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.

• 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