Maurel J, Fernandez-Martos C, Martin-Richard M, Alonso V, Mendez JC, Salud A, Pericay C, Aparicio J, Gallego J, Carmona A, Casado E, Manzano H, Horndler C, Rubini M, Cuatrecasas M, Garcia-Albeniz X, Feliu J. Prospective biomarker validation trial evaluating the prognostic role of the combined expression of phospho-insulin growth factor receptor-1 and matrilysin in KRAS (exon 2) wild-type (WT) metastatic colorectal cancer (mCRC) patients treated with FOLFOX-6 plus panitumumab as first-line therapy [PULSE trial (GEMCAD 09-03)]. Poster presented at the 2016 ASCO Annual Meeting; January 23, 2016. Chicago, IL. [abstract] J Clin Oncol. 2016 Feb; 34(4_Suppl):583. doi: 10.1200/jco.2016.34.4_suppl.583

BACKGROUND: Matrilysin can activate phospho-insulin growth factor receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Matrilysin per se has shown poor prognosis in mCRC and the co-expression of matrilysin and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT KRAS refractory patients (pts) treated with anti-EGFR in retrospective analyses. We performed a prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX plus panitumumab in first-line therapy to validate those findings.

METHODS: Positive cases were defined by immunohistochemistry as those with moderate or strong intensity (++/+++) and > 70% expression for both matrilysin and p-IGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival (PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a difference in median PFS of 6 months (two-sided p< 0.05).

RESULTS: We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013 and 78 pts met inclusion criteria (42 non-DP and 36 DP). Median follow-up was 23 months. There were no differences in baseline characteristics [age, sex, liver metastases, lactate dehydrogenase (LDH) levels, performance status and BRAF mutational status] between both groups. There were no differences in the number of FOLFOX-6 and panitumumab cycles received. Cutaneous toxicity was more frequent in DP pts (p = 0.035). Response rate was 80.5% in non-DP and 72.2% in DP patients (p = 0.37). Median PFS (95% CI) was 7.4 months (95%CI 5.2-13.3) in non-DP and 9.6 months (95% CI 6.7-17.5, p = 0.15) in DP patients. Median overall survival was 19.8 months (11.5-26.3) in non-DP pts and 39.1 months (26-NE, p = 0.071) in DP pts. Adjusted HR for PFS was 0.68 (95% CI 0.41-1.12). Adjusted analysis for OS was 0.50 (95% CI 0.27-0.90).

CONCLUSIONS: We found that co-expression of matrilysin and pIGF-1R is a novel strong prognostic biomarker of survival benefit in mCRC KRAS WT pts treated in first-line with FOLFOX-6 plus panitumumab.

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