Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity

Parmar, Sumit; Schümann, Christian; Rüdiger, S; Boeck, Stefan; Heinemann, Volker; Kächele, Volker; Seeringer, Angela; Paul, Tanusree; Seufferlein, Thomas; Stingl, Julia C.

doi:10.1038/tpj.2011.51

Cited by 33 publications

(59 citation statements)

References 40 publications

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“…A cohort of 211 cancer patients was prospectively included in this study according to a protocol described earlier [39]. There were 77 (36.5 %) female and 134 (63.5 %) male participants with a median age of 69 years (range: 43-87 years).…”

Section: Resultsmentioning

confidence: 99%

“…Plasma samples (n = 211) were derived from patients included in the Dermatoxgen study, which is a prospective, multicenter study designed to investigate pharmacogenetic factors of skin toxicity induced by EGFR inhibitors, as already reported in previous publications [18, 19, 39]. The study includes patients with histologically confirmed solid tumors (pancreatic, colon, head and neck or non-small cell lung cancer) who are first-time treated with an EGFRI (erlotinib, gefitinib, cetuximab or panitumumab).…”

Section: Methodsmentioning

confidence: 99%

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Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

et al. 2017

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Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash. With a predictive value for the rash these biomarkers may also have a prognostic value for survival and disease outcome.The concentrations of amphiregulin, hepatocyte growth factor (HGF) and calcidiol were determined by specific enzyme-linked immunosorbent assays in plasma samples from 211 patients.We observed a significant inverse correlation between the plasma concentration of HGF and overall survival in patients with an inhibitor-induced rash (p-value = 0.0075; mean overall survival low HGF: 299 days, high HGF: 240 days) but not in patients without rash. The concentration of HGF was also significantly inversely correlated with severity of rash (p-value = 0.00124).High levels of HGF lead to increased signaling via its receptor MET, which can activate numerous pathways which are normally also activated by epidermal growth factor receptor. Increased HGF/MET signaling might compensate the inhibitory effect of epidermal growth factor receptor inhibitors in skin as well as tumor cells, leading to less severe skin rash and decreased efficacy of the anti-tumor therapy, rendering the plasma concentration of HGF a candidate for predictive biomarkers.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

et al. 2017

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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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“…Other studies investigated whether genetic variation within the EGFR gene could predict EGFR inhibitor-associated skin toxicity [83, 84]. Some polymorphisms and haplotypes have been identified but have not been confirmed in larger RCTs.…”

Section: Safetymentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer

et al. 2017

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Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is able to prolong survival in patients with mCRC. Panitumumab is used in different lines of therapy in combination with chemotherapy, and as monotherapy for the treatment of wild-type (WT) RAS mCRC. It is administered as an intravenous infusion of 6 mg/kg every 2 weeks and has a t ½ of approximately 7.5 days. Elimination takes place via two different mechanisms, and immunogenicity rates are low. Only RAS mutations have been confirmed as a negative predictor of efficacy with anti-EGFR antibodies. Panitumumab is generally well tolerated and has a manageable toxicity profile, despite a very high prevalence of dermatologic side effects. This article presents an overview of the clinical pharmacokinetics and pharmacodynamics of panitumumab, including a description of the studies that led to its approval in the different lines of therapy of mCRC.

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Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity

Cited by 33 publications

References 40 publications

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

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

Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer

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