EGFR is mainly expressed by basal keratinocytes and the outer root sheath cells.4 EGFR functions like a switch that is turned on and off in hair follicles at the beginning and end of the anagen phase of the hair cycle. EGFR stimulates proliferation, regeneration, and development in normal cells at the level of the skin, hair follicles, lacrimal gland, and ocular surface epithelia.5 Moreover, EGFR is overexpressed or dysregulated in various types of solid tumors, including NSCLC.6 This can lead to increased or uncontrolled proliferation, decreased apoptosis, enhanced tumor cell motility, and angiogenesis. Inhibition of EGFR signaling in epidermal and follicular keratinocytes results in decreased cell proliferation, differentiation, and attachment.5
Although the underlying mechanism of cutaneous toxicities remains elusive, EGFR inhibitors, such as erlotinib, gefitinib, cetuximab, and panitumumab, are related to cutaneous toxicity.7 The selective HER2 inhibitor trastuzumab induces tufted hair folliculitis in some cases.8 Cutaneous reactions can be a positive predictor of tumor response, which is believed to indicate receptor saturation and blockade.9 This may be one of the mechanisms of erlotinib-induced cutaneous toxicity. Our patient developed a spectrum of cutaneous toxicities, including papulopustular rash, mucositis, pruritus, xerosis, paronychia, and facial hirsutism, which is defined as PRIDE syndrome.10 The pathogenesis of these symptoms is largely unknown, but there is evidence that this is directly linked to EGFR inhibition.9
Because the prognosis of advanced NSCLC is poor and the cost of erlotinib is high, it is imperative that molecular or clinical markers are identified to stratify potential responders. Currently, clinicians mainly evaluate the efficiency of erlotinib treatment using EGFR mutation analysis. Several factors, such as female sex, never smokers, adenocarcinomas (particularly bronchoalveolar adenocarcinoma), and Asian origin, are established as positive predictive markers for clinical benefit.11 For Caucasian patients, never-smoking status and male sex predicted a prolonged survival.12 However, sometimes it is not possible to obtain the tumor genotypes owing to tumor characteristics or technical problems. Therefore, there is a need to indirectly speculate tumor response through clinicopathological characteristics.
Several studies have reported a link between the anti-tumor efficacy of EGFR inhibitors and cutaneous adverse effects. The earliest literature suggests that the rash can be used as a marker of EGFR inhibitor treatment efficiency.13 Recently, a meta-analysis showed that patients with skin rash have a longer overall survival than patients without skin rash.11 There are also data suggesting that skin changes may be a surrogate marker for the response of a tumor to EGFR inhibition, and that skin rash is a prognostic factor of patients with NSCLC. Some researchers have reported that patients with erlotinib-induced trichomegaly had a good tumor response, suggesting that it could be used as an effective tool for predicting drug efficacy.14 Recently, it was suggested that cutaneous leukocytoclastic vasculitis may be due to erlotinib and bevacizumab and could be used as a marker of anti-tumor efficacy of EGFR inhibitors.15
Currently erlotinib-induced cutaneous toxicities that have been reported as clinical markers are mostly single adverse events. This is the first case report about the relationship between multiple cutaneous adverse effects and EGFR inhibitor efficacy. A study showed that patients experiencing multiple cutaneous toxicities had better therapeutic outcome compared to those experiencing single cutaneous adverse events.16 The variability in skin rash susceptibility was associated with erlotinib plasma concentrations, which predicted a good response to erlotinib.17 When our patient developed the spectrum of cutaneous reactions, the CT scan showed marked disappearance of the lung metastases. We speculate that multiple cutaneous toxicities indicate a good tumor response. Thus, multiple cutaneous toxicities may be a clinical marker for predicting the response to therapy without knowledge of the EGFR mutation status.