Molecular markers of the EGFR pathway in erlotinib-treated patients with advanced pancreatic cancer (APC): Translational analyses of a randomized, cross-over AIO phase III trial.

Boeck, Stefan; Jung, A.; Laubender, Rüdiger P.; Neumann, Jens; Egg, Rosalind; Goritschan, C.; Vehling-Kaiser, Ursula; Winkelmann, Cornelia; Weikersthal, Ludwig Fischer von; Clemens, Michael; Gauler, Thomas; Märten, Angela; Klein, Stefan; Kojouharoff, G.; Barner, Meagan; Geißler, Michael; Greten, Tim F.; Mansmann, Ulrich; Kirchner, Thomas

doi:10.1200/jco.2011.29.15_suppl.4047

Cited by 6 publications

(4 citation statements)

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“…Other groups were not able to confirm this data 36–38. Comparably, EGFR intron‐1 polymorphism was also not identified as a predictor of Cet‐ST or outcome in patients receiving oral tyrosine kinase inhibitors such as erlotinib or gefitinib 40, 41. Reasons for this ambiguity may be the disconcordance of EGFR intron‐1 repeat number between primary tumour and metastases36 or the varying cut‐off definitions 38.…”

Section: Discussionmentioning

confidence: 98%

Prognostic value of cetuximab‐related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group

Stintzing

Kapaun²,

Laubender

et al. 2012

Intl Journal of Cancer

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Skin toxicity is a frequent adverse event of epidermal growth factor receptor (EGFR) targeting agents. Occurrence of cetuximab-induced skin toxicity (Cet-ST) correlates with better treatment response and longer survival times. Molecular markers predicting Cet-ST are still missing. This investigation analyzed the value of Cet-ST for treatment efficacy in a randomized trial comparing cetuximab plus capecitabine/irinotecan to cetuximab plus capecitabine/oxaliplatin as first-line treatment of metastatic colorectal cancer. Patient characteristics and molecular parameters (KRAS mutation, EGFR-FISH, EGFR-IHC and EGFR intron-1 polymorphism) of the tumour were correlated with response and Cet-ST. Cet-ST grade 0-1 was observed in 31%, grade 2-3 in 69% of patients. Outcome favoured patients with grade 2-3 Cet-ST with regard to overall response rate (62 vs. 41%), PFS (7.8 vs. 5.2 months) and overall survival (OS) (30.3 vs. 18.0 months). First-cycle rash was observed in 66% of patients and corresponded with longer survival (30.7 vs. 20.2 months, p 5 0.007). Patients without Cet-ST had a poor outcome (PFS, 1.9 months; OS, 11 months). The correlation of Cet-ST with survival was specifically evident in patients with KRAS codon-12-mutated tumours assumed to be cetuximab resistant. In multivariate analysis of patient characteristics, male gender and younger age were significantly correlated with Cet-ST. Among molecular parameters, no significant correlation with Cet-ST was found. Cet-ST is an early predictor of treatment efficacy in cetuximab-treated patients. This effect of Cet-ST is independent of the KRAS mutation status, suggesting that Cet-ST rather relates to constitutional factors of the patient than alterations of the EGFR pathway in the tumour.The development of personalized cancer treatment has become a major focus of research. As an important step in this direction, routine KRAS codon 12 and codon 13 testing has been introduced as a key element of decision making when epidermal growth factor receptor (EGFR)-directed antibodies are considered for treatment of metastatic colorectal cancer (mCRC). As a result, this has restricted the approval of cetuximab to KRAS wild-type tumours. Meanwhile, it has become increasingly clear that KRAS mutational status is not the only determinant of cetuximab-related treatment efficacy because even in patients with KRAS wild-type tumours response is not achieved in about 40%. 1,2 Furthermore, there is evidence to suggest that KRAS codon-13-mutated tumours might respond to cetuximab therapy. 3 To further improve outcome prediction, multiple molecular markers are presently being tested. 4,5 In addition, clinical factors may also serve as relevant response predictors. Among these are alterations of blood pressure during treatment with bevacizumab 6 or acneiform skin rash in patients receiving agents directed against the EGFR. 7-10The present investigation was performed in mCRC patients receiving first-line chemotherapy in combination with cetuximab, a monoclonal antibody directed against the...

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Section: Discussionmentioning

confidence: 98%

Prognostic value of cetuximab‐related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group

Stintzing

Kapaun²,

Laubender

et al. 2012

Intl Journal of Cancer

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“…In a retrospective study of patients with advanced pancreatic cancer treated with chemotherapy combined with erlotinib, molecular analysis on Kras mutation status, EGFR expression by IHC and FISH, PTEN expression, EGFR intron 1 polymorphism and EGFR exon 13 R497K polymorphism, only Kras mutation status in codon 12 was associated with survival on univariate analysis with a HR 1.68 (95% CI 1.17-2.41; p=0.005) [169]. …”

Section: Molecular Targeted Agentsmentioning

confidence: 99%

Systemic Therapies for Pancreatic Cancer - The Role of Pharmacogenetics

Soo

Yong

Innocenti³

2012

CDT

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Effective systemic treatment of pancreatic cancer remains a major challenge, with progress hampered by drug resistance and treatment related toxicities. Currently available cytotoxic agents as monotherapy or in combination have provided only a modest survival benefit for patients with advanced disease. Disappointing phase III results with gemcitabine-based combinations in patients with advanced pancreatic cancer might be related to poor efficacy of systemic therapies in unselected patients. Future research strategies should prioritize identification of predictive markers through pharmacogenetic investigations. The individualization of patient treatment through pharmacogenetics may help to improve outcome by maximizing efficacy whilst lowering toxicity. This review provides an update on the pharmacogenetics of pancreatic cancer treatment and its influence on treatment benefits and toxicity.

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“…There is, however, increasing information regarding potential therapeutic targets for biological therapy in pancreatic cancer. KRAS mutations are found in 70–80 per cent of these tumours37, 38 and EGFR amplification is reported to occur in almost 50 per cent37. Further molecular classification has delineated three distinct subgroups of pancreatic cancer that may have differential responses to treatment39 and future studies may stratify according to these molecular signatures.…”

Section: Pancreatic Cancermentioning

confidence: 99%

Impact of targeted neoadjuvant therapies in the treatment of solid organ tumours

Waddell

Cunningham

2013

Journal of British Surgery

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Background: The advent of affordable technologies to perform detailed molecular profiling of tumours has transformed understanding of the specific genetic events that promote carcinogenesis and which may be exploited therapeutically. The application of targeted therapeutics has led to improved outcomes in advanced disease and this approach is beginning to become established in the management of potentially curable disease for surgical patients.Methods: This review article focuses on recent developments in the management of operable cancers of the gastrointestinal (GI) tract, specifically discussing the currently available data that evaluate the incorporation of targeted therapies in this setting.Results: A variety of targeted molecules are now available as treatment options in the management of GI cancers. Most are aimed at growth inhibition by acting on cell surface targets or intracellular pathways. Treatment paradigms are gradually shifting towards more prevalent use of systemic treatment prior to surgical intervention for operable disease with the aim of tumour downsizing and improved rates of long-term cure.Conclusion: A large number of ongoing clinical trials are evaluating novel targeted agents as neoadjuvant therapy in operable GI tumours. Therefore, further progress in the management of early-stage disease will undoubtedly be made over the next few years as these trials continue to report potentially practice-changing results.

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Molecular markers of the EGFR pathway in erlotinib-treated patients with advanced pancreatic cancer (APC): Translational analyses of a randomized, cross-over AIO phase III trial.

Cited by 6 publications

References 0 publications

Prognostic value of cetuximab‐related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group

Prognostic value of cetuximab‐related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group

Systemic Therapies for Pancreatic Cancer - The Role of Pharmacogenetics

Impact of targeted neoadjuvant therapies in the treatment of solid organ tumours

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