Exemestane-Induced Eosinophilic Colitis in a Patient with Grade 3 Ductal Carcinoma In-Situ: A Case Report and Review of the Literature

Abstract

Purpose: A case report of eosinophilic colitis associated with exemestane use is presented. Summary: Approximately after three months of exemestane therapy for breast cancer risk reduction, a 60-year-old female with estrogen receptor positive, right breast ductal carcinoma in situ (DCIS) presented to the emergency room with severe abdominal pain, nausea, vomiting, and diarrhea. Imaging studies revealed severe colitis of the transverse colon. No other medications were started except for exemestane that would have contributed to the patient’s symptoms. Outpatient workup included stool cultures, laboratory studies, and esophagogastroduodenoscopy and colonoscopy with biopsies. Results of the studies were significant for eosinophilic colitis and moderate to borderline severe colitis with increased eosinophilia. The patient was subsequently started on corticosteroids and discontinued exemestane. Her symptoms resolved in two weeks. Approximately two months later, the patient was started on tamoxifen for breast cancer prevention, which she tolerated well. Conclusion: Exemestane was deemed the probable cause of the acute episode of eosinophilic colitis in this case. One other prior case with aromatase inhibitor-induced eosinophilic colitis has been reported with letrozole, however this is the first case report of eosinophilic colitis associated with exemestane. Background Exemestane is an irreversible, steroidal aromatase in-activator that structurally resembles androstenedione [1]. The pharmacological activity of exemestane is centered on the conversion of the drug to an intermediate that irreversibly blocks the active site of aromatase thereby rendering the enzyme permanently inactivated [1]. The inactivation of aromatase results in lower levels of circulating hormones that can increase the growth and size of hormone receptor positive breast cancers [1]. Exemestane first received FDA approval in the United States in 1999 for the treatment of advanced breast cancer in post-menopausal women whose tumors have stopped responding to tamoxifen [2]. Currently, it is approved for: the adjuvant treatment of postmenopausal women with estrogen receptor positive early stage breast cancer who have received two to three years of tamoxifen (an estrogen receptor antagonist) and are switched to exemestane for completion of a total of five years of adjuvant hormonal therapy [1,3,4]. It is also approved for advanced breast cancer in women whose disease has progressed following tamoxifen [1]. The American Society of Clinical Oncology (ASCO) clinical practice guidelines also recommends the use of ISSN: 2378-3419 DOI: 10.23937/2378-3419/1410104 Sanders et al. Int J Cancer Clin Res 2019, 6:104 • Page 2 of 5 • ductal carcinoma in situ with mastectomy were included [13]. Exemestane was found to reduce invasive breast cancer in postmenopausal women who were found to be at moderately increased risk for breast cancer [13] (Table 1). Exemestane is overall well tolerated with side effects that are common to other aromatase inhibitors such as hot flashes, bone loss, cholesterol metabolism, and musculoskeletal effects [14]. Exemestane did appear to have a larger effect on bone loss and cholesterol metabolism when compared with other aromatase inhibitors [15]. The most common gastrointestinal side effect observed in clinical trials was nausea; other gastrointestinal side effects reported were diarrhea, heartburn, vomiting, constipation, abdominal pain, and gastritis [1,2,5-13]. While eosinophilic colitis has been observed with letrozole [16], there have not been any reports with exemestane. Eosinophilic colitis (EC) is a type of eosinophilic gastrointestinal disorder (EGID) characterized by eosinophilic infiltration of the intestinal wall involving the small intestine and less commonly the colon [17]. It is considered to be one of the rarer forms of EGIDs with a twoyear prevalence rate of approximately 0.003% [17]. Patients often present with non-specific symptoms such as abdominal pain, nausea, loss of appetite, and diarrhea [17]. Additionally, the diagnosis of EC typically depends on the increased number of eosinophils seen on mucosal biopsy [17]. While there are a variety of causes such as parasitic and bacterial infections, inflammatory bowel disease, hypereosinophilic syndrome, connective tissue disorders, and myeloproliferative neoplasms, it can also be caused by hypersensitivity to various pharmacological agents [17]. Common agents associated with EC include carbamazepine, gold compounds, clozapine, rifampicin, clofazamine, gemfibrozil, azathioprine, enalapril, naproxen, interferon, and tacrolimus [17-26]. There are currently no randomized controlled trials evaluating the various treatment modalities for EC. Treatment is typically dependent upon the severity of clinical manifestations and includes dietary elimination, steroids, montelukast, cromolyn, ketotifen, exemestane in the setting of breast cancer prevention [5,6]. In the adjuvant setting, exemestane has been studied in both preand post-menopausal women [2,5,79]. It has not been shown to be superior to other aromatase inhibitors such as anastrozole or letrozole in the post-menopausal setting [2,5,7,8]. Additionally, five years of aromatase inhibitor treatment was not found to be superior to two years of treatment with tamoxifen followed by three years of aromatase inhibitor therapy [7]. In the pre-menopausal setting, exemestane in combination with ovarian suppression was superior to tamoxifen with ovarian suppression in decreasing disease recurrence [9]. There was no difference in overall survival between the two therapies [9]. In patients with metastatic disease, exemestane has been compared to multiple other aromatase inhibitors [10-12]. When compared with anastrozole in patients with visceral metastases, there was no difference in outcomes [10]. A systematic review evaluating ten different trials that assessed the switch between non-steroidal aromatase inhibitors (letrozole and anastrozole) and exemestane was conducted [11]. Out of ten, one was a randomized control trial, and the other nine were either non-randomized comparative studies or single arm observational studies [11]. Clinical benefit was seen in patients with relapsed disease who switched from non-steroidal aromatase inhibitors to exemestane and from exemestane to a non-steroidal aromatase inhibitor [11]. Additionally, exemestane has been studied in combination with everolimus in patients previously treated with non-steroidal aromatase inhibitors and demonstrated improvement in progression free survival [12]. Exemestane is also used for reducing the risk of invasive breast cancer in post-menopausal women ≥ 35 years of age with a five-year absolute risk ≥ 1.66% [6]. There is one randomized placebo-controlled trial that has evaluated the use of exemestane for the prevention of invasive breast cancer [13]. Patients with various breast cancer risk factors including prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ and Table 1: Summarizes all the large trials evaluating the use of exemestane in the adjuvant, metastatic, and preventative settings.