Zinc supplements may prevent and treat cutaneous toxicities induced by epidermal growth factor receptor inhibitors.

Abstract

Inhibitors of Epidermal Growth Factor Receptor (EGFRi) widely used in the therapy of cancer are associated with cutaneous adverse reactions (CARs) in >90% of continuously treated patients, including papulo-pustular or acneiform eruptions, xerosis, pruritus, paronychia and alopecia1 and, very occasionally, necrolytic migratory erythema-like (NME) reactions.2, 3 These CAR are usually associated with better treatment response, but may severely impact patient's quality of life and are a frequent reason for treatment withdrawal or dose reduction. The mechanisms underlying these CAR are not completely understood, but have been explained mostly by the pharmacologic activity of the drugs. EGF is involved in the survival, migration, proliferation and maturation of basal epidermal keratinocytes but is essential also in the follicles, nail apparatus, sebaceous and eccrine glands. Therefore, EGF receptor inhibition induces cell growth arrest, premature differentiation and keratinocyte apoptosis, causing thinner skin with epidermal barrier disruption, oxidative stress, inflammation with a Th2 pattern, reduction of skin innate immunity, and disturbance of sebaceous lipids.4, 5 This may explain xerosis, dermatitis and increased lesional Staphylococcus aureus colonization, often observed in these patients. However, based on the report of low-zinc levels in a case of erlotinib-induced NME-like2 and 25 cases of EGFRi-induced xerotic dermatitis with low- or marginal serum zinc levels who improved after zinc supplementation in more than 75% of the cases,6 Chun-Wei Lu and the team of Wen-Hung Chung from Taiwan decided to study the relationship between zinc levels and CAR from EGFRi, as presented in this issue of JEADV.3 They studied 101 patients treated with different EGFR inhibitors targeting the Tyrosine kinase (EGFR-TKI) (gefitinib, erlotinib, afatinib, osimertinib, and zorifertinib) who developed papulo-pustular reactions, dry skin and eczema, paronychia, NME-like eruption and/or dysgeusia. They had a significantly lower plasma zinc level when compared with patients with cancer without these therapies or out-patients with no cancer and no ECGFR therapy. Low-zinc levels occurred in all the phenotypes of CAR and zinc reduction was correlated with CAR severity. Moreover, in 55 patients who received supplementation with zinc gluconate skin lesions improved significantly with no need to reduce the dose or stop the EGFR-TKI.3 To further demonstrate the relation between zinc and EGFRi, the authors have shown that zinc levels decreased significantly in animals treated with erlotinib for 2 weeks, and these rats developed periorificial lesions simulating NME or acrodermatitis enteropathica-like lesions with histopathology similar to the patients who had developed this phenotype of CAR.3 This data supports that zinc deficiency may be one of the drivers of EGFRi-induced CAR, although there is no proven explanation for this effect. Some EGFRi, like erlotinib, may have zinc-binding activity or the EGFRi may interfere with zinc transport during absorption in the duodenum or with keratinocyte zinc transporters (ZnT2).3, 6 Zinc is abundant in the epidermis, controlling multiple metalloenzymes and transcription factors that regulate protein, lipid and DNA synthesis and degradation, and is essential for controlling several epidermal functions (keratinocyte differentiation, proliferation and apoptosis, skin inflammation and wound repair). EGFRi-induced CAR has many similarities with skin manifestations of zinc deficiency, namely NME or acrodermatitis enteropathica, paronychia, alopecia, dysgeusia and Staphylococcal skin colonization. Acneiform or papulo-pustular reactions, as observed in EGFRi-induced CAR, are not reported in zinc deficiency, but even though plasma zinc levels measured in acne are conflicting, topical or systemics treatments with zinc have been proposed for the treatment of acne.7 If zinc deficiency is further confirmed in all these phenotypes of CAR induced by EGFRi, both monoclonal antibodies anti-EGFR and oral ECGR-TKI, it might be important to perform systematic zinc supplementation in association with these therapies, instead of using prolonged treatments with tetracyclines, retinoids or topical steroids which may have other adverse effects. Has participated in advisory boards or performed paid lectures for Abbvie, Astra-Zeneca, Leo, Lilly, Novartis, Pfizer, Sanofi, Takeda. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.