Neoadjuvant endocrine therapy with exemestane followed by response‐guided combination therapy with low‐dose cyclophosphamide in postmenopausal patients with estrogen receptor‐positive breast cancer: A multicenter, open‐label, phase II study

Abstract

Patients with estrogen receptor (ER)‐positive breast cancer are less likely to achieve a pathological complete response (pCR) with neoadjuvant chemotherapy. Neoadjuvant endocrine therapy may be more appropriate than neoadjuvant chemotherapy in these hormone‐sensitive patients. Most patients with ER‐positive breast cancer are postmenopausal, and therefore, generally older and less able to tolerate chemotherapy. We aimed to investigate the efficacy and safety of tailored neoadjuvant endocrine and chemoendocrine therapy for postmenopausal breast cancer patients. Untreated patients with primary invasive ER‐positive, HER2‐negative, stage I‐IIIA breast cancer, and Ki67 index ≤30% were enrolled. Patients received exemestane 25 mg/d for 12 weeks. Based on clinical response and change in Ki67 index, assessed at 8‐12 weeks, patients with complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% before and after treatment were defined as responders. For the subsequent 24 weeks, responders continued exemestane monotherapy (group A), and nonresponders received exemestane 25 mg/d plus cyclophosphamide 50 mg/d (group B). The primary endpoint was clinical response at weeks 24 and 36. A total of 59 patients (median age, 69 years) started initial exemestane monotherapy. After exclusion of three patients who discontinued during this period, 56 remained enrolled to receive subsequent treatment. Clinical response rates (CR and PR) and 95% CI at weeks 24 and 36 were 85% (12/14; 57.2%‐98.2%) and 71% (10/14; 41.9%‐91.6%), respectively, in group A; and 54% (23/42; 38.7%‐70.2%) and 71% (30/42; 55.4%‐84.3%), respectively, in group B. At week 36, no significant difference was found in median Ki67 index between the groups (3.5% and 4.0%). There were no treatment‐related deaths. We found that clinical response comparable to that of responders was achieved in nonresponders after addition of cyclophosphamide to the initial endocrine therapy.

Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 12 weeks' exemestane exposure in patients with estrogen receptor‐positive breast cancer: A multicenter, open‐label, phase II study

“…The study design, which closely followed the one used in our previously reported study, is shown in Figure . Both are multicenter, open‐label, phase II studies.…”

“…The eligibility criteria were postmenopausal status; diagnosis of primary invasive ER‐positive, human epidermal growth factor receptor 2 (HER2)–negative, stage I‐IIIA (T1c–T3, N0‐2, M0) breast cancer (confirmed by needle biopsy or histological findings); Ki67 labeling index ≤30%; Eastern Cooperative Oncology Group performance status 0 or 1; indication for partial or total mastectomy; and no previous treatment for cancer. ER‐positive status was confirmed by immunohistochemistry, and HER2‐negative status by either immunohistochemistry or fluorescence in situ hybridization, as described previously . Patients with or without axillary lymph node metastasis were eligible for inclusion.…”

“…We used a similar study design to investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane alone followed by tailored treatment: continued exemestane monotherapy for responders or exemestane plus docetaxel–cyclophosphamide (administered intravenously, ie TC) combination therapy for nonresponders. The hypothesis was that in nonresponders to the initial exemestane monotherapy, the TC regimen might have different therapeutic effects than the low‐dose cyclophosphamide, administered orally, used in our previous study, with acceptable tolerability. We selected the TC regimen as chemotherapy because docetaxel and cyclophosphamide have been shown to be equally effective for hormone receptor–positive disease as well as receptor–negative disease .…”

“…We have investigated the use of the Ki67 labeling index, which represents the percentage of Ki67‐positive carcinoma cells, for monitoring response to neoadjuvant endocrine therapy and guiding subsequent treatment. Specifically, we have focused on changes in Ki67 labeling index in response to exposure to exemestane, and the interpretation of such changes to tailor neoadjuvant therapy to maximize its therapeutic effects …”

“…We recently reported the results of a multicenter, open‐label, phase II study in which Ki67 labeling index before and after an initial period of endocrine therapy, namely, treatment with exemestane alone (25 mg/d, administered orally), was used to help classify postmenopausal patients with ER‐positive breast cancer as responders or nonresponders . Responders (ie patients with adequate biologic response, ie change in Ki67 index, as well as clinical response) continued to receive exemestane monotherapy, whereas nonresponders (again based on biologic as well as clinical response) were switched to chemoendocrine therapy, namely, exemestane plus low‐dose cyclophosphamide (50 mg/d, administered orally).…”