Introduction: Addition of BV to first-line irinotecan plus 5FU improves PFS and OS of mCRC pts. Meanwhile, the anti-VEGF causes specific toxicities and increases costs of treatment. At the same time, not all pts derive an equal benefit from the VEGF inhibitor. Molecular predictors of BV efficacy have not yet been identified. Specific VEGF polymorphisms may affect gene transcription, thus indirectly influencing BV efficacy. Methods: Peripheral blood samples for genomic DNA extraction were collected from consecutive mCRC pts receiving FOLFIRI plus BV as first-line treatment (BV-group). VEGF -2578A/C, -460C/T, +405C/G, +936C/T polymorphisms were analysed by means of PCRRFLP. One-hundred-seven pts, treatedwith FOLFIRI alone, served as historical control group. Results: One-hundred-eleven pts were included in the BV-group. M/F=57/54, median age=63 (34-82), Ko¨hne score (low/intermediate/high/data missing)=57/39/12/3. Sixtynine out of 111 pts achieved response (RR=62%). Median PFS (mPFS) and median OS (mOS) were 10.2 and 22.2 months, respectively. -460C/C, C/T and T/T allelic variants were found in 20%, 54% and 26% of pts, respectively. -460 T allele demonstrated shorter PFS and OS with an additive effect of each T allele (PFS:HR=2.65[1.49- 6.62],p=0.003; OS:2.47[0.91-7.66],p=0.074). -460C/C pts achieved longer PFS and OS in comparison to pts carrying at least one T allele (mPFS:12.8 vs 9.8 months;HR=0.48[0.28-0.85],p=0.012; mOS:27.3 vs 20.5 months; HR=0.38[0.19- 0.94],p=0.034). In the control group mPFS and mOS were 8.2 and 20.6 months; -460C/ C, C/T and T/T variants were found in 23%, 52% and 25% of pts; there was no significant association with PFS or OS. Other polymorphisms did not affect outcome neither in BV-group nor in the control group. Conclusions: At our knowledge this is the first report of a pharmacogenetic determinant of improved PFS and OS for mCRC pts treated with first-line BVcontaining therapy. The observation that VEGF -460C/T variants did not influence the outcome in the control group led to hypothesize a predictive other than a prognostic role for such genetic signature. These preliminary data deserve investigation in prospective, randomized, validating trials.

VEGF GENE POLYMORPHISMS IN THE PREDICTION OF BENEFIT FROM FIRST-LINE FOLFIRI PLUS BEVACIZUMAB (BV) IN METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS)

RUZZO, ANNAMARIA;MAGNANI, MAURO;
2009-01-01

Abstract

Introduction: Addition of BV to first-line irinotecan plus 5FU improves PFS and OS of mCRC pts. Meanwhile, the anti-VEGF causes specific toxicities and increases costs of treatment. At the same time, not all pts derive an equal benefit from the VEGF inhibitor. Molecular predictors of BV efficacy have not yet been identified. Specific VEGF polymorphisms may affect gene transcription, thus indirectly influencing BV efficacy. Methods: Peripheral blood samples for genomic DNA extraction were collected from consecutive mCRC pts receiving FOLFIRI plus BV as first-line treatment (BV-group). VEGF -2578A/C, -460C/T, +405C/G, +936C/T polymorphisms were analysed by means of PCRRFLP. One-hundred-seven pts, treatedwith FOLFIRI alone, served as historical control group. Results: One-hundred-eleven pts were included in the BV-group. M/F=57/54, median age=63 (34-82), Ko¨hne score (low/intermediate/high/data missing)=57/39/12/3. Sixtynine out of 111 pts achieved response (RR=62%). Median PFS (mPFS) and median OS (mOS) were 10.2 and 22.2 months, respectively. -460C/C, C/T and T/T allelic variants were found in 20%, 54% and 26% of pts, respectively. -460 T allele demonstrated shorter PFS and OS with an additive effect of each T allele (PFS:HR=2.65[1.49- 6.62],p=0.003; OS:2.47[0.91-7.66],p=0.074). -460C/C pts achieved longer PFS and OS in comparison to pts carrying at least one T allele (mPFS:12.8 vs 9.8 months;HR=0.48[0.28-0.85],p=0.012; mOS:27.3 vs 20.5 months; HR=0.38[0.19- 0.94],p=0.034). In the control group mPFS and mOS were 8.2 and 20.6 months; -460C/ C, C/T and T/T variants were found in 23%, 52% and 25% of pts; there was no significant association with PFS or OS. Other polymorphisms did not affect outcome neither in BV-group nor in the control group. Conclusions: At our knowledge this is the first report of a pharmacogenetic determinant of improved PFS and OS for mCRC pts treated with first-line BVcontaining therapy. The observation that VEGF -460C/T variants did not influence the outcome in the control group led to hypothesize a predictive other than a prognostic role for such genetic signature. These preliminary data deserve investigation in prospective, randomized, validating trials.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2303294
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