnould Laurent, Centre Georges-François Leclerc, Dijon; Balaton André, Cabinet d'Anatomopathologie, Bie`vres; Bibeau Fréderic, Centre Val d'Aurelle Paul Lamarque, Montpellier; Blanc-Fournier Cécile, Centre François Baclesse, Caen; Chenard Marie-Pierre, CHU Hautepierre, Strasbourg; Conan-Charler Virginie, Hôpital Morvan, Brest; Ettore Francette, Centre Antoine Lacassagne, Nice; Guinebretie`re Jean-Marc, Centre René Huguenin, Saint Cloud; Guiu Michel, Cabinet d'Anatomopathologie, Perpignan; Jacquemier Jocelyne, Institut Paoli-Calmettes, Marseille; Laberge Sophie, Centre Henri Becquerel, Rouen; Lacroix-Triki Magali, Institut Claudius Regaud, Toulouse, Leroux Agne`s, Centre Alexis Vautrin, Vandoeuvre Les Nancy; MacGrogan Gaétan, Institut Bergonié, Bordeaux; Mathieu Marie-Christine, Institut Gustave Roussy, Villejuif; Maury Florence, Centre Médical République, Clermont-Ferrand; Penault-Llorca Frédérique, Centre Jean Perrin, Clermont-Ferrand; Roche-Combet Isabelle, IHCP, Le Bouscat; Roger Pascal, Hôpital Lapeyronie, Montpellier; Roignot Patrick, Cabinet d'Anatomopathologie, Dijon, Tas Patrick, Cabinet Richier, Rennes.

Table 1. Concordance of HER2 status determined by IHC, CISH and SISH (on core-needle biopsy specimens) with FISH results (on surgical specimens)
HER2 status evaluation method	Discordant rate % [95% CI]	Sensitivity (Se) Specificity (Sp) % [95% CI]	Pos. (PPV) and Neg. (NPV) predictive values % [95% CI]	False Pos. (FPR) false Neg. (FNR) rates % [95% CI]	Kappa coefficient %
IHC (Pathologists' scoring)	2 [0; 3]	Se 99 [98; 100]	PPV 98 [96; 100]	FPR 2 [0; 4]	0.97
201 Conclusive cases		Sp 97 [93; 100]	NPV 99 [96; 100]	FNR 1 [0; 4]
IHC (ASCO)	2 [0; 4]	Se 98 [96; 100]	PPV 98 [96; 100]	FPR 2 [0; 4]	0.96
194 Conclusive cases		Sp 97 [93; 100]	NPV 97 [93; 100]	FNR 3 [0; 7]
IHC (GEFPICS)	4 [2; 7]	Se 95 [91; 100]	PPV 98 [96; 100]	FPR 2 [0; 4]	0.92
230 Conclusive cases		Sp 98 [95; 100]	NPV 93 [87; 98]	FNR 7 [2; 13]
CISH	2 [0; 4]	Se 99 [96; 100]	PPV 99 [96; 100]	FPR 2 [0; 4]	0.96
234 Conclusive cases		Sp 98 [95; 100]	NPV 98 [95; 100]	FNR 2 [0; 5]
SISH	3 [0; 6]	Se 96 [92; 100]	PPV 99 [96; 100]	FPR 1 [0; 4]	0.94
150 Conclusive cases		Sp 98 [95; 100]	NPV 95 [90; 100]	FNR 5 [0; 10]

IHC, immunohistochemistry; FISH, fluorescence in-situ hybridization; CISH, chromogenic in-situ hybridization; SISH, silver in-situ hybridization; ASCO, American Society of Clinical Oncology; GEFPICS, Groupe d'Etude des Facteurs Pronostiques IHC dans le Cancer du Sein.

Table 2. Concordance of HER2 status determined by each test (IHC, FISH, CISH and SISH) on core-needle biopsy specimens and surgical specimens
HER2 status evaluation method	Discordant rate % [95% CI]	Sensitivity (Se) Specificity (Sp) % [95% CI]	Pos. (PPV) and Neg. (NPV) Predictive Values % [95% CI]	False Pos. (FPR) False Neg. (FNR) Rates % [95% CI]	Kappa coefficient %
IHC (Pathologists' scoring)	1 [0; 2]	Se 99 [98; 100]	PPV 100 [100; 100]	FPR 0 [0; 0]	0.99
201 Conclusive cases		Sp 100 [100; 100]	NPV 99 [96; 100]	FNR 1 [0; 4]
IHC (ASCO)	1 [0; 2]	Se 99 [98; 100]	PPV 100 [100; 100]	FPR 0 [0; 0]	0.99
194 Conclusive cases		Sp 100 [100; 100]	NPV 99 [96; 100]	FNR 1 [0; 4]
IHC (GEFPICS)	2 [0; 3]	Se 98 [96; 100]	PPV 98 [96; 100]	FPR 2 [0; 4]	0.97
230 Conclusive cases		Sp 98 [95; 100]	NPV 98 [95; 100]	FNR 2 [0; 5]
FISH	1 [0; 1]	Se 99 [98; 100]	PPV 100 [100; 100]	FPR 0 [0; 0]	0.99
220 Conclusive cases		Sp 100 [100; 100]	NPV 99 [97; 100]	FNR 1 [0; 3]
CISH	1 [0; 2]	Se 99 [97; 100]	PPV 100 [100; 100]	FPR 0 [0; 0]	0.98
234 Conclusive cases		Sp 100 [100; 100]	NPV 98 [95; 100]	FNR 2 [0; 5]
SISH	1 [0; 2]	Se 99 [96; 100]	PPV 100 [100; 100]	FPR 0 [0; 0]	0.99
150 Conclusive cases		Sp 100 [100; 100]	NPV 99 [96; 100]	FNR 2 [0; 4]

IHC, immunohistochemistry; FISH, fluorescence in-situ hybridization; CISH, chromogenic in-situ hybridization; SISH, silver in-situ hybridization; ASCO, American Society of Clinical Oncology; GEFPICS,Groupe d'Etude des Facteurs Pronostiques IHC dans le Cancer du Sein.

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