Data from Coaltered <i>Ras/B-raf</i> and <i>TP53</i> Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer
Jashodeep DattaJ. Joshua SmithWalid K. ChatilaJohn C. McAuliffeCyriac KandothEfsevia VakianiTimothy L. FrankelKaruna GaneshIsaac WassermanMarla Lipsyc-SharfJosé G. GuillemGarrett M. NashPhilip B. PatyMartin R. WeiserLeonard B. SaltzMichael F. BergerWilliam R. JarnaginVinod BalachandranT. Peter KinghamNancy E. KemenyAndrea CercekJulio García‐AguilarBarry S. TaylorAgnès VialeRona YaegerDavid B. SolitNikolaus SchultzMichael I. D’Angelica
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<div>AbstractPurpose:<p>We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer.</p>Experimental Design:<p>We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (<i>n</i> = 17) and ≥10-year (<i>n</i> = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients.</p>Results:<p>In the extremes-of-survivorship cohort, significant co-occurrence of <i>KRAS</i> hotspot mutations and <i>TP53</i> alterations was observed in ≤2-year survivors (<i>P</i> < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic <i>Ras/B-raf</i> (i.e., either <i>KRAS, NRAS</i>, or <i>BRAF</i>) and <i>TP53</i> alteration generated three prognostic clusters: (i) <i>TP53</i>-altered alone (median OS, 132 months); (ii) <i>Ras/B-raf</i>–altered alone (65 months) or <i>Ras/B-raf</i>- and <i>TP53</i> pan-wild-type (60 months); and (iii) coaltered <i>Ras/B-raf</i>–<i>TP53</i> (40 months; <i>P</i> < 0.0001). Coaltered <i>Ras/B-raf</i>–<i>TP53</i> was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; <i>P</i> < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered <i>Ras/B-raf</i>–<i>TP53</i> was associated with worse OS in patients with liver (<i>n</i> = 490) and lung (<i>n</i> = 172) but not peritoneal surface (<i>n</i> = 149) metastases. Moreover, coaltered <i>Ras/B-raf</i>–<i>TP53</i> tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.</p>Conclusions:<p>Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered <i>Ras/B-raf</i>–<i>TP53</i> and its association with distinct patterns of colorectal cancer metastasis.</p></div>Microsatellite Instability
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Colorectal cancer is one of the most frequently diagnosed malignant tumors in men and women, which is a highly heterogeneous group of neoplasms consisting of subclasses with different molecular and clinical characteristics, and, as a consequence, patients with different types of tumors require different treatment protocols. Among the predictive factors of treatment response in patients with metastatic colorectal cancer, the most studied are the genes of the RAS family (KRAS, NRAS). Determination of RAS status is the first step in individual selection of drug therapy in patients with metastatic colorectal cancer. Patients with certain mutations in KRAS and NRAS genes are resistant to anti-EGFR therapy and have a lower median survival than WT (wild type) genotypes, indicating a negative prognosis in the presence of mutations.
Targeted Therapy
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Determination of the mutations' status in the KRAS and NRAS genes is a necessary requirement in the treatment of patients with colorectal cancer (CRC). Patients with certain mutations in the KRAS and NRAS genes are resistant to anti-EGFR drug therapy and have a lower median survival rate than those with WT (wild type) genotypes, that indicates a negative prognosis in the case when mutations are present. Currently, there are no registered targeted drugs for carriers of the KRAS and NRAS genes mutations, however, preparations based on small molecules are under way. The gold standard for detecting mutations in the KRAS and NRAS genes is the analysis of the biopsy material in paraffin blocks. However, this method has significant limitations that can be circumvented by the analysis of circulating tumor DNA a promising new method in the diagnosis of colorectal cancer.
Targeted Therapy
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On the 2013 ASCO conference,there were three important clinical study results released in which involved the hot spots of metastasis colorectal cancer,such as optimization of targeted drug therapy,the best mode of treatment and curative effect prediction.The FIRE3 study failed to make a clear conclusion on the comparison of the first-line drug cetuximab and bevacizumab in the treatment of the wild type KRAS metastatic colorectal cancer.CARIO3 research supported bevacizumab plus capecitabine as a new mode of chemotherapy for colorectal cancer.The follow-up data from the PRIME study and other clinical research results showed that NRAS,BRAF and PIK3CA gene mutation might be a negative predictors of the EGFR monoclonal antibody effectiveness,except KRAS.
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Objective
To investigate the CpG island methylation phenotype (CIMP) in metastatic colorectal cancer (CRC) and identify the relationship between the methylation status and clinical response to Cetuximab.
Methods
We retrospectively reviewed the medical records of 74 patients who received Cetuximab for KRAS/NRAS wild-type metastatic CRC. Then we analyzed the relationship between CIMP and clinical response to Cetuximab, and evaluated the predictive power and value of the CIMP.
Results
28.4% patients showed CIMP positive, clinical outcomes were significantly worse in the CIMP(+ ) group than in CIMP(-) group (response rate, 9.5% vs 56.6%, P=0.00; disease control rate, 23.8% vs 75.5%, P=0.00; hazard ratio for progression-free survival, HR 4.34, 95% CI 1.53~13.90, P=0.01; overall survival, HR 4.60, 95% CI 2.12~19.35, P=0.01).
Conclusions
CIMP is an independent poor prognosis factor in patients with KRAS wild-type metastatic colorectal cancer, and the CIMP positive patients may not benefit from Cetuximab.
Key words:
Metastatic colorectal cancer; CpG island methylation phenotype; Cetuximab
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Abstract Introduction Several studies show that mutational profiles could influence treatment decisions in patients with metastatic CRC (mCRC). KRAS mutational status was the first step in biomarkers development in the era of molecular targeted therapies. Recently, NRAS mutational status was identified as an independent prognostic factor for the response to treatment with anti-EGFR moAbs. The aim of this observational study was to assess the feasibility of the KRAS/NRAS mutational analysis in patients with metastatic colorectal cancer in Greece and to identify any correlations with known clinical characteristics and histopathologic features. Methods From January 2014 until September 2014 all patients registered to the GIC-SG database with newly diagnosed metastatic disease from colon or rectal cancer were included and tumor samples were analyzed for kras/nras mutations in 9 different certified laboratories in Greece. Results Samples from 510 patients were analyzed. Mutations’ distribution was as follows: 173 (33,9%) KRAS exon 2, 10 (2%) KRAS exon 3, 25 (4,9%) KRAS exon 4, 22 (4,3%) NRAS exon 2, 11 (2,2%) NRAS exon 3 and 3 (0,6%) NRAS exon 4. The only factor significantly associated with RAS mutational status was primary tumor location, with right sided tumors exhibiting higher rates of mutations. Discussion The incidence and distribution of KRAS or NRAS exon 2-4 mutations are in accordance with those reported in the literature. The most significant clinical or pathological parameter revealed from the analysis is the location of the primary tumor.
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Pyrosequencing
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Microsatellite Instability
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Introduction: RAS status is a predictive biomarker for anti-EGFR response in metastatic colorectal cancer (mCRC). The Idylla technology (IT) is a fully automated molecular testing system based on real-time PCR and provides rapid results in a very short preparation time. In this study, we aimed to evaluate the full RAS mutation status in Moroccan patients with mCRC.
Molecular biomarkers
Panitumumab
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