Abstract PS18-09: Endocrine Response in Women with Invasive Lobular Carcinoma (TBCRC 037): A Multicenter Randomized Clinical Trial

Abstract Background: Adjuvant endocrine therapy (ET) recommendations for patients (pts) with invasive lobular carcinoma (ILC) are no different than for other breast cancer subtypes. However, due to unique differences in estrogen pathway signaling of ILC, identifying biological markers of ET sensitivity or resistance could have a major impact on its clinical management. Pre-clinical studies suggest that fulvestrant may be more effective than anastrozole or tamoxifen for ILC. Here we test reduction in the proliferation marker Ki67 as a surrogate for treatment response to ET. Methods: This open label, randomized, controlled, multicenter phase 0 window of opportunity trial (NCT02206984) was conducted at 12 TBCRC institutions between 10/8/15 and 7/28/23. Postmenopausal women with previously untreated hormone receptor-positive (HR+), HER2 negative ILC, centrally histologically confirmed on diagnostic core needle biopsy (CNB), measuring ≥ 1 cm, were eligible. Stage IV was excluded. Pts were randomized 1:1:1 to fulvestrant (500 mg IM on days 1 and 15), anastrozole (1mg/day) or tamoxifen (20 mg/day). After 21-27 days of treatment, pts underwent operation (from which a CNB of residual tumor bed was taken) or a post-treatment image-guided CNB. The primary endpoint was change in Ki67 immunohistochemistry at post-treatment compared to baseline. Given the log-normal distribution of Ki67 measurements generally observed in this population, values were log-transformed for statistical analysis [log (post/pre)]. Group medians were compared using a quantile regression linear model adjusting for institutional-level random effects. A linear mixed model (glmmTMB R package) was fit that allowed for treatment level error variance. Post-hoc pairwise comparison of log(post/pre) were performed using Tukey adjustment for multiple comparison. Results: 201 women were randomized, 172 completed the assigned treatment, and 138 (fulvestrant n=37; anastrozole n=49; tamoxifen n=52) had evaluable pre- and post-treatment tissue. No serious adverse events or deaths occurred. Pre-treatment demographic and tumor characteristics were well-balanced between the treatment groups. Median [range] age was 67 [48-86] years. Race was reported as Asian in 2 (1.5%), Black in 15 (10.9%), other in 4 (2.9%) and White in 117 (84.8%). Presenting clinical stage was IA in 54 (39.1%), IB in 4 (2.9%), IIA in 51 (37%), IIB in 19 (13.7%), IIIA in 4 (2.9%), IIIB in 5 (3.6%), and IIIC in 1 (0.7%). Median H-score [IQR] was ER 260 [50], PR 140 [215]. In the fulvestrant, anastrozole and tamoxifen groups respectively, pre-treatment Ki67 [IQR] was 13.8 [13.5], 13.6 [8.7], and 12.6 [11.9]; and post-treatment Ki67 [IQR] was 4.8 [5.4], 4.5 [5.6], and 5.7 [10]. A statistically significant reduction in Ki67 was found favoring fulvestrant vs tamoxifen (p=0.0419). No significant difference after adjustment was seen between anastrozole and tamoxifen (p = 0.2602) or between fulvestrant and anastrozole (p = 0.6643). Conclusions: A greater reduction in Ki67 was seen post-treatment in CNB of pts with ILC treated with fulvestrant vs tamoxifen. Interestingly, tamoxifen treatment resulted in a reduction in Ki67 of a similar magnitude to anastrozole, despite clinical concerns about its reduced efficacy in ILC. Planned correlative studies will determine whether Ki67 reduction is associated with alterations in expression of ER and ER-regulated genes and/or in other novel pathways, potentially opening avenues for improved treatment strategies in ILC. Citation Format: Priscilla McAuliffe, Clark BZ, Hieken TJ, Mukhtar RA, Linden H, Nangia J, Gallagher K, Stringer-Reasor E, Bedrosian I, Feldman S, Nanda R, Boisvert M, Rothman J, Sikora MJ, Atkinson JM, Thorpe H, Tatsuoka C, Lee AV, Thompson A, Davidson NE, Oesterreich S, Jankowitz RC; on behalf of the Translational Breast Cancer Research Consortium (TBCRC). Endocrine Response in Women with Invasive Lobular Carcinoma (TBCRC 037): A Multicenter Randomized Clinical Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS18-09.