Introduction: PTEN loss and KRAS mutations lead to resistance to EGFRblockade due to uncontrolled activation of PI3K/AKT and RAS/RAF/MAPK signalling pathways. Methods: We retrospectively investigated the role of pAKT immunoreactivity (IHC) (data not shown), PTEN-IHC and KRAS mutations (PCR-sequencing) on primaries (prim) and related metastases (mets) in predicting CetIri activity in EGFR+ mCRC pts pretreated with irinotecan. We defined responders pts obtaining a complete (CR) or partial (PR) response (RECIST) or disease stabilization lasting>6 mos, clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (SD6). Results: One-hundred-two pts have been evaluated. M/F=60/42, median age=67 (39- 78), median number of previous lines=2 (1-5). Overall response rate=19% (13 PR, 1 CR, 5 SD6). On 96 prim, PTEN resulted positive (+), negative () or unconclusive (NE) in 49, 36 and 11; KRAS was mutated (mut), wild type (wt) or NE in 35, 53 and 8 cases. On 59 mets PTEN resulted +, or NE in 33, 22, 4; KRAS was mut, wt or NE in 21, 27, 11 cases. PTEN concorded in 27/45 pairs (60%,95%CI4674); KRAS in 41/43 (95%,95%CI8499). On prim PTEN was not predictive of response nor PFS. On mets, PTEN was in 21 not responders (50%) vs 1 responder (8%) (p=0.008). On prim, KRAS was mut in 33 not responders (45%) vs 2 responders (13%) (p=0.023). On mets, 9/13 (70%) responders resulted KRAS-wt and PTEN+ vs 8/35 not responders (23%) (p=0.006). Median PFS in pts with PTEN+ mets was 4.7 vs 3.3 mos in PTEN- (p=0.005, HR=0.49,95%CI0.21–0.76). Median PFS in pts with PTEN+ and KRAS-wt mets was 5.5 vs 3.8 in all others (p=0.0012, HR=0.42,95%CI0.17–0.65). Conclusions: KRAS mutations, tested on prim or mets, predict activity of CetIri. Loss of PTEN expre

PTEN EXPRESSION AND KRAS MUTATIONS AS PREDICTORS OF BENEFIT FROM CETUXIMAB PLUS IRINOTECAN (CETIRI) IN METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS)

RUZZO, ANNAMARIA;MAGNANI, MAURO;
2008-01-01

Abstract

Introduction: PTEN loss and KRAS mutations lead to resistance to EGFRblockade due to uncontrolled activation of PI3K/AKT and RAS/RAF/MAPK signalling pathways. Methods: We retrospectively investigated the role of pAKT immunoreactivity (IHC) (data not shown), PTEN-IHC and KRAS mutations (PCR-sequencing) on primaries (prim) and related metastases (mets) in predicting CetIri activity in EGFR+ mCRC pts pretreated with irinotecan. We defined responders pts obtaining a complete (CR) or partial (PR) response (RECIST) or disease stabilization lasting>6 mos, clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (SD6). Results: One-hundred-two pts have been evaluated. M/F=60/42, median age=67 (39- 78), median number of previous lines=2 (1-5). Overall response rate=19% (13 PR, 1 CR, 5 SD6). On 96 prim, PTEN resulted positive (+), negative () or unconclusive (NE) in 49, 36 and 11; KRAS was mutated (mut), wild type (wt) or NE in 35, 53 and 8 cases. On 59 mets PTEN resulted +, or NE in 33, 22, 4; KRAS was mut, wt or NE in 21, 27, 11 cases. PTEN concorded in 27/45 pairs (60%,95%CI4674); KRAS in 41/43 (95%,95%CI8499). On prim PTEN was not predictive of response nor PFS. On mets, PTEN was in 21 not responders (50%) vs 1 responder (8%) (p=0.008). On prim, KRAS was mut in 33 not responders (45%) vs 2 responders (13%) (p=0.023). On mets, 9/13 (70%) responders resulted KRAS-wt and PTEN+ vs 8/35 not responders (23%) (p=0.006). Median PFS in pts with PTEN+ mets was 4.7 vs 3.3 mos in PTEN- (p=0.005, HR=0.49,95%CI0.21–0.76). Median PFS in pts with PTEN+ and KRAS-wt mets was 5.5 vs 3.8 in all others (p=0.0012, HR=0.42,95%CI0.17–0.65). Conclusions: KRAS mutations, tested on prim or mets, predict activity of CetIri. Loss of PTEN expre
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2303289
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