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

• Published in: Clinical cancer research Vol. 29; no. 20; pp. 4153 - 4165
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 13.10.2023
• Subjects: Amphiregulin - metabolism; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Artificial Intelligence; Cetuximab - therapeutic use; Colonic Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Epiregulin - metabolism; Epiregulin - therapeutic use; ErbB Receptors - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Panitumumab; Precision Medicine and Imaging; Proto-Oncogene Proteins p21(ras) - metabolism; Rectal Neoplasms - drug therapy; Retrospective Studies
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-23-0859

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. 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). 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 = 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 = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 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. 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. See related commentary by Randon and Pietrantonio, p. 4021.