Clinical Newswire, January 5, 2010-KRAS mutations can predict resistance to the anti-EGFR therapy cetuximab in advanced colorectal cancer (CCR), however only a subset of wild type KRAS tumors are responders, implying the existence of additional resistance markers. Some of these have now been identified in a study published in the International Journal of Cancer by G Perkins and colleagues, who found that over expression of the EGFR downstream signaling phosphoproteins pMEK1 and pP70S6K is predictive of shorter progression-free survival (PFS) independent of KRAS status.
The study involved 42 patients (24 males, mean age of 61.8 years) with advanced CRC who were retrospectively analyzed from a previous series of 114 patients evaluable for tumor response and for whom tumor protein material was available. Patients were treated with cetuximab in monotherapy (n=2) or in combination with irinotecan (alone, n=37; FOLFIRI regimen, n=2) (initial dose of 400mg/m2 followed by weekly infusions of 250mg/m2), or panitumumab alone (n=1; 6mg/kg every 2 weeks). Anti-EGFR treatment was given as first-line, second-line, third-line, fourth-line and fifth line or more in 1, 16,17, 5, and 3 cases respectively. Median follow-up was 10.1 months. Patients with complete and partial response (CR and PR) were considered responders. KRAS mutation status was determined on tumor samples obtained prior to anti-EGFR treatment by an allelic discrimination assay. Expression of selected signaling phosphoproteins was performed by multiplex Luminex bead immunoanalysis and was expressed in arbitrary units.
KRAS mutations were found in 45% of analyzed tumors (n=19), and were significantly associated with absence of response to cetuximab (p<0.001). Univariate analysis showed that median PFS and OS were longer in patients with wild type (WT) tumors vs. mutant tumors, at 32 weeks, CI95%[14.7-46] vs. 8 weeks, CI95%[6.1-9], (log-rank p<10-4) and 13.9 months, CI95%[6.5-21.6] vs. 6.4 months, CI95%[2.8-10.1] (log-rank test p= 0.02), respectively. An objective response to cetuximab was observed in 28.6% of patients (CR:1, PR:11).
Cetuximab is a chimeric IgG1 monoclonal antibody that targets and binds the EGFR receptor and blocks the ligand-induced phosphorylation cascade responsible for activating signaling pathways like RAS/RAF/MAPK, PI3K/AKT, and STAT.
Analysis of all phosphoproteins involved in activation of these pathways indicated elevated expression in KRAS mutated tumors vs. WT tumors, with pP70S6K, pGSK3B, and pMEK1 expression significantly higher. Expression of pP70S6K was significantly lower in cetuximab responders vs. non-responders (20.5 vs. 50 arbitrary units respectively; p=0.024). Patients that had elevated pMEK1 expression had a shorter PFS than those with low pMEK1 (median PFS: 7±0.1 weeks, CI95% [4.4-12] vs. 20±3.4 weeks, CI95% [8.6-33]; p=0.0001). Shorter PFS was also observed in patients with elevated pP70S6K vs. lower levels (median PFS: 8±0.1 weeks, CI95% [8-16] vs 33.1± 0.04 weeks, CI95% [14.8-58.1]; p=0.0006). Multivariate analysis showed that the association of pMEK1 and pP70S6K with PFS is independent of KRAS status. PFS was significantly associated with both pMEK1 and pP70S6K when stratified by KRAS status (p=0.002 and p=0.01, respectively). Finally, patients with low levels of pP70S6K had a better OS than those with high pP70S6K (median OS 21.6 months, CI95% [6.1-26.3) vs. median OS 6.5± 0.1 months, CI95% [3.8-10.5]; p=0.003).
The authors concluded that in addition to KRAS status, expression levels of EGFR downstream signaling phophoproteins are also important for prediction of response to cetuximab and survival in advanced CRC patients. The response rate to cetuximab or panitumumab therapy was linked to the level of expression of pMEK1 and pP70S6K, and the authors suggested that the activation of RAS/MAPK and PI3K/PTEN/AKT pathways, respectively, are therefore likely important in resistance to this type of treatment. Patients with high expression of pMEK1 and pP70S6K phosphoproteins had shorter survival time than those with low expression, regardless of KRAS status. The authors point out that RAS/MAPK and PI3K/AKT pathways are likely activated by mechanisms other than KRAS mutations, including BRAF or PI3KCA.
|
