KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer

Boeck, Stefan; Jung, Andreas; Laubender, Rüdiger P.; Neumann, Jens; Egg, Rosalind; Goritschan, C.; Ormanns, Steffen; Haas, Michael; Modest, Dominik Paul; Kirchner, Thomas; Heinemann, Volker

doi:10.1007/s00535-013-0767-4

Cited by 70 publications

(41 citation statements)

References 13 publications

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“…Epidermal Growth Factor Receptor (EGFR) is overexpressed in a high proportion of PDAC tumors and can be detected in exosomes secreted by the epithelial component of tumours [93]. A key determinant of response to EGFR-targeted therapy is the presence of mutations in genes encoding downstream effector proteins such as KRAS [94]. Recently, it was demonstrated that exosomes from PDAC patients contain double-stranded genomic DNA fragments, including the KRAS gene, suggesting that it is possible to identify patients who would benefit from EGFR-targeted therapy without the need for invasive biopsies of the tumor [95].…”

Section: Exosomes As New Treatment Methodsmentioning

confidence: 99%

Exosomes: Navigating a New Route in Pancreatic Cancer

Zhang¹,

Wang²,

Xu³

et al. 2017

J Biomol Res Ther

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Pancreatic cancer is a fatal disease, and even with an increased commitment to pancreatic cancer research, the 5-year survival rate remains at approximately 6%. However, in the last decade, there has been a rising interest in the role of small extracellular vesicles called exosomes in the cancer field. Accumulating evidence shows that exosomes participate in early processes of tumorigenesis, tumor progression, and metastasis by mediating communication between cells or between cells and their surrounding microenvironment. In pancreatic cancer, exosomes play key roles in building pre-metastatic niches in the liver, inducing immune evasion, changing metabolism, mediating crosstalk between tumor and stromal cells, and causing low chemosensitivity. Although research exploring the roles of exosomes in pancreatic cancer is still in its infancy, the studies presented in this review highlight their potential value in developing novel tools, such as lipid biomarkers, treatment targets, and efficient drug delivery devices, for cancer diagnosis and therapy.

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Section: Exosomes As New Treatment Methodsmentioning

confidence: 99%

Exosomes: Navigating a New Route in Pancreatic Cancer

Zhang¹,

Wang²,

Xu³

et al. 2017

J Biomol Res Ther

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“…KRAS wild type patients had an improved survival (HR =1.68, P=0.005) and this trend was also observed during non-erlotinib containing 2nd-line chemotherapy. The authors concluded that KRAS is more likely a prognostic rather than predictive biomarker in pancreatic cancer (26). In contrast to erlotinib, the anti-EGFR antibody cetuximab did not improve outcomes when combined with gemcitabine in a phase III randomized study.…”

Section: Targeting Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 98%

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Vijayvergia

Cohen

2016

J. Gastrointest. Oncol.

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In 2015, pancreatic cancer was the 10th most commonly diagnosed cancer and the fourth leading cause of cancer death in the United States. The incidence of pancreatic cancer has been slowly rising over the past 10 years. It is estimated that about 53,000 new cases were diagnosed and 42,000 people died from pancreatic cancer in 2015 (1). The small difference between the incidence and death rate of pancreatic cancer reflect the early distant spread and inadequacy of current therapies. The 5-year survival rates for localized and advanced pancreatic cancer are 27% and less than 5%, respectively, lower than all other common cancers (2). The majority of patients are diag nosed at an advanced stage and are not eligible for surgical resection (2). These patients are often symptomatic and quickly deteriorate in the absence of effective therapy and many are unable to receive second and third line therapies for the same reason. Hence, finding the optimal first line regimen may be the key to improving outcomes. Increases in our knowledge of hu man and cancer genomics provide opportunities to un derstand the impact of genetic alterations on pancreatic cancer outcomes and develop predictive biomarkers for newer targeted therapies (3,4). Unfortunately, the amount of tissue obtained by fine needle aspiration of the primary pancreatic tumor is usually insufficient to perform adequate molecular analysis. As we move into the era of personalized medicine, obtaining core biopsy samples from metastatic sites, like liver, may help eliminate this problem. What do we know about pancreatic cancer genetically?Pancreatic cancer is a disease of significant genetic variability. Recent whole exome and genome sequencing have identified a wide range of genetic alterations including mutations and copy number variations that characterize pancreatic cancer (4,5). Some of these are recurrent and are clearly needed to identify subsets of patients likely to benefit from these therapies. Advances in our understanding of the molecular drivers of pancreatic cancer offer the hope of personalized therapy that may benefit our patients. In this review, we summarize the current knowledge about the biology of pancreatic cancer and its implication for treatment. We discuss recent advances in targeted therapies and the role of potential biomarkers in predicting response to established therapies. We also review novel therapeutic approaches that may be able to fulfill the promise of personalized therapy for pancreatic cancer.

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“…Multiple parameters, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, EGFR gene copy number alterations, protein expression and polymorphisms and phosphatase and tensin homolog (PTEN) protein expression have been examined in the populations of the PA.3 (2) and AIO-PK0104 (3) randomized trials. Unfortunately, none demonstrated predictive significance for benefit from EGFR modulation, whereas the results about their prognostic role were conflicting (4)(5)(6)(7)(8). Consequently, no specific molecular alteration has been found to predict response to EGFR inhibitors (9).…”

Section: Gene Expression Unsupervised Hierarchical Clustering Accordmentioning

confidence: 99%

“…Moreover, to our knowledge, no published study has examined the prognostic/predictive significance of growth and survival pathway gene-expression profiling in patients with pancreatic cancer treated with EGFR inhibitors. Among such genes, the most important is KRAS, which has been found to be mutated in approximately 70-90% of cases (5). EGFR and AKT serine/threonine kinase 2 (AKT2) amplification, and PTEN deletion are other important genetic aberrations.…”

Section: Gene Expression Unsupervised Hierarchical Clustering Accordmentioning

confidence: 99%

Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer

Pectasides

Kotoula

Papaxoinis

et al. 2016

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Abstract. Aim: The aim of this study was to evaluate the mRNA expression pattern of growth-and survival-related genes and assess their prognostic significance in patients withThe epidermal growth factor receptor (EGFR) pathway has a major importance in pancreatic cancer(1). Erlotinib, a tyrosine kinase inhibitor (TKI) of EGFR, was tested in combination with gemcitabine as first-line treatment in a randomized trial of patients with advanced pancreatic cancer (2). The addition of erlotinib to gemcitabine demonstrated a modest but statistically significant survival benefit. Therefore, the identification of biomarkers for the selection of patient subgroups with a more meaningful benefit from erlotinib is mandatory. Multiple parameters, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, EGFR gene copy number alterations, protein expression and polymorphisms and phosphatase and tensin homolog (PTEN) protein expression have been examined in the populations of the PA.3 (2) and AIO-PK0104 (3) randomized trials. Unfortunately, none demonstrated predictive significance for benefit from EGFR modulation, whereas the results about their prognostic role were conflicting (4-8). Consequently, no specific molecular alteration has been found to predict response to EGFR inhibitors (9). 6347

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KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer

Abstract: This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.

Cited by 70 publications

References 13 publications

Exosomes: Navigating a New Route in Pancreatic Cancer

Exosomes: Navigating a New Route in Pancreatic Cancer

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer

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