Background: Invasive lobular carcinoma (ILC) is biologically distinct from invasive ductal carcinoma (IDC). Pre-clinical studies in human cell lines demonstrate that ILC has a unique epigenetic state and estrogen receptor (ER) transcriptional axis, resulting in relative resistance to tamoxifen (T). Retrospective analyses of phase III clinical trials of adjuvant endocrine therapy (ET) (BIG 1-98, SOFT and TEXT) also support this hypothesis, with a greater difference between tamoxifen (T) and an aromatase inhibitor in ILC compared to IDC; PELOPS was designed to prospectively test this hypothesis. Methods: PELOPS was a multi-center randomized phase II trial with both a window and treatment phase. Postmenopausal patients (pts) with early-stage ER+ breast cancer were randomized to a 2- week window of neoadjuvant letrozole (L) or T. Subsequently, pre and postmenopausal pts were randomized 2:1 to 6-cycles of neoadjuvant palbociclib (P) plus ET or ET alone. Histological subtype was among the stratification factors. Primary endpoints included 1) change in Ki67 after two weeks of T or L in the window phase within cohorts of pts with different histological subtypes, and 2) residual cancer burden (RCB) scores between arms in the treatment phase. Wilcoxon-rank sum test with two-sided alpha of 0.05 was used for both endpoints. Event-free survival (EFS) was defined as time from registration to the first event of disease progression precluding surgery, locoregional ipsilateral invasive recurrence, contralateral invasive breast cancer, distant recurrence or death from any cause. Biopsies were collected at baseline, after 2 weeks of ET and at surgery, and were subjected to RNAseq. Gene set variation analysis (GSVA) pathway analysis was performed. Results: A total of 116 pts were evaluable for the window phase of the study (T=58, L=58). The Ki67 log-scale fold change (FC) was significantly lower with L compared to T among pts with both IDC (T: N=27, median FC=-0.121, L: N=28, median FC =-1.26, p=0.0045) and ILC (T: N=25, median FC=-0.452, L: N=25, median FC=-1.8, p=0.0161). In the treatment phase, 188 pts were evaluable (P+ET=128 and ET=60). The RCB scores in the two arms were comparable (median RCB 3.13 and 3.09, p-value = 0.9288). Median follow up was 4.65 years (IQR: 3.66 – 5.56 years), five-year EFS rate was 79.4% (95% CI: 71.2% - 88.5%) for P+ET and 80.9% (95% CI: 70.8% - 92.4%) for ET (hazard ratio 0.97 [95% CI, 0.47-2.00], p=0.926). RNAseq was completed on biopsies from a subgroup of pts highly representative of the entire population (279 biopsies from 97 pts). Most pts had luminal B breast cancers. Hierarchical clustering of baseline samples showed a distinct ILC transcriptome compared to IDC (Fisher’s exact test, p<0.001). Pathway analysis revealed a significant reduction in expression of the cell cycle pathways after two weeks of T in IDC pts (paired T-test, p<0.05). In contrast, T did not suppress the cell cycle in ILC pts (lowest p=0.2). Interaction tests of GSVA changes after T treatment between ILC and IDC met significance or near significance (E2F targets p=0.051; Mitotic Spindle p=0.002; G2M checkpoint p=0.05, unequal variances t-tests). L treatment significantly decreased cell cycle pathways in both ILC and IDC, but other gene expression changes were disparate, underscoring the unique ER axis in ILC. Conclusions: In the neoadjuvant setting, two-week treatment with letrozole achieved a superior reduction in Ki67 compared to tamoxifen in IDC and ILC, however, the addition of palbociclib to ET for 6 cycles did not improve RCB scores. Comprehensive molecular studies of biopsies from PELOPS provides the first prospective evidence of differential responses to T in ILC versus IDC. These results highlight the importance of molecular analyses in neoadjuvant ET trials and warrant trials for the optimization of ET specifically in ILC. Additional gene expression analyses, including data from ET+/- palbociclib will be presented. Citation Format: Rinath Jeselsohn, Douglas Russo, Qingchun Jin, Patrick Kurnia, Jorge Gomez Tejeda, Kavya Prasad, Shira Sherman, Michelle K Demeo, Ying Huang, Jane Brock, Deborah A. Dillon, Tari A. King, Denise Yardley, Ingrid A Mayer, William F Symmans, Chip Stewart, Eric Winer, Nabihah Tayob, Gaddy Getz, Sara M Tolaney, Otto Metzger. Primary results and the transcriptomic analysis of PELOPS, a randomized phase II study of neoadjuvant palbociclib with or without endocrine therapy for breast cancer patients with invasive lobular carcinoma or invasive ductal carcinoma [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 PS18-06.
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