Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study
ABSTRACT The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).
The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.
Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.
- SourceAvailable from: Nicola Normanno
British Journal of Cancer 09/2012; 107(10). DOI:10.1038/bjc.2012.431 · 4.82 Impact Factor
- "Therascreen kit were assessed (Amado et al, 2008; Karapetis et al, 2008; Van Cutsem et al, 2009; Bokemeyer et al, 2011). The data regarding the role of codon 61 mutations in the resistance to anti- EGFR agents in CRC have not been obtained in the context of randomized clinical trials. "
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- "The recommendation to test for mutations in codons 12 and 13 of the KRAS gene reflects the high frequency of these activating mutations in colorectal tumours: 24–43% of colorectal tumours contain KRAS mutations, of which B82% are in codon 12% and B17% are in codon 13 (Samowitz et al, 2000; Andreyev et al, 2001). Following the initial retrospective analysis showing that patients with activating KRAS mutations did not respond to treatment, the majority of subsequent clinical trials of anti-EGFR antibodies in CRC have excluded patients with tumours harbouring codon 12 and 13 mutations (Amado et al, 2008; Douillard et al, 2010; Peeters et al, 2010; Bokemeyer et al, 2011; Van Cutsem et al, 2011). An emerging body of data suggests that KRAS mutations in codon 61 may also be predictors of non-responsiveness to anti- EGFR therapies. "
ABSTRACT: KRAS mutation testing is required to select patients with metastatic colorectal cancer (CRC) to receive anti-epidermal growth factor receptor antibodies, but the optimal KRAS mutation test method is uncertain. We conducted a two-site comparison of two commercial KRAS mutation kits - the cobas KRAS Mutation Test and the Qiagen therascreen KRAS Kit - and Sanger sequencing. A panel of 120 CRC specimens was tested with all three methods. The agreement between the cobas test and each of the other methods was assessed. Specimens with discordant results were subjected to quantitative massively parallel pyrosequencing (MPP). DNA blends were tested to determine detection rates at 5% mutant alleles. Reproducibility of the cobas test between sites was 98%. Six mutations were detected by cobas that were not detected by Sanger, and five were confirmed by MPP. The cobas test detected eight mutations which were not detected by the therascreen test, and seven were confirmed by MPP. Detection rates with 5% mutant DNA blends were 100% for the cobas and therascreen tests and 19% for Sanger. The cobas test was reproducible between sites, and detected several mutations that were not detected by the therascreen test or Sanger. Sanger sequencing had poor sensitivity for low levels of mutation.British Journal of Cancer 06/2012; 107(2):345-51. DOI:10.1038/bjc.2012.259 · 4.82 Impact Factor
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- "In recent years, the KRAS pathway has been proven to have an important predictive role in the treatment of CRC (Cunningham et al, 2004; Van Cutsem et al, 2007; Karapetis et al, 2008; Douillard et al, 2010; Bokemeyer et al, 2011). Anti-EGFR therapy is effective and approved for the management of metastatic CRC (mCRC) without KRAS mutations. "
ABSTRACT: Increased Aurora kinase A gene copy number (AURKA-CN) has been reported in metastatic colorectal cancer (mCRC), with unknown relationship to clinical outcome. We correlated increased AURKA-CN in mCRC tumours with KRAS mutation status, overall and progression-free survival (OS, PFS).Methods:Sixty-one mCRC tumours were analysed for AURKA-CN using q-PCR, and KRAS mutation status by direct sequencing. Expression of AURKA protein was analysed by immunohistochemistry. Cox-proportional hazard method, Kaplan-Meier curves and log-rank statistics were used to estimate and compare the hazard ratios and median survival between the groups. In all, 68% of tumour exhibited high AURKA-CN, and 29% had a KRAS mutation, without correlation between the two. Patients with high AURKA-CN tumours had longer median OS (48.6 vs 18.8 months, P=0.01), with stronger trend among KRAS wild-type tumours (median OS not reached vs 18.8 months, P=0.003). Progression-free survival was longer on first-line or second-line chemotherapy among patients with KRAS wild-type and high vs low AURKA-CN (first: 17.6 vs 5.13 months, P=0.04; second: 10.4 vs 5.1 months, P=0.01). AURKA-CN level did not affect outcomes among patients with KRAS mutant tumours. Increased AURKA-CN is common in mCRC tumours and is associated with longer OS and longer PFS during chemotherapy, particularly in KRAS wild-type tumours.British Journal of Cancer 02/2012; 106(4):748-55. DOI:10.1038/bjc.2011.587 · 4.82 Impact Factor