Eligible patients were identified from the breast cancer database of Seoul National University Hospital, Seoul, Republic of Korea. All patients were postmenopausal women with metastatic or recurred disease that was ER-positive or progesterone receptor (PR)-positive, and had progressed after NSAI treatment or diseases had recurred during or after adjuvant NSAI treatment. Menopause was defined as follows: prior bilateral oophorectomy, age >60 years and age less than 60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range [2]. A total of 118 patients were identified using these criteria; however, six patients were excluded because they were lost to follow-up before the first-response evaluation. This protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H-1110-021-380) and was exempted from the requirement to obtain informed consent.

The medical records of enrolled patients were reviewed to collect demographic, clinical, and pathology data. Treatment history, dominant site of metastasis, and clinical outcomes were extracted from the medical records. We summarized the ER, PR, human epidermal growth factor receptor 2 (HER2), and Ki-67 status as determined by immunohistochemical (IHC) staining, and HER2 gene amplification status as determined by fluorescent in situ hybridization (FISH). Tumors with an IHC score of 3+ or showing unequivocal amplification by FISH (HER2/CEP17 ratio >2.0) were considered HER2-positive [7]. Tumors with negative FISH results, or with IHC scores of 0- 2+ in the absence of FISH results, were considered HER2-negative. Ki-67 was considered high if IHC showed that ≥14% cells were positive [8]. Radiological responses were evaluated according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Tumors were defined as NSAI-sensitive if the patient had a complete response, partial response, or stable disease for at least 6 months during previous NSAI treatment, or disease recurred 2 years after initiating adjuvant NSAI treatment. All other tumors including those that recurred within 2 years of adjuvant NSAI treatment were categorized as NSAI-resistant. Progression-free survival (PFS) was measured from the first day of exemestane treatment until radiological or clinical disease progression. Overall survival (OS) was calculated from the first day of exemestane treatment to patient death or the last date of follow-up. Objective response rate (ORR) was defined as the proportion of patients with the best response of either a complete or partial response. The clinical benefit rate (CBR) was defined as the proportion of patients achieving a best overall response of complete response, partial response, or stable disease for at least 6 months.

All patients received 25 mg exemestane daily until objective disease progression or other event that required treatment termination. Patients were seen regularly during the treatment period by their medical oncologists and underwent physical examinations and laboratory testing, including complete blood cell counts and a chemistry panel. Treatment response was evaluated using the appropriate imaging modalities every 2 months for the first 6 months and every 3 months thereafter or whenever there was clinical suspicion of disease progression.

Categorical variables were compared with the Pearson's chi-square test or Fisher's exact test, as appropriate. Median OS and PFS were calculated using the Kaplan-Meier method. Groups were compared by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. Two-sided p-values <0.05 were considered significant. All analyses were performed using the PASW version 18.0 software package (SPSS Inc., Chicago, USA).

A total of 112 postmenopausal women with metastatic, hormone receptor-positive breast cancer were included in this analysis. Clinicopathological characteristics and previous treatment history are summarized in Table 1. The mean age at diagnosis of metastatic or recurred disease was 53.6±9.9 years (median, 54.5 years). Of the 112 patients, 78 (69.6%) were ER and PR positive, 28 (25.0%) were ER-positive/PR-negative, and six (5.4%) were ER-negative/PR-positive. HER2 status was known for 107 patients, and 12 patients (10.7%) were HER2-positive. Ki-67 was determined in 67 patients; 14 (12.5%) were high, and 53 (47.3%) were low. Fifty-two patients (46.4%) had bone-dominant disease at the initiation of exemestane treatment, and 25 patients (22.3%) were lymph node- or soft tissue-dominant. Of the 35 patients (31.3%) who had viscera-dominant disease, 17 (48.6%) were symptomatic because of extensive visceral metastases, and 18 (51.4%) had small visceral metastases without symptoms.

All patients had a history of hormone therapy including treatment with selective estrogen receptor modulators and NSAIs. Among the 94 patients with recurred disease, 66 (70.2%) underwent adjuvant hormone therapy after surgery. For metastatic disease, 18 patients (16.1%) used exemestane as first-line treatment after failure of adjuvant NSAI. Fifty-nine patients (52.7%) used exemestane as a second-line hormonal agent for metastatic disease, 31 (27.7%) as third-line treatment, and four (3.6%) as fourth-line treatment. The median number of palliative chemotherapy regimens prior to exemestane treatment was two, and 32% of the patients (36/112) had received three or more prior chemotherapy treatments. About 35% of the patients (41/112) underwent palliative radiotherapy before exemestane treatment.

The median follow-up for the 112 patients treated with exemestane was 53.5 months, and the median duration of treatment was 5.6 months. Seventeen patients (15.2%) were still receiving exemestane at the data cutoff point. The most common reason for discontinuing exemestane was disease progression (96.8%), followed by patient refusal (2.1%), and drug toxicity (arthralgia grade 3, 1.1%).

The median PFS and OS were 5.7 months (95% CI, 4.4-7.0 months) (Figure 1) and 21.9 months (95% CI, 13.6-30.3 months), respectively. Among the 110 patients with evaluable lesions, seven (6.4%) showed an objective response to exemestane, and the CBR was 46.4% (Table 2). The median PFS did not differ among patients, whether they received exemestane as first-line (5.7 months), second-line (4.8 months), or third- or later-line palliative hormone therapy (6.2 months, p=0.745). Similarly, the median PFS did not differ significantly between the NSAI-sensitive (5.5 months) and NSAI-resistant groups (11.2 months, p=0.164). Results of a subgroup analysis revealed that the CBR for patients with symptomatic visceral disease (17.6%) was significantly lower than that of patients with bone-dominant disease (62.7%), lymph node- or soft tissue-dominant disease (29.2%), or asymptomatic visceral disease (50.0%, p=0.003) (Table 3). A multivariate analysis was performed to determine whether age, hormone receptor status, HER2 status, Ki-67, dominant metastatic site, or NSAI sensitivity predicted PFS. The results showed that only symptomatic visceral metastasis was associated with a shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001). NSAI sensitivity was not significantly associated with PFS (Table 4).

Assessment of toxicity was limited due to the retrospective nature of this study. Most adverse events were mild, except for grade 3 arthralgia and nausea toxicity in two cases. The three most frequently observed adverse events were arthralgia (3.6%), fatigue (3.6%), and myalgia (2.7%). Information about bone health was available in 34 patients (30.4%); three (8.8%) patients experienced new-onset or worsening osteoporosis while using exemestane, which were defined by National Cancer Institute-Common Toxicity Criteria (version 4.0).