Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR

Heinemann, Volker; Stintzing, Sebastian; Kirchner, Thomas; Boeck, Stefan; Jung, Andreas

doi:10.1016/j.ctrv.2008.11.005

Cited by 179 publications

(130 citation statements)

References 86 publications

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“…1,3,11,12 In this study, BRAF mutations were observed in only 1% of the small intestinal adenocarcinomas. In accord with previous reports for colorectal cancers 23 and small intestinal adenocarcinomas, 1,3,12 KRAS and BRAF mutations Abbreviations: D, duodenum; J, jejunum; I, ileum; NS, not stated. a V600E (n = 4) and a 3-bp deletion (c1869-1871; n = 1).…”

Section: Discussionsupporting

confidence: 74%

“…In the literature on colorectal cancer, codon 12 mutations of the KRAS are associated with a mucinous phenotype. 23 By contrast, codon 13 mutations tend to be nonmucinous and are characterized as more aggressive with a greater metastatic potential. 23 In this study, we did not find any difference in clinicopathologic findings in terms of mucinous/nonmucinous histologic subtype with respect to codon 12/13 mutations of KRAS among the small intestinal adenocarcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…3,6 On the other hand, BRAF mutations occur at a lower rate (0-13%) than KRAS mutations in colorectal cancers. 23 BRAF mutations are also rarely encountered among small intestinal adenocarcinomas, where the prevalence of BRAF mutation ranges from 3 to 14%. 1,3,11,12 In this study, BRAF mutations were observed in only 1% of the small intestinal adenocarcinomas.…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Jun

Kim

et al. 2016

Modern Pathology

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Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G4A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P = 0.034) and more frequent pancreatic invasion (P = 0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G4A transitions and G12D mutations) were significantly correlated with higher pT classification (P = 0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P = 0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P = 0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wildtype KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Jun

Kim

et al. 2016

Modern Pathology

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“…Abnormal activation of EGFR signaling pathways can lead to abnormal cell growth, proliferation, and differentiation, and finally to tumor initiation, tumor progression, angiogenesis, and metastasis information (Salomon et al, 1995;Friday and Adjei, 2005). KRAS mutations are predictive of resistance to anti-EGFR treatment in such a way that a successful targeting of the EGFR axis with Cetuximab or Panitumumab depends on the presence of wild-type KRAS (Lievre et al, 2006(Lievre et al, , 2008Di Fiore et al, 2007;De Roock et al, 2008;Karapetis et al, 2008;Heinemann et al, 2009). KRAS plays an important role in transduction of extracellular signals from EGFR to downstream effectors involved in cell division, apoptosis, and differentiation of cells, and KRAS mutations occur in 35-45% of all colorectal cancers (Brink et al, 2003;Baldus et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA profiling differentiates colorectal cancer according to KRAS status

Mosakhani

Sarhadi

Borze

et al. 2011

Genes Chromosomes & Cancer

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Recent studies have shown the important role of microRNAs (miRNAs) in a variety of biological processes, and in its ability to distinguish tumors according to their prognostic and predictive properties. To identify miRNA signatures associated with colorectal carcinoma (CRC) and with KRAS status, we studied, using Agilent's miRNA microarrays, miRNA expression in primary tumors from 55 metastatic CRC patients, including 15 with mutant and 40 with wild-type KRAS. Comparing these with normal colon tissue, we identified 49 miRNAs-including 19 novel miRNAs-significantly deregulated in tumor tissue. The presence of the KRAS mutation was associated with up-regulation of miR-127-3p, miR-92a, and miR-486-3p and down-regulation of miR-378. Increased expression of miR-127-3p and miR-92a in KRAS mutant tumors was significantly confirmed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (P < 0.05). We identified some predicted target genes of differentially expressed miRNAs between mutated and wild-type KRAS, such as RSG3 and TOB1, which are involved in apoptosis and proliferation. Target prediction and pathway analysis suggest a possible role for deregulated miRNAs in nicotinamide adenine dinucleotide phosphate (NADPH) regeneration and G protein-coupled receptor signaling pathways.

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“…Thus, imatinib mesylate is useful in the treatment of gastrointestinal stromal tumors with specific activating mutations in the KIT gene; 3 trastuzumab frequently induces clinical responses in breast carcinomas with ERBB2 amplification, 4 and cetuximab is only effective in colorectal carcinomas with wild-type KRAS. 5 Although targeted therapy is not yet available for germ cell tumor-derived PNETs, it makes sense to analyze the nature of these neoplasms from their histomorphological, immunohistochemical and genetic aspects in anticipation of the application of targeted therapy at some future time. This is particularly the case with PNET, because the term 'PNET' is applied to several tumor types, notably a family of central nervous system neoplasms that occur mostly in children and which have an embryonal-type morphology (central PNET), [6][7][8] as well as to a more homogenous entity-Ewing sarcoma/PNET-that is caused by a specific chromosomal translocation (t (11;22)) (peripheral PNET).…”

mentioning

confidence: 99%

Primitive neuroectodermal tumors in patients with testicular germ cell tumors usually resemble pediatric-type central nervous system embryonal neoplasms and lack chromosome 22 rearrangements

et al. 2010

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Primitive neuroectodermal tumors (PNETs) are one of the most frequent types of 'non-germ cell' tumor in patients with testicular germ cell tumors and have a guarded prognosis when present in metastatic sites after cisplatin-based chemotherapy. Improved treatments, including targeted therapy, require understanding the biology of these neoplasms. We therefore analyzed the morphologic, immunohistochemical and molecular biologic features of 14 PNETs from 14 patients with concurrent or previous testicular germ cell tumors; 12 tumors were from metastatic sites and 2 were primary in the testis. Using standard light microscopic criteria for central nervous system and peripheral PNETs, we classified nine tumors as medulloepithelioma, three as medulloblastoma/supratentorial PNET, one as neuroblastic tumor with abundant neuropil and true rosettes and one as small cell embryonal tumor/PNET (Ewing sarcoma-like). Immunostains directed against INI1, CD57, S-100 protein, NeuN, WT1, neurofilament, CD99, GFAP, synaptophysin, chromogranin, AE1/AE3 cytokeratin, Fli-1 and collagen IV were performed for each case. INI1 was diffusely and strongly positive in all tumors whereas the other stains, except for cytoplasmic WT1 (which showed substantial reactivity in most tumors), were mostly focal to negative, including CD99 (eight negative, six focal) and Fli-1 (all negative). The most consistently reactive 'neuroendocrine' marker was CD57. Each case was also analyzed for chromosome 22 rearrangements using a FISH-based break-apart probe method. Only 1 tumor, classified as medulloepithelioma, was scored positive for chromosome 22 translocation (22% rearranged cells) and the remaining 13 were negative, including the one case that resembled peripheral PNET. We conclude that PNETs derived from testicular germ cell tumors mostly resemble central nervous system PNETs and generally lack the chromosome 22 translocation of peripheral PNETs. Future treatment strategies should take these findings into account.

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Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR

Cited by 179 publications

References 86 publications

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

MicroRNA profiling differentiates colorectal cancer according to KRAS status

Primitive neuroectodermal tumors in patients with testicular germ cell tumors usually resemble pediatric-type central nervous system embryonal neoplasms and lack chromosome 22 rearrangements

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