Aromatase inhibitors are used as adjuvant therapy in the management of estrogen receptor-positive breast cancer. There are two main classes of aromatase inhibitors: nonsteroidal and steroidal. Nonsteroidal aromatase inhibitors include anastrozole and letrozole, which reversibly inhibit the enzyme. Steroidal aromatase inhibitors include testolactone and formestane; these are first- and second-generation aromatase inhibitors, neither of which are currently used. The only third-generation steroidal aromatase inhibitor is exemestane, which irreversibly inactivates aromatase [1, 2].
A review of the relevant literature indicated that erythema nodosum occurred as an adverse skin reaction to aromatase in three patients (Table 1) [3]. Five women receiving either anastrozole, letrozole, or exemestane also developed vasculitis (Table 2) [4,5,6,7,8]. In addition, various other dermatoses have been observed in patients undergoing treatment with aromatase inhibitors (Table 3) [9,10,11,12,13,14,15,16,17,18].
Table 1 Erythema nodosum associated with aromatase inhibitor use Table 2 Cutaneous vasculitis associated with aromatase inhibitor use Table 3 Adverse cutaneous reactions with aromatase inhibitor treatment Three women developed erythema nodosum after receiving letrozole (Table 1) [3]. The women ranged in age from 47 to 51 years (median 50 years), and presented with either stage II or stage III breast cancer. Each woman received a mastectomy and exhibited their symptoms 2–3 months (median 3 months) after starting letrozole [3].
Erythema nodosum improved after the discontinuation of letrozole. In the case of the 51-year-old patient (case 3 in Table 1), her skin reaction improved 6 weeks after discontinuation of letrozole and the administration of systemic corticosteroids [3].
For the 50-year-old patient (case 2 in Table 1), anastrozole was started as an alternate agent after discontinuation of letrozole. However, 1 year following the discontinuation of letrozole, the erythema nodosum continued to persist. The 51-year-old patient (case 3 in Table 1) was started on anastrozole 1 year after discontinuing letrozole, which led to an exacerbation of the patient’s erythema nodosum; the anastrozole was therefore discontinued [3].
Vasculitis occurred in five women who were treated with aromatase inhibitors (Table 2) [4,5,6,7,8]. Their ages ranged from 63 to 80 years (median 72 years). The onset of vasculitis was specified in 3 women; it ranged from 5 to 10 days (median 7 days). One patient (case 2 in Table 2) who had developed vasculitis after taking letrozole was switched to exemestane and noted gradual improvement of her vasculitis [5]. The offending aromatase inhibitor was stopped and no relapses were observed in the remaining women [6, 7].
The morphology of the other aromatase inhibitor-induced dermatoses—summarized in Table 3 [9,10,11,12,13,14,15,16,17,18]—included subacute cutaneous lupus erythematosus (2 women) [9, 16], hypersensitivity papular eruption (1 woman—our patient), purpuric papules and plaques (1 woman) [15], erythema multiforme (1 woman) [11], systemic sclerosis (1 woman) [10], and cutaneous nodulosis (1 woman) [14, 19]. The remaining patients’ clinical presentation was designated either a grade 2 (1 woman) [13] or a grade 3 (1 woman) [18] skin reaction. The appearance of the cutaneous adverse event was not described for two of the women [17].
Two of the women experienced aromatase inhibitor-induced dermatoses at the site of previous breast cancer excision or radiotherapy [11, 15]. A 72-year-old woman who had undergone a left breast mastectomy developed an irregular purpuric plaque with papules at the site of the postoperative scar 6 months after the administration of anastrozole [15]. A 64-year-old woman whose advanced breast cancer had previously been treated with radiotherapy demonstrated a bullous eruption localized to the affected breast after starting an aromatase inhibitor [11]. We postulate that the aromatase inhibitor-induced skin adverse events in these women occurred in an immunocompromised district—a localized area of immune destabilization (resulting from either the excision or radiotherapy) that enabled the development of the dermatosis in that location [20].
Three of the women (case 3 in Table 1 and cases 5 and 9 in Table 3) experienced a recurrence or exacerbation of their initial skin reaction when they were again treated with either the same medication or a different aromatase inhibitor of the same drug class [3, 12, 16]. Another patient (case 2 in Table 1) showed improvement in drug-induced erythema nodosum (although it persisted) when letrozole was switched to anastrozole. Although her skin nodules initially decreased, some were still present after 1 1/3 years on anastrozole [3]. Surprisingly, a woman who had developed purpuric papules and plaques after being placed on anastrozole did not develop skin lesions after receiving the same drug. Following initial therapy with hydroxyquinoline and topical corticosteroids, she was again treated with anastrozole (1 month after cessation) and did not develop a recurrence of her cutaneous reaction during the subsequent 18 months [15].
Our patient was treated with an alternative aromatase inhibitor of a different drug class, exemestane, after discontinuing anastrozole and did not experience a recurrence of her dermatosis. An aromatase inhibitor from a different drug class may be considered for patients who develop an adverse skin reaction from their initial aromatase inhibitor therapy.
In summary, the patient described in this paper is important not only due to the onset of cutaneous side effects of aromatase inhibitors but also because of her relevance to the potential management of individuals who experience this adverse skin event. Specifically, she exemplifies a case of delayed onset of an aromatase inhibitor-related adverse cutaneous event: her dermatosis initially appeared 2 months after starting the medication. In addition, the patient was able to be treated with a aromatase inhibitor of a different drug class without recurrence of her dermatosis or a different dermatologic adverse event. Hence, when aromatase inhibitor therapy is essential for the management of the patient’s cancer but there has been a cutaneous side effect of this therapy, it may be possible to initiate treatment using a different drug class of aromatase inhibitor therapy.
Including our patient, cutaneous adverse events associated with aromatase inhibitor use have been described in 20 women. Their ages ranged from 42 to 80 years old; the median age was 68 years. Patients were receiving either anastrozole (6 women), exemestane (4 women), or letrozole (9 women); the specific aromatase inhibitor was not described for one of the patients. The onset of skin reactions following the initiation of aromatase inhibitor therapy was specified in 13 women; the onset of the skin reaction ranged from 5 days to 6 months (median 2 months) after the start of treatment.