Change in pattern of HER2 fluorescent in situ hybridization (FISH) results in breast cancers submitted for FISH testing

Experience of a reference laboratory using US Food and Drug Administration criteria and American Society of Clinical Oncology and College of American Pathologists guidelines

Mithun Vinod Shah, Anne E. Wiktor, Reid G. Meyer, Kathleen S. Tenner, Karla V. Ballman, Stefan J. Green, William R. Sukov, Rhett P. Ketterling, Edith A. Perez, Robert Brian Jenkins

Research output: Contribution to journalArticle

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Abstract

Purpose: In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods: Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results: IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion: In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.

Original languageEnglish (US)
Pages (from-to)3502-3510
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number29
DOIs
StatePublished - Oct 10 2016

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United States Food and Drug Administration
Fluorescence In Situ Hybridization
Guidelines
Breast Neoplasms
Immunohistochemistry
human ERBB2 protein
Pathologists
Chromosomes, Human, Pair 17
Cytogenetics
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Change in pattern of HER2 fluorescent in situ hybridization (FISH) results in breast cancers submitted for FISH testing : Experience of a reference laboratory using US Food and Drug Administration criteria and American Society of Clinical Oncology and College of American Pathologists guidelines. / Shah, Mithun Vinod; Wiktor, Anne E.; Meyer, Reid G.; Tenner, Kathleen S.; Ballman, Karla V.; Green, Stefan J.; Sukov, William R.; Ketterling, Rhett P.; Perez, Edith A.; Jenkins, Robert Brian.

In: Journal of Clinical Oncology, Vol. 34, No. 29, 10.10.2016, p. 3502-3510.

Research output: Contribution to journalArticle

@article{7e5f93ce584b43dab94551dad033bde8,
title = "Change in pattern of HER2 fluorescent in situ hybridization (FISH) results in breast cancers submitted for FISH testing: Experience of a reference laboratory using US Food and Drug Administration criteria and American Society of Clinical Oncology and College of American Pathologists guidelines",
abstract = "Purpose: In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods: Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results: IHC results were available for 1,922 patient samples (67.4{\%}), 137 of which were from Mayo Clinic. Distribution was 2.4{\%} IHC 0, 7.9{\%} IHC 1+, 84.8{\%} IHC 2+, and 2.5{\%} IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8{\%} (FDA), 9.4{\%} (AC2007), and 24.1{\%} (AC2013). Overall, 11.8{\%} (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3{\%} (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0{\%} (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2{\%}) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4{\%} overall) patients to FISH-positive and 36 (1.3{\%} overall) patients to FISH-negative, whereas 157 (5.5{\%} overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6{\%}) was increased (P < .001) compared with FDA (13.1{\%}) and AC2007 (11{\%}) guidelines. Conclusion: In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4{\%} overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.",
author = "Shah, {Mithun Vinod} and Wiktor, {Anne E.} and Meyer, {Reid G.} and Tenner, {Kathleen S.} and Ballman, {Karla V.} and Green, {Stefan J.} and Sukov, {William R.} and Ketterling, {Rhett P.} and Perez, {Edith A.} and Jenkins, {Robert Brian}",
year = "2016",
month = "10",
day = "10",
doi = "10.1200/JCO.2015.61.8983",
language = "English (US)",
volume = "34",
pages = "3502--3510",
journal = "Journal of Clinical Oncology",
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publisher = "American Society of Clinical Oncology",
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T1 - Change in pattern of HER2 fluorescent in situ hybridization (FISH) results in breast cancers submitted for FISH testing

T2 - Experience of a reference laboratory using US Food and Drug Administration criteria and American Society of Clinical Oncology and College of American Pathologists guidelines

AU - Shah, Mithun Vinod

AU - Wiktor, Anne E.

AU - Meyer, Reid G.

AU - Tenner, Kathleen S.

AU - Ballman, Karla V.

AU - Green, Stefan J.

AU - Sukov, William R.

AU - Ketterling, Rhett P.

AU - Perez, Edith A.

AU - Jenkins, Robert Brian

PY - 2016/10/10

Y1 - 2016/10/10

N2 - Purpose: In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods: Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results: IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion: In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.

AB - Purpose: In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods: Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results: IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion: In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.

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U2 - 10.1200/JCO.2015.61.8983

DO - 10.1200/JCO.2015.61.8983

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JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

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