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题目:: Molecular determinants of cetuximab efficacy.
作者:: Vallböhmer(D),Zhang(W),Gordon(M),Yang(D Y),Yun(J),Press(O A),Rhodes(K E),Iqbal(S),Danenberg(K D),Lenz(H-J)
状态:: 发布时间2016-12-12 , 更新时间 2016-12-12
期刊:: J Clin Oncol
摘要:: 3551 Background: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), demonstrates promising efficacy in patients with metastatic colorectal cancer (CRC). However, no molecular marker is established to identify patients who will most likely benefit from this drug. We investigated whether mRNA expression levels of cyclinD1 (CCND1), cyclooxygenase-2 (Cox-2), EGFR, interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with metastatic CRC treated with cetuximab.,39 patients with metastatic CRC, refractory to irinotecan and oxaliplatin, were enrolled in IMCL-0144 (Lenz et al; ASCO 2004). All patients had intratumoral EGFR protein expression. Cetuximab was administered at standard loading dose 400mg/m over 2 hours, followed by weekly 250mg/m treatment over 1 hour. Intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8 and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative Real-Time PCR.,There were 21 women and 18 men (median age 64 years; range 35-83). The median survival time was 5.5 months, the median follow-up 7.1 months. Partial response was observed in 2 (6%), stable disease in 21 (60%) and progressive disease in 12 (34%) patients (response was inevaluable in 4 patients). 12 (31%) patients had a grade 1, 20 (51%) a grade 2 and one (3%) patient a grade 3 skin reaction. Higher mRNA levels of VEGF were associated with resistance to cetuximab (p= 0.038). The combination of lower mRNA levels of Cox-2, EGFR and IL-8 was significantly associated with overall survival (13.5 vs. 2.3 months; p=0.028). Both findings were independent of skin toxicity which was itself significantly correlated to survival. Patients with lower mRNA levels of EGFR had a longer overall survival compared with patients that had higher levels (7.3 vs. 2.2 months; p=0.09). Patients with lower mRNA levels of Cox-2 had a significantly higher rate of grade 2-3 skin reactions under cetuximab treatment. (p=0.009).,This study suggests that gene expression levels of Cox-2, EGFR, IL-8 and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in cetuximab treatment. [Table: see text].
语言:: eng
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