Aromatase, present in both gonadal and extra-gonadal tissues, catalyzes the conversion of testosterone to estrogens (Stocco, 2012; Kharb et al., 2020). Excessive estrogen levels have been implicated in various diseases, notably contributing to the high malignancy rate of breast cancer (BC) in postmenopausal women (Diamond et al., 2015; Patel, 2017; Rižner and Romano, 2023). Consequently, inhibiting estrogen synthesis or blocking estrogenic activity is a key strategy in BC treatment, underlying the development of aromatase inhibitors (AIs) (Kharb et al., 2020). AIs are a class of drugs that target the aromatase enzyme, which is responsible for converting androgens to estrogens. AIs have evolved through three generations, each improving upon the limitations of the previous. First-generation AIs, such as aminoglutethimide, were introduced in the 1970s but lacked selectivity and specificity (Buzdar et al., 2001). Second-generation AIs, like fadrozole and formestane, offered more selectivity but still had limitations in targeting aromatase efficiently (Dellapasqua and Colleoni, 2010). The third-generation AIs, including exemestane, anastrozole and letrozole, were developed to address these shortcomings, offering greater potency and specificity, and have shown efficacy in high-risk BC patients (Kharb et al., 2020). For instance, two clinical trials involving 5,738 patients demonstrated that AIs moderately reduced distant recurrences in premenopausal BC patients, leading to improved progression-free survival (PFS) across a broad population of BC patients (Francis et al., 2018; Robertson et al., 2021). However, adverse events (AEs) associated with AIs, such as cardiovascular events, dizziness, dyslipidemia, fatigue, headache, hot flushes, joint pain, muscle pain, nausea, osteoporosis, sweating, and vaginal dryness, pose significant clinical challenges, particularly for postmenopausal BC patients (Zhang et al., 2024), thus impacting the optimal use of AIs in BC therapy. Increasingly, attention has turned to the frequent occurrence of AIs’ adverse effects.

Among the AEs associated with AIs, dermatologic reactions are particularly prevalent. For example, erythematous patches, papules, and plaques have been reported (with a median onset of 2 months) in an estrogen- and progesterone-receptor-positive BC patient receiving anastrozole (Santoro et al., 2011). Among the AEs associated with AIs, dermatologic reactions are particularly prevalent. For example, erythematous patches, papules, and plaques have been reported in an estrogen and progesterone receptor-positive BC patient receiving anastrozole, with a median onset of 2 months (Sonke et al., 2018). In an international, multicenter, randomized, double-blind, placebo-controlled phase III trial with 720 BC patients receiving exemestane, rash was the second most common AE, with other skin-related reactions also reported (Pritchard et al., 2013). These findings underscore growing concerns regarding the dermatologic safety of AIs.

Given the confirmed association between dermatologic AEs and AIs such as anastrozole, exemestane, and letrozole, it is essential to clarify the relationship between specific AI agents and dermatologic AEs. The FDA Adverse Event Reporting System (FAERS), a global spontaneous reporting system, provides extensive real-world data to identify AE risk signals (Gu et al., 2023). In this chapter, we analyze standardized FAERS data to assess the potential risk of dermatologic toxicity linked to key AI agents, aiming to inform safer options for BC therapy.

AIs, categorized as nonsteroidal and steroidal, are widely used as adjuvant therapy and represent the gold standard for estrogen receptor (ER)+ BC management. Among the nonsteroidal AIs, anastrozole and letrozole significantly benefit ER + BC patients by inhibiting aromatase activity through multiple mechanisms (Fusi et al., 2014; Jameera Begam et al., 2017). For example, a clinical trial involving 3,864 postmenopausal women with BC demonstrated that anastrozole provided greater clinical benefits than placebo, underscoring its therapeutic value (Wollina et al., 2018). Additionally, the combination of ribociclib with letrozole has shown substantial efficacy, with a median PFS of 21.8 months (95% CI, 13.9–25.3) (Fasching et al., 2024). Exemestane, the only third-generation steroidal AI, is also clinically beneficial for postmenopausal BC patients (Jameera Begam et al., 2017). The frequent clinical use of anastrozole, exemestane, and letrozole warrants examination in this study. However, the dermatologic risks associated with AIs cannot be overlooked. For instance, a phase 3b study of ribociclib in BC reported a 35.1% incidence of alopecia with letrozole treatment. Additional dermatologic adverse effects, such as hot flashes, pruritus, and rash, have been noted in the literature (Fasching et al., 2024). These adverse dermatologic events not only impact patients’ quality of life but may also lead to interruptions or even discontinuation of cancer therapy (Sussman et al., 2019). While the benefits of AIs generally outweigh the risks, proactive prevention strategies are essential. This study conducts a comprehensive assessment of dermatologic risks associated with the commonly used AIs—exemestane, anastrozole, and letrozole—over the past 2 decades, utilizing real-world data from an AE reporting database.

In our study, the relatively low ROR for dermatologic AEs associated with letrozole (ROR = 0.94) compared to anastrozole and exemestane may be attributed to several pharmacokinetic and pharmacodynamic differences. Letrozole has a longer half-life (approximately 4 days) and reaches steady-state plasma concentrations over a longer period (60 days) (Buzdar et al., 2002) compared to anastrozole and exemestane, which have shorter half-lives (1–2 days) and quicker peak drug levels (Hamadeh et al., 2018). This steady accumulation may result in fewer fluctuations in drug levels, potentially reducing the incidence of acute skin reactions. Therefore, letrozole’s pharmacokinetic profile, with a longer half-life and stable plasma concentrations, might lead to a more gradual onset of adverse effects, including dermatologic reactions. Additionally, each AI is metabolized via different pathways, which can influence the formation of reactive metabolites or drug–drug interactions. Letrozole is primarily cleared by CYP2A6 (with minor involvement of CYP3A4), and it notably inhibits CYP2A6 itself, potentially leading to self-limited metabolism and more stable drug levels over time (De Placido et al., 2018). In contrast, anastrozole is mainly metabolized by CYP3A4 (with contributions from CYP3A5, CYP2C8, and glucuronidation), and it can weakly inhibit several CYP enzymes (e.g., 1A2, 2C8/9, 3A4) (De Placido et al., 2018). Exemestane undergoes oxidation by CYP3A4 and reduction by CYP450 enzymes, including 11β-hydroxylation via CYP4A11 (De Placido et al., 2018). Given this metabolic profile, letrozole’s unique CYP2A6 pathway, combined with its steady accumulation and lack of active metabolites, may make it less prone to certain immune-mediated skin reactions or erratic plasma fluctuations that could precipitate rashes. This could partly explain why letrozole has a lower ROR for dermatologic issues relative to anastrozole and exemestane.

Recent clinical publications have highlighted the dermatologic toxicities induced by aromatase inhibitors (AIs) (Wilkinson and Hardman, 2017), Moreover, AIs have been shown to influence humoral immunity and immunoglobulin levels (Cutolo et al., 2012; Aguilar-Pimentel et al., 2020). Increasing evidence suggests that reduced estrogen levels can provoke hyperactive neutrophils, which adhere to vascular endothelium, potentially triggering autoimmune vasculitis and adverse dermatologic responses (Zarkavelis et al., 2016; Woodford et al., 2019). Estrogen thus plays a critical role in preserving skin vasculature and function. Although AIs benefit postmenopausal women with BC by reducing estrogen, excessive estrogen deficiency adversely impacts skin maintenance. Consequently, AIs in clinical use often leads to dermatologic side effects such as hot flushes, sweating, vaginal dryness, nail disorders, onychoclasis, hypopigmentation, and vascular purpura (Pagani et al., 2014; Fasching et al., 2024; Zhang et al., 2024). The prevalence of these adverse effects calls for rigorous dermatologic monitoring to ensure safe AI application.

Alopecia is particularly common in BC patients treated with AIs, with a notable incidence among AEs (Fasching et al., 2024). Alopecia affects approximately 2.5% of BC patients, and about 8% discontinue AI therapy due to this adverse effect (Freites-Martinez et al., 2018; Ferreira et al., 2019; Behbahani et al., 2021). In our retrospective pharmacovigilance analysis, 76.55% of alopecia cases were associated with anastrozole (555 out of 725 reports). All three AIs were linked to hair abnormalities, with alopecia and abnormal hair growth linked to anastrozole, androgenetic alopecia linked to letrozole, and abnormal hair growth linked to exemestane. These findings predict a high risk of alopecia with AIs in BC therapy, suggesting that concurrent use of AIs with minoxidil may help sustain hair follicle health (Freites-Martinez et al., 2018; Ferreira et al., 2019).

Our analysis found positive signals for onychoclasis, vascular responses (e.g., hypersensitivity vasculitis, vascular purpura), hair abnormalities (e.g., alopecia, androgenetic alopecia, hair growth abnormality), and nail toxicity (e.g., nail disorder, discoloration, nail dystrophy) across all three AIs, indicating a need for appropriate patient care. Additionally, dry skin, erythema, hyperhidrosis, pruritus, and rash were frequently associated with AI-related skin impairments, emphasizing the necessity for concurrent protective strategies during AI treatment in BC patients. While letrozole showed a negative association with skin-related AEs (ROR 0.94; 95% CI 0.91–0.98), anastrozole (ROR 1.07; 95% CI 1.03–1.11) and exemestane (ROR 1.1; 95% CI 1.04–1.16) had significant positive associations, underscoring the need for close monitoring of dermatologic adverse effects with these drugs.

Regarding onset time, all three AIs were associated with urticaria, with a median onset of just 2 days for exemestane, indicating a rapid adverse response. Most positive PTs had onset times of less than 50 days (dry skin, alopecia, erythema, night sweats, onychoclasis, pruritus, rash, urticaria, angioedema, and maculopapular rash), suggesting acute impacts on patient quality of life. These findings highlight the need for proactive intervention, enabling targeted measures based on onset timing.

This pharmacovigilance study has limitations. First, duplicate reports, false information, and missing data in the FAERS database reduce data accuracy. For example, reports with inaccurate dates were excluded, though they may have contained relevant information on AI-related dermatologic AEs. Second, FAERS data are based on voluntary submissions, primarily from healthcare providers, which lack direct causality. This limitation is particularly relevant when interpreting discrepancies between our findings (e.g., the relatively low ROR for letrozole) and prior literature, as FAERS cannot establish a direct causal relationship between AIs and dermatologic AEs. Third, this study reflects only FAERS reports, suggesting an elevated risk of AEs with AIs but not a causal relationship with dermatologic effects. Finally, FAERS is a spontaneous global reporting system that introduces selection bias. Most reports in this study originated from the United States, limiting geographical diversity in the data.

Given the high incidence of AI-induced dermatologic toxicity in postmenopausal women with BC treatment, tailored management strategies should be prioritized the specific dermatologic impact of each AI. Our analysis is the first to highlight the global prevalence of dermatologic adverse reactions associated with AIs, emphasizing that these AEs are a critical factor in AI utilization. Addressing drug-induced skin disorders is essential to ensure the broader application of AIs. This chapter calls for further research into AI-related dermatologic damage in BC management to optimize patient care comprehensively. For high-risk patients, especially those with pre-existing dermatologic conditions, close monitoring is recommended to detect skin-related AEs early and allow for timely intervention. Regular assessments for dryness, alopecia, and rashes, combined with patient education on managing these issues, will help maintain quality of life during treatment.