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Editorial
. 2023 Oct 13;29(20):4153-4165.
doi: 10.1158/1078-0432.CCR-23-0859.

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

Christopher J M Williams  1   2 , Faye Elliott  2 , Nancy Sapanara  3 , Faranak Aghaei  3 , Liping Zhang  3 , Andrea Muranyi  3 , Dongyao Yan  3 , Isaac Bai  3 , Zuo Zhao  4 , Michael Shires  1 , Henry M Wood  1 , Susan D Richman  1 , Gemma Hemmings  1 , Michael Hale  1 , Daniel Bottomley  1 , Leanne Galvin  1 , Caroline Cartlidge  1 , Sarah Dance  5 , Chris M Bacon  6   7 , Laura Mansfield  7 , Kathe Young-Zvandasara  7 , Ajay Sudan  7 , Katy Lambert  7 , Irena Bibby  7 , Sarah E Coupland  8 , Amir Montazeri  9 , Natalie Kipling  8 , Kathryn Hughes  9 , Simon S Cross  10 , Alice Dewdney  11 , Leanne Pheasey  11 , Cathryn Leng  11 , Tatenda Gochera  11 , D Chas Mangham  12 , Mark Saunders  13 , Martin Pritchard  12 , Helen Stott  13 , Abhik Mukherjee  14 , Mohammad Ilyas  14 , Rafael Silverman  15 , Georgina Hyland  14 , Declan Sculthorpe  14 , Kirsty Thornton  15 , Imogen Gould  14 , Ann O'Callaghan  16 , Nicholas Brown  17 , Samantha Turnbull  17 , Lisa Shaw  17 , Matthew T Seymour  2 , Nicholas P West  1 , Jenny F Seligmann  2 , Shalini Singh  3 , Kandavel Shanmugam #  3 , Philip Quirke #  1
Affiliations
Editorial

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

Christopher J M Williams et al. Clin Cancer Res. .

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 = 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.

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. See related commentary by Randon and Pietrantonio, p. 4021.

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Figures

Figure 1. PFS (A) and OS (B) Kaplan–Meier (KM) curves for RAS-wt patients and PFS (C) and OS (D) for RAS- and BRAF-wt patients with low (blue line) and high (red line) AREG/EREG expression (AREG and EREG ≤20% vs. AREG or EREG >20%).
Figure 1.
PFS (A) and OS (B) Kaplan–Meier (KM) curves for RAS-wt patients and PFS (C) and OS (D) for RAS- and BRAF-wt patients with low (blue line) and high (red line) AREG/EREG expression (AREG and EREG ≤20% vs. AREG or EREG >20%).
Figure 2. Forest plot displaying the prognostic effect of AREG/EREG on PFS and OS, stratified by key variables. Estimated crude HRs and 95% CIs for the effect of the combined AREG/EREG model (20% cut-off point) on PFS and OS in RAS-wt patients treated with anti-EGFR therapy, stratified by primary tumor location, chemotherapy backbone, anti-EGFR agent (restricted to patients who received anti-EGFR therapy as part of first-line treatment), and tumor specimen type. FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PTL, primary tumor location.
Figure 2.
Forest plot displaying the prognostic effect of AREG/EREG on PFS and OS, stratified by key variables. Estimated crude HRs and 95% CIs for the effect of the combined AREG/EREG model (20% cut-off point) on PFS and OS in RAS-wt patients treated with anti-EGFR therapy, stratified by primary tumor location, chemotherapy backbone, anti-EGFR agent (restricted to patients who received anti-EGFR therapy as part of first-line treatment), and tumor specimen type. FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PTL, primary tumor location.
See this image and copyright information in PMC

Comment in

References

    1. Oliveras-Ferraros C, Cufí S, Queralt B, Vazquez-Martin A, Martin-Castillo B, de Llorens R, et al. Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour cells. Br J Cancer 2012;106:1406–14. - PMC - PubMed
    1. Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 2013;14:749–59. - PMC - PubMed
    1. Williams CJM, Seligmann JF, Elliott F, Shires M, Richman SD, Brown S, et al. Artificial intelligence-assisted amphiregulin and epiregulin IHC predicts panitumumab benefit in RAS wild-type metastatic colorectal cancer. Clin Cancer Res 2021;27:3422–31. - PubMed
    1. Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, et al. Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34:10–32. - PubMed
    1. Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen Y-J, Ciombor KK, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2021;19:329–59. - PubMed

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