Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

Abstract

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.

Development of a nanoliposomal formulation of erlotinib for lung cancer and in vitro/in vivo antitumoral evaluation

“… 15 Accumulation of erlotinib in tumors is just 2 times greater than in skin, and previous studies have shown that liposome encapsulation can result in higher tumor drug concentration compared with that in skin. 16 …”

Predictive Value of Cetuximab-Induced Skin Toxicity in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and NECK

“…At the basic research phase of SCCHN, an EGFR-R521K genotype (G/G) was reportedly associated with increased Cmab-induced skin toxicity (20). Other reports, which included SCCHN patients, found a significant inverse correlation between the plasma concentration of hepatocyte growth factor and EGFR inhibitor-induced rash (17). On the other hand, identification of clinical factors related to the occurrence of Cmab-induced skin toxicity in SCCHN is still lacking, and we were also unable to identify such factors in the present study (Table 3).…”

“…However, few studies have focused on the correlation between Cmab-induced skin toxicity and efficacy in R/M SCCHN. Klinghammer et al observed a trend toward longer PFS and OS in patients who experienced grade 1 rash compared with those with grade 0 among R/M SCCHN patients who were treated with the combination of Cmab and docetaxel (17). In our present study, we found that severe (≥grade 3) Cmab-induced skin toxicity within 90 days (“early skin toxicity”) is an independent and more robust predictive factor for a favorable clinical outcome after adjusting for sex, age, primary site and treatment regimen (with HR of 0.363 for PFS and HR of 0.187 for OS).…”

An inventory of medicinal products causing skin rash: Clinical and regulatory lessons

“…It is interesting to notice that the large majority of protein kinase inhibitors have rash as an adverse reaction with a very high frequency, except for tofacitinib (rash described as ‘common’), baricitinib, and ruxolitinib (no rash at all). All three exceptions are inhibitors of Janus kinases, and it is interesting to contrast this minority with the high majority, for which rash is not only very frequent, but it may also be a useful marker for efficacy (36,37). It is also interesting to note that whereas baricitinib has no rash as an adverse reaction, it does have acne as such a reaction, and the rash in the case of other protein kinase inhibitors may be acneiform (papulopustular) and be prevented by oral tetracyclines (37,38).…”

“…All three exceptions are inhibitors of Janus kinases, and it is interesting to contrast this minority with the high majority, for which rash is not only very frequent, but it may also be a useful marker for efficacy (36,37). It is also interesting to note that whereas baricitinib has no rash as an adverse reaction, it does have acne as such a reaction, and the rash in the case of other protein kinase inhibitors may be acneiform (papulopustular) and be prevented by oral tetracyclines (37,38). Although most protein kinase inhibitors do have rash as a very common adverse drug reaction, meta-analysis data indicate that there are differences among different molecules, e.g., it is significantly more frequent with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (39).…”