Abstract PS05-09: A single-arm Phase II clinical study of fulvestrant combined with chemotherapy in the neoadjuvant treatment of HR+/HER2- locally advanced breast cancer

Background: HR+/HER2- breast cancer has been found to be less sensitive to neoadjuvant chemotherapy (NCT), leading to an objective response rate (ORR) of approximately 65%. Endocrine therapy combined with chemotherapy may help improve the ORR in these patients. The objective of this Phase II study was to evaluate the efficacy and safety of adding fulvestrant to NCT in patients with HR+/HER2- locally advanced breast cancer(LABC). Additionally, the study aimed to investigate the association of 18F-FES PET/CT and metabolites with efficacy. Methods: In this single-arm Phase II study, eligible patients were females with histologically confirmed HR+/HER2- LABC (Stage IIB-IIIC). Patients received fulvestrant (500 mg, on days 0, 14, 28, then every 28 days thereafter, every 4 weeks for six cycles) plus AC-T regimen, followed by surgery. Premenopausal women were administered a concomitant GnRH analogue. Patients underwent 18F-FES PET/CT before the initiation of fulvestrant, and plasma samples were collected for LC-MS analysis at baseline. The primary endpoint was ORR. Secondary endpoints included pathological complete response (tpCR) and safety. Results: From December 2020 to September 2022, 36 patients were enrolled. The median age was 53 years (range35-67). 78% were ECOG PS of 1, 69% were postmenopausal, 92% were nodal involved, and 83% were in stage III. After neoadjuvant therapy, the ORR was 86.1%. All patients completed the surgery, with a tpCR rate of 8.3% (3/36). 80.6% (29/36) patients were classified as Miller-Payne (MP) grade ≥3. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 22% (8/36) of the participants. The most common TEAEs were neutropenia (13.9%) and leukopenia (8.3%). The expression of ER, PR, and Ki-67 in postoperative pathology significantly decreased compared to baseline (p < 0.05). Additionally, the change in ER expression was significantly correlated with the regression volume of primary breast tumors (R = 0.56, p = 0.0044). The decrease in ER value in patients with MP ≥ 4 was significantly larger than in patients with MP ≤ 3 (p = 0.0054). Among the 36 patients, 24 completed the 18F-FES PET/CT scan before initiating fulvestrant.The average SUVmax in primary breast lesions was 4.17 (range 1.00-12.80). The SUVmax of breast lesions was significantly correlated with clinical efficacy (p = 0.0018) and with changes in ER expression before and after treatment (R = 0.68, p = 0.00023). Meanwhile, the SUVmax of patients with MP ≥ 4 grade was significantly higher than that of patients with MP ≤ 3 grade (p=0.018). A total of 25 plasma samples were available for metabolic analysis. Among these samples, 13 differential metabolites were identified between patients with MP ≥ 4 grade and MP ≤ 3 grade, which were markedly enriched in 19 metabolic pathways. Conclusions: The addition of fulvestrant to NCT showed manageable toxicity and promising antitumor activity for patients with HR+/HER2- LABC. 18F-FES PET/CT might serve as a tool to predict the effectiveness of neoadjuvant combination therapy. Altered metabolites or metabolic pathways might be associated with the response to this combined treatment approach. Keywords: breast cancer, HR+/HER2-, fulvestrant, neoadjuvant treatment, 18F-FES PET/CT Citation Format: Qing Shao, Jing Wu, Ningning Zhang, Xiaohua Zeng. A single-arm Phase II clinical study of fulvestrant combined with chemotherapy in the neoadjuvant treatment of HR+/HER2- locally advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-09.