Abstract
BackgroundTo investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy.MethodsPrimary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded.Results KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absecence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS.ConclusionsThese results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti-EGFR treatment.
Highlights
Despite the progress made in the management of metastatic colorectal cancer over the last few years, the disease remains a major public health problem in the western world with an estimated 146,970 new CRC cases and 49,920 deaths for 2009 in the United States [1].Two monoclonal antibodies targeting EGFR, both by binding to the extracellular domain, and leading to inhibition of its downstream signaling, the chimeric IgG1 moAb cetuximab and the fully humanized IgG2 moAb panitumumab, have entered clinical practice in the mCRC setting and have proven to provide a modest clinical benefit in pretreated patients, either used alone or in combination with chemotherapy [2,3,4,5]
In KRAS wt patients to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with BRAF (p = 0.0001 and p,0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p,0.0001, respectively) and grade 0-1 skin rash (p,0.0001 and p,0.0001, respectively)
KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absecence of severe/moderate skin rash (HR: 3.7, p,0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS. These results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti-EGFR treatment
Summary
Despite the progress made in the management of metastatic colorectal cancer (mCRC) over the last few years, the disease remains a major public health problem in the western world with an estimated 146,970 new CRC cases and 49,920 deaths for 2009 in the United States [1].Two monoclonal antibodies targeting EGFR (anti-EGFR moAbs), both by binding to the extracellular domain, and leading to inhibition of its downstream signaling, the chimeric IgG1 moAb cetuximab and the fully humanized IgG2 moAb panitumumab, have entered clinical practice in the mCRC setting and have proven to provide a modest clinical benefit in pretreated patients, either used alone or in combination with chemotherapy [2,3,4,5]. From the beginning became clear that not all patients derive a benefit from the incorporation of these agents into the treatment combinations; non-randomized retrospective studies [6,7,8,9,10,11] as well as retrospective analysis of prospective randomized trials [12,13,14,15,16] demonstrated that the presence of KRAS mutations were predictive of resistance to anti-EGFR moAbs therapy and were associated with a worse prognosis and a shorter survival Based on this knowledge, a primary tumor’s KRAS mutational status is mandatory for the treatment of metastatic disease with an anti-EGFR moAb (European Medicine Agency – EMEA-H-C-741 and H-C-558 and U.S Food and Drug Administration - FDA Application No (BLA) 125084 and No (BLA) 125147). To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy
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