Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer

Williams, Christopher J M; Elliott, Faye; Sapanara, Nancy; Aghaei, Faranak; Zhang, Liping; Muranyi, Andrea; Yan, Dongyao; Bai, Isaac; Zhao, Zuo; Shires, Michael; Wood, Henry M; Richman, Susan D; Hemmings, Gemma; Hale, Michael; Bottomley, Daniel; Galvin, Leanne; Cartlidge, Caroline; Dance, Sarah; Bacon, Chris M; Mansfield, Laura; Young-Zvandasara, Kathe; Sudan, Ajay; Lambert, Katy; Bibby, Irena; Coupland, Sarah E; Montazeri, Amir; Kipling, Natalie; Hughes, Kathryn; Cross, Simon S; Dewdney, Alice; Pheasey, Leanne; Leng, Cathryn; Gochera, Tatenda; Mangham, D Chas; Saunders, Mark; Pritchard, Martin; Stott, Helen; Mukherjee, Abhik; Ilyas, Mohammad; Silverman, Rafael; Hyland, Georgina; Sculthorpe, Declan; Thornton, Kirsty; Gould, Imogen; O'Callaghan, Ann; Brown, Nicholas; Turnbull, Samantha; Shaw, Lisa; Seymour, Matthew T; West, Nicholas P; Seligmann, Jenny F; Singh, Shalini; Shanmugam, Kandavel; Quirke, Philip

Abstract

Purpose: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis.

Experimental Design: Patients who received panitumumab or cetuximab + chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS).

Results: A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/ EREG expression (n ¼ 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56–0.95; P ¼ 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50–0.86; P ¼ 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection.

Conclusions: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice.

Citation

Williams, C. J. M., Elliott, F., Sapanara, N., Aghaei, F., Zhang, L., Muranyi, A., …Quirke, P. (2023). Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer. Clinical Cancer Research, 29(20), 4153-4165. https://doi.org/10.1158/1078-0432.CCR-23-0859

• Journal Article Type: Article
• Acceptance Date: Jun 22, 2023
• Online Publication Date: Jun 26, 2023
• Publication Date: Oct 15, 2023
• Deposit Date: Oct 5, 2023
• Publicly Available Date: Oct 5, 2023
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Electronic ISSN: 1557-3265
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 20
• Pages: 4153-4165
• DOI: https://doi.org/10.1158/1078-0432.CCR-23-0859
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/22989964
• Publisher URL: https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-0859/727784/Associations-between-AI-Assisted-Tumor