Acneiform eruption induced by molecularly targeted agents in antineoplastic therapy: A review

Various biologic agents targeting specific molecules present new treatment options for various tumors. Acneiform eruption is a very common skin reaction to these agents. Although not life‐threatening, acneiform eruption can affect patients' emotional and social lives. In very exceptional cases, it can lead to cancer therapy interruption.


| INTRODUC TI ON
Over the past decade, many biologic agents targeting molecules involved in tumor growth and immune response have been developed for use in targeted therapies. These agents have a remarkable effect on patients, but present new challenges. Patients treated with these agents experience fewer systemic side effects than from conventional chemotherapy, but mostly experience many more cutaneous side effects, including acneiform eruption, maculopapular rash, hair and nail changes, and xerosis, and pruritus, which can significantly impact patients' health and quality of life. Acneiform eruption, which is also called papulopustular eruption or acne-like rash, is the most common cutaneous manifestation of targeted therapies, especially those based on epidermal growth factor receptor (EGFR) inhibitors and mitogen-activated protein kinase (MEK) inhibitors. 1 Although not life-threatening, acneiform eruption always occurs on the face and chest and thus has a negative impact on patient emotional and social activities. Acneiform eruption can also increase the risks of secondary infections. In very exceptional cases, it can lead to cancer therapy interruption. 2 Early recognition and appropriate treatment of acneiform eruption are important to enable clinicians to prevent severe symptoms and discontinuation of antitumor therapy, thereby increasing patient compliance and optimizing clinical outcomes.
This review is an overview of the acneiform eruption induced by molecular-targeted agents and includes clinical presentation, pathogenesis, and management.

| MATERIAL S AND ME THODS
A literature search was conducted using PubMed, Embase, and Cochrane from 1979 to the present using the following search terms: 'acneiform eruption' and 'papulopustular eruption' or 'acne-like rash'; 'skin toxicity', 'cutaneous toxicity', 'skin reactions' and 'dermatological toxicities'; and 'target therapy' or 'drug therapy'. Exclusions were studies not related to targeted agents, studies for which the fulltext was not available and articles that were not written in English.
A total of 235 articles were found in the literature search. After selection for eligibility, 73 articles were finally included in the review, of which 61 were original articles and 12 were case reports or case series. The following types of original articles were included: randomized controlled trials, cohort studies, and case-control studies.

| Acneiform eruptions with targeted agents
In recent years, various molecularly targeted agents have emerged as treatment options for autoimmune diseases and tumors. The targets include EGFR, human epidermal growth factor receptor (HER)-2, BRAF, MEK, mammalian target of rapamycin(mTOR), programmed death (PD)-1, cytotoxic T lymphocyte-associated antigen (CTLA)-4, and vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. These biological agents can be classified into three categories: monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and immunosuppressants. 3 These agents offer the advantage of decreasing systemic side effects compared to conventional chemotherapy, but commonly produce dermatological effects because targeted signaling pathways are involved in both cell malignant behavior and normal homeostatic functions of the skin and appendages (Table 1).
EGFR inhibitors can be classified into two categories: monoclonal antibodies for EGFR and TKIs specific to EGFR. Acneiform eruption occurs in 45%-100% of EGFRI patients 17 and always develops within the first 4 weeks of treatment. The incidence of acneiform eruption is higher for treatment with monoclonal antibodies than treatment with TKIs. 4 The rash severity is usually mild to moderate but can sometimes be very severe. 18,19 The incidence of grade 3-4 skin reactions is 0%-17%, and severe skin reactions occur more commonly in patients treated with monoclonal antibodies than in those treated with TKIs. 5 Acneiform eruption of HER2 inhibitors has also been reported, but at much lower rates. 9,20 The skin reactions of most patients are mild to moderate in grade. Both BRAF inhibitors and MEK inhibitors are inhibitors of the RAS-RAF-MEK-ERK pathway. The reported incidence of acneiform eruption in BRAF inhibitors is 3%-9%. 10 Acneiform eruption is more common using MEK inhibitors (74%-89%) 3 than BRAF inhibitors. The combined application of BRAF and MEK inhibitors was found to increase the risks of all-grade rashes compared to the use of single BRAF inhibitors, [21][22][23] and the corresponding incidence of rashes was even lower than that of using MEK inhib-  24 Cutaneous reaction is typical with the use of mTOR inhibitors and usually manifests as acneiform dermatitis. 12 Several clinical trials also reported acneiform eruption as cutaneous adverse events associated with the use of PD-1 inhibitors 25 and CTLA-4 inhibitors. 16

| Clinical presentation and assessment
Acneiform eruptions usually occur during the first 2 weeks of treatment with targeted biologic agents. Typical lesions usually consist of erythematous papules and pustules, which are similar to acne vulgaris. However, comedones are rarely seen in acneiform eruptions, which helps to distinguish acneiform eruptions from acne vulgaris.
Acneiform eruption is usually accompanied by functional symptoms, such as pruritus, xerosis, and a burning sensation. 26 Acneiform eruption typically occurs in regions rich in sebaceous glands, such as the face, upper trunk, and scalp, but can also extend to the extremities. Different biologic agents may produce different characteristics in acneiform eruptions (Table 2).
Some studies show that rashes induced by EGFRI are dosedependent, and the incidence and / or rash severity increases with higher drug exposure, but a dose-dependent relationship has not been reported for other inhibitors of BRAF, MEK, mTOR, and PD-1.
It has also been observed that patients with higher baseline sebum levels present with higher toxicity when treated with EGFRI. 27 More extensive inflammatory lesions appear in postpubertal patients (above 8 years old), which may be caused by sebaceous gland maturation and changes in skin flora. 12,28 Acneiform eruption generally improves with time but rarely disappears during the treatment of biologic agents. After treatment discontinuation, however, acneiform eruption usually heals spontaneously within 4 weeks without sequelae.
The grade of skin reactions in studies is usually evaluated in studies using the National Cancer Institute-common terminology criteria for adverse events (NCI-CTCAE). The 4.0 version published in 2010 provides a classification scheme for the severity of acneiform eruptions. Rash severity is classified into grades that depend on the affected area, severity, and superinfection (Table 3). Acneiform eruption in most patients is generally classified as grade 1-2, 29,30 which is mild and usually manageable but can cause significant discomfort. Moderate or severe toxicities can sometimes occur, which always leads to dose modification or interruption. Therefore, effective management of acneiform eruption is crucial to maximize treatment efficacy and maintain quality of life.

| Pathogenesis
Although the pathogenesis of acneiform eruptions remains to be elucidated, follicular epithelium abnormalities and inflammation have been shown to play important roles. 7 EGFR is primarily expressed in undifferentiated, proliferating keratinocytes in the basal and suprabasal layers of the epidermis and the outer layers of the hair follicle. Essential skin functions such as keratinocyte proliferation, differentiation, keratinization, survival, and motility, are all maintained by EGFR activation. Alterations in EGFR expression and activities contribute to the formation of some tumors and some epidermal hyperproliferation disorders, such as acne, psoriasis, and hidradenitis suppurativa. 31 EGFR also plays a role in suppression of chemokine production.
Blocking EGFR signaling can affect keratinocytes by inducing apoptosis and growth arrest, decreasing cell migration, and increasing cell differentiation and cell attachment, which can cause follicular plugging and mechanical breakage. 32 35  Patients' skin barriers are always impaired by xerosis and pruritus. General skin care guidance includes mild cleaning with gentle shampoos and soaps, moisturizer treatment, and protection from the sun. 8,40 Restoration of skin barrier function by using moisturizers can reduce lesions. 40,41 For early-stage and low-grade (grade 1) acneiform eruption, topical antibiotic treatment (e.g., administration of 2% mupirocin ointment, 1% clindamycin emulsion, or metronidazole cream) is recommended twice daily. Nowadays a novel topical doxycycline foam has been shown to be safe and well tolerated to prevent the onset of acneiform eruption in patients receiving EGFRIs therapy. 42 Benzoyl peroxide or topical tretinoin is not recommended because skin irritation and dryness may result. Other regimens include treatment with topical corticosteroids (e.g., 1% or 2.5% hydrocortisone for the face and neck and 0.1% triamcinolone for the trunk and extremities), and topical calcineurin inhibitors twice daily (e.g., 0.1% tacrolimus ointment and 1% pimecrolimus cream). 43,44 Topical agents must be used with caution, as patients who receive molecularly targeted agents seem to be abnormally sensitive to irritants or allergens. Solutions or alcohol-containing gels can enhance dryness and should therefore be avoided in the treatment of acneiform eruption. It has recently been shown that vitamin K1 has the potential to prevent EGFR inhibitor-induced rash, 44 and may decrease the incidence and severity of acneiform eruption. EGF ointment may be another potential In more severe cases (grade ≥2), oral tetracyclines such as minocycline (50-100 mg bid) or doxycycline (100 mg bid), are considered first-line agents in treatment. 6,45,46 Most patients usually need antibiotic treatment for more than 2 months, male and younger patients may need a longer course of treatment than other patients. 6 However, refractory cases to such treatment remain. For refractory cases, oral isotretinoin can be considered an alternative treatment option, 18

| CON CLUS IONS
An increasing number of new molecularly targeted agents that expand the therapeutic landscape have been approved for use in patients. Acneiform eruption is very common in patients treated with these agents and impacts the patients' quality of life. Therefore, early recognition and effective management of this cutaneous adverse reaction may improve patients' quality of life and prevent unnecessary drug reduction or discontinuation. Despite the current knowledge of acneiform eruption induced by molecularly targeted agents described in this review, further studies tailored to different targeted agents need to be performed, because the effects of these agents are specific to the mechanism of action involved. The treatment of acneiform eruption depends on the severity of the skin reaction and the response to basic therapies, and patients who are refractory to initial therapy should be referred to dermatologists.
Additionally, close collaboration between oncologists and dermatologists is crucial for reducing the severity and duration of skin reactions, optimizing therapy, and improving patient survival.

AUTH O R CO NTR I B UTI O N S
Baoxi Wang had the idea for the article, Chen Yuan performed the literature search and data analysis and Chen Yuan drafted the article, Baoxi Wang critically revised the work.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors have no conflict of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

E TH I C A L S TATEM ENT
Not applicable.