FormalPara Key Summary Points

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 (anastrozole and letrozole) and steroidal (exemestane).

In contrast to other drug-induced skin reactions, the onset of aromatase inhibitor-associated cutaneous reactions was delayed for at least a month in 69.2% (9 of 13 women) after initiating therapy with the medication, and the median onset was 2 months after starting treatment with the aromatase inhibitor.

The morphology of aromatase inhibitor-associated cutaneous reactions predominantly includes vasculitis, erythema nodosum, and subacute cutaneous lupus erythematosus.

Management of aromatase inhibitor-associated cutaneous reactions requires discontinuing the specific aromatase inhibitor.

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.

Introduction

Anastrozole is an aromatase inhibitor [1]. Anastrozole competitively inhibits the aromatase enzyme, which synthesizes estrogen [1, 2]. It is used for estrogen receptor-positive breast cancers [1, 2]. Skin-related adverse events associated with anastrozole inhibitor use are uncommon [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. The purpose of this paper is to summarize the cutaneous adverse events associated with aromatase inhibitors. To this end, a woman with breast cancer who developed anastrozole-induced dermatitis is described and cutaneous side effects associated with aromatase inhibitors are reviewed. A review of the relevant literature indicated that there can be a delay in the onset of aromatase inhibitor-induced skin-related adverse events; indeed, the median time to the appearance of dermatologic side effects is 2 months. The most common adverse reactions are vasculitis, erythema nodosum, and subacute cutaneous lupus erythematosus. Treatment of the drug-associated dermatosis requires the discontinuation of the aromatase inhibitor; therapy with topical corticosteroids or oral corticosteroids or both has also been initiated for some patients. Switching to an alternate aromatase inhibitor may also be considered following the resolution of the drug-related dermatosis.

Case Report

A 67-year-old Filipino woman noted a lump in her left breast; she underwent a screening mammogram in August 2018 which revealed a small mass. In November 2018, a repeat mammogram was performed; the mass had increased to 2 cm. A biopsy established a diagnosis of moderately differentiated, high-grade ductal carcinoma in situ that was estrogen and progesterone receptor positive and HER2/neu negative.

She underwent a left breast mastectomy and lymph node dissection on January 8, 2019; a lymph node was positive for her cancer, placing her breast carcinoma at stage IIa. She completed one cycle of docetaxel and cyclophosphamide on February 12, 2019. She was unable to tolerate the chemotherapy and received no further treatment with these drugs.

She was started on anastrozole on March 20, 2019. On May 15, 2019, an itchy rash on her back, neck, and arms was noted.

Cutaneous examination on June 5, 2019 showed a pruritic eruption along with erythematous patches, papules, and plaques on her upper (Fig. 1) and lower (Fig. 2) back in addition to her posterior neck and arms.

Fig. 1
figure 1

Anastrozole-induced dermatitis presenting as erythematous patches, papules, and plaques on the upper back of a 68-year-old Filipino woman

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Fig. 2
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The lower back of the 68-year-old Filipino woman also developed pruritic red patches, papules, and plaques 2 months after she started anastrozole

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Microscopic examination of the 3-mm punch biopsy of her lower back lesion showed a superficial and deep lichenoid and perivascular infiltrate of lymphocytes and numerous eosinophils. These pathologic changes were consistent with a hypersensitivity reaction to a medication. Correlation of the patient’s clinical history with the pathologic findings established a diagnosis of a drug reaction to anastrozole.

The anastrozole was discontinued on June 5, 2019 after conferring with her oncologist. She was prescribed oral prednisone (60 mg daily for 7 days, followed by 40 mg daily for 5 days and then 20 mg daily for 3 days) and topical betamethasone cream 0.05% twice daily. At her follow-up visit 6 days later, her pruritus had markedly diminished and the dermatitis had improved by 90%. The subsequent follow-up showed complete clearance of the anastrozole-induced dermatitis.

Her oncologist started her on exemestane, an irreversible steroidal aromatase inactivator, at a daily dosage of 25 mg on July 6, 2019. She had not experienced a recurrence of her dermatitis after 5 months of follow-up. Informed consent was obtained from the participant before they were included in the study. The patient signed a consent providing permission to include clinical photographs in this article.

Discussion

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
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Table 2 Cutaneous vasculitis associated with aromatase inhibitor use
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Table 3 Adverse cutaneous reactions with aromatase inhibitor treatment
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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.

Conclusions

Aromatase inhibitors are an integral component in the management of breast cancer. Although adverse skin events associated wih aromatase inhibitor use are uncommon, they may occur. In contrast to other drug-induced skin reactions, the onset of aromatase inhibitor-associated cutaneous reactions was delayed for at least a month in 69.2% of women (9 of 13) after initiating therapy with the medication; indeed, the median onset was 2 months after starting treatment with the aromatase inhibitor. In our patient, the onset of her aromatase inhibitor-induced hypersensitivity papular eruption occurred 2 months after starting anastrozole. Management requires discontinuing the specific aromatase inhibitor; however, our patient was able to be treated with an alternative aromatase inhibitor from a different drug class without a recurrence of her adverse skin reaction.