Abstract 1030: Concordance between the DESTINY-Breast04 clinical trial assay (4B5CDx) and other HER2 IHC assays for HER2-low breast cancer in real-world practice: First phase of a large-scale, multicenter global ring study

Abstract Background: DESTINY-Breast04 (DB-04) showed that trastuzumab deruxtecan improves survival vs chemotherapy in patients with human epidermal growth factor receptor 2 (HER2) -low (immunohistochemistry IHC 1+ or IHC 2+ with in situ hybridization negative) metastatic breast cancer (BC). The VENTANA 4B5 (CDx) IHC assay, now approved in the United States (US) as a companion diagnostic, was used as the clinical trial assay (CTA) in DB-04. Real-world differentiation of HER2-low vs HER2 IHC 0 BC with non-CTAs is difficult. This is the first phase of a study assessing agreement between CTA and non-CTA scores. Methods: 50 clinical BC samples with HER2 IHC scores of 0, 1+, 2+, and 3+ were sent to laboratories in Europe, Canada, and the US for HER2 IHC testing per ASCO/CAP 2018 guidelines. After routine protocol scoring, pathologists were trained and rescored the samples 2 weeks later. Post training scores were compared with reference CTA scores determined by a central laboratory and a panel of experts. The primary endpoint was positive percentage agreement (PPA) and negative percentage agreement (NPA) between CTA and non-CTA scores, assessed after training, considering HER2-low as positive and HER2 IHC 0 as negative. Results: A total of 3449 post training non-CTA scores were available for analysis. PPA for HER2-low vs HER2 IHC 0 was 87. 5% and NPA was 61. 9%, with Cohen κ of 0. 51 (Table). HER2-low vs HER2 IHC 0 agreement between CTA and non-CTA varied across subgroups. PPA 95% was shown with 4B5 Laboratory Developed Tests (LDTs) and HercepTest (Omnis), NPA of 80% with Leica, and overall agreement 80% with HercepTest (Link48), 4B5 LDTs, and German, French, and Italian laboratories. Conclusions: The degree of concordance between the CTA and non-CTAs varied among assay types and laboratory locations. A low NPA for some non-CTAs suggests the need for further assay optimization for HER2 IHC 0 evaluation. Post training non-CTA results HER2-low vs HER2 IHC 0 BC Post training scores PPA (95% CI), % NPA (95% CI), % Overall percentage agreement (95% CI), % Cohen κ (95% CI) Overall non-CTA test results (N = 3449) 87. 5 (86. 0-89. 0) 61. 9 (58. 9-64. 9) 78. 7 (77. 1-80. 1) 0. 51 (0. 48-0. 54) Non-CTA subgroups HercepTest (Omnis) (n = 467) 95. 5 (92. 3-97. 7) 36. 9 (28. 9-45. 4) 75. 2 (70. 8-79. 4) 0. 37 (0. 28-0. 46) HercepTest (Link48) (n = 790) 88. 5 (85. 2-91. 2) 64. 3 (57. 8-70. 4) 80. 3 (77. 2-83. 2) 0. 55 (0. 48-0. 61) Leica (n = 96) 59. 3 (45. 0-72. 4) 80. 0 (61. 4-92. 3) 66. 7 (55. 5-76. 6) 0. 35 (0. 17-0. 53) Non-4B5 LDTs (n = 1609) 83. 8 (81. 2-86. 1) 67. 8 (63. 5-72. 0) 78. 2 (75. 9-80. 3) 0. 52 (0. 47-0. 57) 4B5 LDTs (n = 487) 96. 0 (93. 0-98. 0) 58. 8 (50. 4-66. 8) 83. 0 (79. 1-86. 4) 0. 59 (0. 51-0. 68) Country subgroups Germany (n = 340) 93. 1 (88. 5-96. 3) 64. 4 (54. 2-73. 6) 83. 1 (78. 3-87. 2) 0. 61 (0. 51-0. 70) France (n = 342) 95. 4 (91. 5-97. 9) 64. 4 (54. 4-73. 6) 84. 7 (80. 1-88. 6) 0. 64 (0. 55-0. 73) Italy (n = 395) 89. 9 (85. 2-93. 5) 72. 5 (63. 6-80. 3) 83. 9 (79. 6-87. 6) 0. 64 (0. 55-0. 72) Spain (n = 567) 83. 0 (78. 4-86. 9) 64. 2 (56. 6-71. 3) 76. 3 (72. 3-80. 0) 0. 48 (0. 40-0. 56) US/Canada (n = 1029) 86. 6 (83. 6-89. 2) 61. 8 (56. 1-67. 3) 78. 2 (75. 4-80. 8) 0. 50 (0. 44-0. 56) Europe, other (n = 776) 85. 0 (81. 3-88. 2) 52. 8 (46. 2-59. 3) 73. 8 (70. 3-77. 1) 0. 40 (0. 32-0. 47) Citation Format: Hans-Ulrich Schildhaus, Sunil Badve, Corrado D’Arrigo, Gelareh Farshid, Annette Lebeau, Vicente Peg, Fréderique Penault-Llorca, Josef Rueschoff, Wentao Yang, Neil Atkey, Jessica Baumann, Elisabeth Beyerlein, Amy Hanlon Newell, Alexander Penner, Akira Moh, Guiseppe Viale. Concordance between the DESTINY-Breast04 clinical trial assay (4B5CDx) and other HER2 IHC assays for HER2-low breast cancer in real-world practice: First phase of a large-scale, multicenter global ring study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1030.