KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers

Background:

Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics.

Methods:

The population-based study included individuals diagnosed with CRC between 1998–2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status.

Results:

Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13–1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival.

Conclusion:

Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.     

Combined assessment of EGFR pathway-related molecular markers and prognosis of NSCLC patients

The purpose of this study is to evaluate the prognostic value of the combined assessment of multiple molecular markers related to the epidermal growth factor receptor (EGFR) pathway in resected non-small cell lung cancer (NSCLC) patients. Tumour specimens of 178 NSCLC patients were collected and analysed for EGFR and KRAS mutation status by DNA sequencing, and for EGFR copy number by fluorescent in situ hybridisation. Tissue microarrays were generated and used to determine the expression of multiple EGFR pathway-related proteins by immunohistochemistry. We analysed the association between each marker and patient prognosis. Univariate analyses for each clinical variable and each molecular marker were performed using Kaplan–Meier curves and log-rank tests. From these results, we selected the variables KRAS mutations and expression of cytoplasmic EGFR, granular pERK, nuclear pSTAT3, cytoplasmic E-cadherin and cytoplasmic pCMET to enter into a Cox proportional hazards model, along with stage as the strongest clinical variable related with prognosis. Of the EGFR-related markers evaluated here, the markers EGFR, pERK, pSTAT3, E-cadherin, pCMET and mutations in KRAS were associated with survival when analysed in combination in our patient cohort, with P=0.00015 as the P-value for a test of the additional impact of markers on prognosis, after taking stage into consideration. Confirmation of the impact of these markers in independent studies will be necessary.     

EGFR靶向药物个体化治疗转移性结直肠癌的研究进展

靶向表皮生长因子受体(epidermal growth factor receptor,EGFR)单抗目前已成为晚期结直肠癌治疗的一个突破,对此类药物相关基因的研究也开创了结直肠癌个体化治疗的先河。EGFR信号转导系统中EGFR基因、配体以及下游的KRAS,BRAF和PIK3CA基因一直都是研究的热点。本文就EGFR靶向药物疗效相关预测因子的研究现状做一综述。     

Neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma

Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a müllerian origin and the current approach to extrapolate the results from ovarian mucinous cystadenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas.     

A systematic review and meta-analysis of KRAS status as the determinant of response to anti-EGFR antibodies and the impact of partner chemotherapy in metastatic colorectal cancer

Background

In the setting of metastatic colorectal cancer (CRC), anti-EGFR antibodies are not currently recommended for individuals with KRAS mutant tumours. This is based on subgroup analyses of individual clinical trials rather than a formal synthesis of evidence for KRAS status as a predictive biomarker, while newer trials report no benefit for anti-EGFR antibodies irrespective of KRAS status. This study systematically reviewed the evidence for KRAS mutation status as a treatment effect modifier of response to anti-EGFR antibodies and the influence of partner chemotherapy.

Methods

Medline (1966-2010), EMBASE and American and European oncology meeting abstracts were searched for randomised controlled trials reporting the influence of KRAS status on effectiveness of anti-EGFR antibodies in metastatic CRC. The treatment efficacy was summarised by KRAS status using hazard ratios (HR) for progression-free survival (PFS) and risk differences (RD) for objective response. For each study, a measure of effect modification was calculated, and aggregated using random effects meta-analysis to assess the interaction between KRAS and treatment effect.

Findings

Eleven studies (8924 patients) were selected from 198 reports. Two studies assessed anti-EGFR antibodies as monotherapy and nine their use with chemotherapy. KRAS status was reported in 7555 cases. In subgroup analysis, the progression HR for KRAS wild patients assigned to anti-EGFR antibodies was 0.80 (4436 patients 95%CI: 0.64, 0.99) and for mutant cases 1.11 (3119 patients, 95%CI: 0.97, 1.27). A significant treatment effect interaction between KRAS status and addition of anti-EGFR antibodies to standard treatment was found for PFS (ratio of HRs 0.71, 95%CI: 0.57, 0.90 p = 0.005) and response rate difference (difference in RDs 15%, 95%CI: 8, 22%, p < 0.001). There was no evidence that the extent of effect modification differed between chemotherapeutic partners for both PFS (p = 0.3) and response rate (p = 0.6).

Interpretation

KRAS mutation status is a treatment effect modifier for anti-EGFR antibodies in metastatic CRC. Further evidence is needed to determine whether this is true for all chemotherapy partners and all clinical circumstances.     

Correlation of genes associated with drug response to prognosis of large cell lung carcinoma

Platinum-based chemotherapy remains the main treatment of advanced lung cancer. However, platinum resistance has become a major treatment obstacle. Novel therapies, particularly tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) and agents that target vascular endothelial growth factor (VEGF), have improved the treatment. Both chemotherapy and targeted therapy have their molecular mechanisms. This study aimed to determine the mutation, amplification, or expression status and inter...     

Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review

Background.

Currently, only Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status is used as a decisional marker for epidermal growth factor receptor (EGFR) inhibitor therapy in colorectal cancer (CRC) patients. Concordance of KRAS status between primary tumors and metastases has always been considered to be close to perfect; however, cases of discordance have been reported. The actual rate of concordance of KRAS status remains unclear, as is the same for v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatidylinositol 3-kinase CA subunit (PIK3CA), and loss of phosphatase and tensin homologue deleted on chromosome ten (PTEN). Therefore, it is unknown whether it is necessary to perform mutational analysis on metastases instead of on (or in addition to) primary tumors.

Design.

A systematic literature search was conducted to collect all studies testing concordance of KRAS in CRC, and also of BRAF, PIK3CA, and loss of PTEN.

Results.

Twenty-one studies have reported concordance of KRAS, with an overall concordance rate of 93% (range, 76%–100%). Overall concordance rates of studies testing concordance of BRAF status and loss of PTEN were 98% and 68%, respectively. Three studies reported concordance of PIK3CA status (range, 89%–94%).

Conclusion.

Though discordance of KRAS status does occur, it is uncommon. When considering the downsides of testing metastatic tissue in all patients along with the low incidence of discordance, we conclude that that testing the primary tumor (or whatever tissue available) is sufficient for clinical decision making on EGFR inhibitor therapy.     

西妥昔单抗联合FOLFOX4方案在转移性结直肠癌一线治疗的疗效预测

1 文献来源 Bokemeyer C, Bondarenko I, Makhon A, et al. Fluorouracil, Leucovorin, and Oxaliplatin with and without Cetuximab in the first-line treatment of metastatic colorectal cancer [J]. J Clin Oncol,2009,27（5）：663-671.     

Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS-mutant human lung cancer cells

Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%–25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS-mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant human lung cancer. LC-MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS-mutant H358 non-small cell lung cancer cells. Furthermore, l -methionine (methyl-¹³C) isotope tracer was used to explore the effect of belinostat on one-carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α-ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino-succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. ¹³C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2-regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.