Persistent hair growth during treatment with the EGFR inhibitor erlotinib1. Georgetown Dermatology, Washington, DC. firstname.lastname@example.org
Doru T Alexandrescu MD1, C Lisa Kauffman MD1, Constantin A Dasanu MD PhD2
Dermatology Online Journal 15 (3): 4
2. Department of Hematology/Oncology, St Francis Hospital and Medical Center, Hartford, Connecticut
Medications belonging to the group of epidermal growth factor (EGFR) inhibitors are currently in widespread use for the treatment of epithelial malignancies. Many cutaneous side effects are known to develop as a result of the use of these agents. Trichomegaly is a newly described side effect, consisting of premature maturation (terminal differentiation) of the hair of the eyelashes and the scalp, which is characterized by a hairy phenotype. Although occurrence of the acneiform skin rash is clearly associated with favorable tumor responses and improvement in patient survival during the use of EGFR inhibitors for the treatment of cancer, the significance of trichomegaly is less clear. A review of all published cases is provided, leading to the observation that trichomegaly also developed in patients whose tumors had a positive response to anti-EGFR therapy. The apparent lack of the development of tolerance to this medication effect and, therefore, the continued clinical sign of trichomegaly is in contrast to the time-limited nature of other cutaneous side effects of EGFR inhibitors, such as the classical papulo-pustular rash. The persistence of trichomegaly in some patients brings into question the precise mechanism of this phenomenon and suggests the possibility of using EGFR inhibition therapeutically to stimulate hair growth.
The widespread use of epidermal growth factor receptor (EGFR) inhibition for the treatment of patients with various malignancies, such as colorectal, lung, breast, head-and-neck, and pancreatic cancers, has resulted in valuable clinical responses, along with the identification of new and often puzzling side effects. Skin toxicities, the characteristic "acneiform" papulo-pustules, pruritus, paronichia, fissures, xerosis, and telangiectasias, also include a stimulation of hair growth, which is accompanied by a special curly texture. Along with its occurrence in uncommon congenital conditions (oculocutaneous albinism type I, familial hypertrichosis) , trichomegaly is known to be induced by infections (HIV, uveitis) and drugs belonging to various classes, such as cyclosporine, tacrolimus, minoxidil, diazoxide, latanoprost, zidovudine, topiramate, and interferon-alpha. The discovery of an association between the occurrence of a specific skin findings and the development of objective responses to tumors has encouraged the search for markers that would predict the tumor response during EGFR blockade treatment. Recent reports link the use of EGFR inhibitors to the development of trichomegaly, which appears to occur as a class effect for erlotinib, gefitinib, and cetuximab. The biological significance of trichomegaly, and whether it tends to persist with continued treatment is currently unknown. We present a case of persistent hypertrichosis during the treatment with erlotinib for lung cancer, which demonstrates the possibility of using medications from the class of EGFR inhibitors as a therapy to stimulate the growth of hair.
A 76-year-old Caucasian female, with no history of smoking, presented in September, 2004 with a 2.5 cm mass in the upper lobe of her right lung. Surgery was performed, consisting of right upper and middle lobectomies. The pathology specimen showed a moderately differentiated adenocarcinoma, which was clinical Stage I A. No other therapy was administered at the time. However, in March 2005 the patient developed persistent midline lumbar pain. A CT scan and plain X-rays of the spine demonstrated the presence of lower spinal metastases and local radiation therapy was administered. The patient refused systemic chemotherapy. Because new metastases developed in the next few months in the right sacrum, ribs, and skull bones, systemic epidermal growth factor receptor (EGFR) inhibition with the tyrosine kinase inhibitor, erlotinib (Tarceva®), was initiated at a dose of 150 mg per day orally. The treatment commenced in November, 2005 and was continued until the present with the exception of a small period of interruption in 2006, due to the lack of prescription coverage.
Three months after commencing erlotinib, the patient noticed the development of long curly eyelashes and thickening of the hair on the entire surface of her scalp (Fig. 1). A generalized darkening of her hair, predominantly in the frontal area, eyebrows, and eyelashes was apparent and progressed gradually. Both the trichomegaly and the darkening of the hair were maintained during the whole duration of her EGFR inhibition therapy, over two and one-half years. A papulo-pustular eruption on the anterior chest and arms was present intermittently, predominantly at the beginning of her treatment with erlotinib. In addition, the patient noticed the development of paronychias of her fingernails. Both the rash and paronychias were mild and responded to skin moisturization. The patient had a stabilization of her disease, which did not progress during the almost three years of treatment with the oral regimen of EGFR inhibition.
The tyrosine kinase inhibitors, erlotinib and gefitinib, act by preventing epidermal growth factor receptor (EGFR) receptor autophosphorylation. This effect results in blocking the transmembrane EGFR, a mediator of extracellular signals involved in cellular proliferation, apoptosis, cell cycling, and metastatic potential. Similar effects result from the extracellular blockade of the EGF receptor using the monoclonal antibody, cetuximab. EGFR inhibitors are important components of the armamentarium directed against cancer in the era of molecular targeted therapies; new agents continue to be developed.
In addition to the antitumor activity, the effects of EGFR inhibition also extend to other tissues that normally express EGFR, such as the basal and suprabasal layers of the epidermis, sebaceous glands, and the outer root sheath of the hair follicles [2, 3]. Important cellular functions that are altered during EGF receptor blocking therapy consist of differentiation, proliferation, apoptosis, attachment, and migration, with an overall dominating effect of inducing keratinocyte growth arrest and terminal differentiation of the keratinocytes in the basal layers . EGFR plays a central role in the normal differentiation and development of the hair follicle . The effects of EGFR blockade on the hair cycle include a premature maturation (terminal differentiation) of the hair follicle, which in certain cases may result in trichomegaly. EGF receptors are also distributed in the eye at the level of the corneal and conjunctival epithelial cells; the ligand epidermal growth factor (EGF) is present in the tears. In the eye, physiological roles of the EGF axis consist of maintaining ocular homeostasis and repair of corneal epithelial wounds . Trichomegaly of the eyelashes, as an isolated occurence, or frequently as part of a generalized phenomenon, is associated with the use of the TKIs, gefitinib and erlotinib [1, 7], as well as the recombinant antibody cetuximab .
Trichomegaly develops in a subset of patients treated with EGFR inhibition. Although its incidence has not been accurately assessed, it probably develops in a minority of subjects and has not yet been evaluated in relation to the occurrence of other cutaneous or systemic toxicities, or with the positive or negative response of the underlying malignancy to the treatment with EGFR inhibition. The occurrence of trichomegaly of the eyelashes has been associated with trichiasis, conjunctivitis, and keratoconjunctivitis sicca (overall noted in 12% of patients) and development of corneal ulcerations, which appear to be infrequent and possibly related to the use of contact lenses. Therefore, an ophthalmological evaluation is warranted . In addition to the increase in eyelash elongation commonly reported with the EGFR blocker, gefitinib , irregular coarse curls have also been observed . Our case demonstrates growth stimulation of the eyelashes and scalp hair, which assumed a curly phenotype.
Observation of our case and other similar ones in the literature [1, 7, 9-14] (Table 1), leads to several interesting observations. First, all the reported patients who manifested trichomegaly also had a positive response of their tumor. This response rate is clearly more than the expected one with this class of biological agents, which generally occurs in about 10 percent of cases  (Table 1). Although no definitive conclusions can be drawn in such a small series of patients, an additional interesting fact is that all patients who developed trichomegaly had a response to the EGFR treatment and all cases who developed trichomegaly are women. An obvious analogy can be made with the situation of non-small cell lung cancer, in which the young non-smoking Asian females had much higher response rates than other subgroups of patients . The explanation in the later scenario is the presence of a distinctive mutation in the EGFR receptor.
A correlation between tumor response in lung cancer with the presence of EGFR tyrosine kinase domain mutations in tumors is well substantiated, with three quarters of the responding lung tumors carrying EGFR mutations. In comparison, only approximately one-tenth of patients expressing a wild-type EGF receptor gene show a response . In addition, other beneficial therapeutic effects of EGFR inhibition have also been associated with the development of a skin rash. Thus, a median survival duration of 1.5 months occurs for patients with non-small cell lung cancer having no rash vs. 8.5 months for grade 1, and 19.6 months for grades 1 or 3 rash . However, no direct association between the presence of EGFR mutations and the occurrence of skin toxicity, either as an acneiform eruption, or as development of trichomegaly could be made so far. Yet, one report of trichomegaly of the eyelashes describes the response of a tumor carrying an exon 19 mutation in the EGFR gene .
All reported cases that developed hair growth were associated with a favorable tumor response consisting of shrinking or no progression [1,7,9-13]. In contrast, one case of colon cancer unresponsive to cetuximab was associated with loss of eyelashes (e.g., madarosis) . Although the demonstration of a correlation between tumor response and development of trichomegaly requires data support from a much larger series, this preliminary observation appears intriguing, in view of the fact that the presence of specific EGFR mutations may be associated with the occurrence of hair growth.
It is only in a clinical trial setting using topical agents that the effects of administration of local EGFR blocking agents on the development of hair growth can be assessed. This effort appears to be worthwhile because the EGFR inhibition appeared to have a persistent stimulatory effect on hair growth that did not seem to be subject to the development of tolerance. Future targeted EGFR inhibitors may be developed to specifically inhibit the particular pathways that suppress the initiation or progression of hair growth, or otherwise interfere with other inhibitory influences via modulation of EGFR signaling.
Finally, it is remarkable that in our case, as well as others [10, 12], the trichomegaly lasted for a long period of time, typically for the duration of the treatment before the tumor escaped therapeutic control. This finding is in contrast with the development of the majority of other side effects of EGFR inhibitors, including the acneiform rash. Thus, in a patient developing trichomegaly, and in whom the acneiform eruption is expected to gradually improve over time, the therapeutic effect in stimulating hair growth should not be affected by the treatment interruptions necessitated by development of skin rashes during the first weeks after initiating treatment.
Current data indicating an association between hair growth and EGFR inhibition focus on preclinical and animal models, in which hair formation and support of the anagen phase are established findings [19, 20]. It is therefore unknown why trichomegaly develops only in a subset of patients treated with EGFR inhibition and why, in some cases, the hair growth appears to continue long-term, unlike all the other cutaneous toxicities of the EGFR inhibitors, in which tolerance develops. However, the presence of this phenomenon is of interest. In the future, EGFR inhibition may be clinically utilized to stimulate hair growth.
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