Metzger, Otto

Abstract Background Central nervous system (CNS) metastases are a major clinical concern in patients with HER2-positive metastatic breast cancer (MBC). The PATINA phase III study showed improved PFS with palbociclib added to maintenance anti-HER2/endocrine therapy (44.3 vs. 29.1 months; hazard ratio 0.75; 95% CI 0.59-0.96; 1-sided P=0.0109). Preclinical and early clinical data suggest palbociclib may have CNS activity. We conducted a pre-specified secondary analysis to evaluate the incidence and timing of CNS progression. Methods CNS progression was defined as the emergence of new intracranial lesions per investigator assessment. Baseline CNS imaging was not mandated but recommended if symptomatic. Competing risks analyses evaluated time from registration to first CNS progression or death (CNS PFS), treating non-CNS progression as a competing event. All randomized patients were included in the primary analysis, regardless of known baseline CNS involvement. Patients with baseline CNS metastases were not censored if progression involved the CNS. A secondary analysis excluded patients with CNS metastases present at baseline. Cumulative incidence functions were estimated and compared using 2-sided Gray’s test. Results Data cutoff for this analysis was on October 15, 2024. 518 participants were enrolled between June 2017 and July 2021, 261 to the palbociclib arm and 257 to the control arm. CNS metastases at baseline were present in 11 patients in the palbociclib arm and 9 patients in the control arm. Among all randomized patients, CNS progression occurred in 35 of 261 (13.4%; 95% CI: 9.5-18.2) in the palbociclib arm and 50 of 257 (19.5%; 95% CI: 14.8-24.8) in the control arm. When excluding patients with CNS metastases at baseline, CNS progression was observed in 32 of 250 (12.8%; 95% CI: 8.9-17.6) in the palbociclib arm and 47 of 248 (19.0%; 95% CI: 14.3-24.4) in the control arm. The median follow-up for patients who were alive and progression-free was 53.5 months. At 36 months, the cumulative incidence of CNS PFS was 13.4% vs. 19.9% for palbociclib versus control (Gray’s test p=0.0386). Importantly, when the analysis was restricted to pts without evidence of CNS disease at baseline (Table 1), —the CNS benefit with palbociclib was maintained (13.0% vs. 19.2% at 36 months, Gray’s test p = 0.0378). Conclusion The addition of palbociclib to anti-HER2 and endocrine therapy was associated with a lower incidence of CNS metastases. Among patients without known baseline CNS involvement, the absolute reduction in CNS progression at 36 months was 6.2% in favor of palbociclib. This benefit was observed at 12 months and sustained over 3 years (Table 1). These findings suggest that palbociclib may help delay or prevent CNS involvement in HR+/HER2+ MBC, warranting confirmation in future studies. Citation Format: O. Metzger, S. Mandrekar, T. Dockter, L. Gianni, E. Ciruelos, A. De Michele, J. Gligorov, E. Lim, S. Loibl, X. Gonzàlez Farré, F. Lynce, J. Lanzillotti, L. Carey, S. Goel, A. Partridge, E. Winer. Central Nervous System Outcomes from the Phase III PATINA Trial (AFT-38) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF4-01.

Abstract Background PALLAS trial compared palbociclib plus endocrine therapy (ET) vs. ET alone in stage II-III HR+/HER2- breast cancer. SETER/PR index quantifies transcriptional activity related to estrogen and progesterone receptors and serves as a measure of endocrine sensitivity. In CALGB 9741, low SETER/PR (< 0.75) - reflecting endocrine resistance - predicted survival benefit from adjuvant anthracycline/taxane-based treatment. In PALLAS low SETER/PR was associated with worse prognosis and early recurrence. Early recurrences driven by endocrine-resistant tumors may obscure the benefit of palbociclib by disproportionately contributing events from a more resistant population. We hypothesized that palbociclib efficacy might vary by endocrine sensitivity and prior chemotherapy regimen, with greatest benefit in patients with intermediate SETER/PR index. Methods Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots and the treatment arms were compared with a log-rank test. Cox models estimated the hazard ratio (HR) with 95% confidence interval (95%CI) (significance level used was a two-sided 0.05). SETER/PR index was successfully obtained for 3,090 PALLAS patients (TransPALLAS ITT cohort, Metzger et al. ASCO 2024). SETER/PR index cut points (0.75 and 1.50) were proposed from previous studies comparing different adjuvant chemotherapy regimens. Results Table 1 summarizes the efficacy of adjuvant palbociclib by prior (neo)adjuvant chemotherapy regimen. Palbociclib was associated with longer iDFS in the group who received prior anthracycline-paclitaxel chemotherapy (AC-P), though the chemo regimen x palbociclib interaction term was not significant (Table 1). In the 1,132 patients from the TransPALLAS cohort who received AC-P chemotherapy, the 518 (46%) patients with intermediate SETER/PR (0.75≤ SETER/PR <1.50) had longer iDFS with palbociclib (HR 0.58; 95% CI: 0.40-0.84; p=0.004; 7-yr iDFS 80.2% vs. 68.4%), but this subset did not predict palbociclib benefit relative to all others, i.e., 206 (18%) patients with low SETER/PR (<0.75) and 408 (36%) high SETER/PR (≥1.50); P interaction=0.11. Exploratory analysis of SETER/PR index as a continuous variable in patients who received prior AC-P chemotherapy revealed a non-linear relationship with the hazard ratio favoring palbociclib observed in the subset with SETER/PR values between 1.1 and 1.8, compared to all others (P interaction=0.01). Conclusions In PALLAS, we observed a numerical benefit favoring palbociclib among pts treated with adjuvant AC-P; in this subset a moderate level of endocrine transcriptional activity (SETER/PR index between 1.1 and 1.8) predicted palbociclib benefit. These results are hypothesis-generating. Citation Format: O. Metzger, P. O'Brien, K. Ballman, M. Gnant, M. Watson, E. Chen, K. Tran, D. Hlauschek, M. Martin, J. Balko, Z. Nowecki, O. Hahn, C. Denkert, C. Curtis, F. Liu, A. Dueck, C. Fesl, E. Mayer, A. De Michele, W. Symmans. Exploratory analysis of palbociclib benefit in the PALLAS trial by SETERPR index and prior chemotherapy regimens (ABCSG-42/AFT-05/BIG-14-13) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-08-13.

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) subtype, accounting for up to 15% of cases. Although several biologic differences between ILC and invasive carcinoma of no special type (NST) have been described, most data are derived from primary tumors. In contrast, the biology of metastatic ILC remains poorly defined. This study aimed to investigate the unique genomic, transcriptomic, and immune landscapes of metastatic ILC using a multi-omic approach. Methods: This real-world study included patients with confirmed NST or pure ILC who had a biopsy of a metastatic lesion or a breast lesion in the setting of known metastatic disease. Tumors underwent whole exome sequencing (NGS 592, NextSeq; WES, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Demographic and baseline molecular features were compared across histologic subtypes. Tumor mutational burden (TMB; high ≥10 mut/MB) was assessed by NGS. Immune cell populations were estimated by RNAseq deconvolution (quanTIseq). Pathway enrichment analysis was determined by GSEA. Overall survival (OS) was defined from the date of biopsy to death from any cause using Kaplan-Meier estimates. Statistical tests included chi-square and Mann-Whitney U with multiple testing correction (q<0.05). Results: Among 2,651 metastatic BC samples (ILC n = 608; NST n = 2,043), patients with ILC were older (median 67 vs 63 yrs) and more likely white (81.5% ILC vs 73.1% NST), all p<0.05. By IHC, ILC were more frequently HR+/HER2- (83.6% vs 55.9%), less commonly triple-negative (11.9% vs 29.8%) or HER2+ (4.6% vs 14.3%), all p<0.05. PAM50 subtypes differed between ILC and NST: luminal A (Lum A) (31.1% vs 13.7%) and luminal B (Lum B) (44.9% vs 43.8%) intrinsic subtypes were enriched in ILC, while NST was more frequently basal (1.2% vs 22.4%) and HER2-enriched (19.8% vs 22.2%), all p<0.05. Within luminal BC, Lum B was more common than Lum A in both histologies, but Lum A was proportionally more frequent in ILC (ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B), p<0.0001. Comparative multi-omic analysis focused on the 922 HR+/HER2- tumors (ILC n = 275; NST n = 647). Compared to NST, ILC had higher frequency of CDH1 (87.3% vs 6.1%), PIK3CA (52.7% vs 38.5%), FOXA1 (9.0% vs 3.4%), ERBB2 (7.1% vs 2.0%), ARID1A, and NF1 (both q < 0.05) mutations and TMB high (17.7% vs 9.9%), but lower frequency of TP53 (15.7% vs 33.3%), ESR1 (10.9% vs 18.1%) and GATA3 (2.3% vs 14.9%) mutations along with FGFR1 amplifications (15.3% vs 6.7%), all q<0.05. ILC had higher expression of androgen receptor (91.2% vs 83.5%, q<0.05) and higher MAPK activation score (-0.81 vs -1.19, q<0.05), consistent with a luminal, hormone-driven phenotype. NST tumors demonstrated enrichment of pathways involved in the cell cycle and metabolic activity, including E2F targets, G2M checkpoint, MYC targets, mTORC1 signaling, glycolysis, and unfolded protein response (NES: 1.5-2.7, FDR<0.25). ILC tumors had higher infiltration of B cells, dendritic cells, neutrophils, NK cells and M2 macrophages, but lower M1 macrophages, all q<0.05. ILC had differential expression of immune checkpoint genes (upregulation: CD274 (PD-L1), PDCD1 (PD-1), TNFSF14, CEACAM1, CD160, fold change (FC): 1.2-1.5; down: HAVCR2 (TIM-3): FC: 1.2), all q<0.05. Median OS (mOS) was similar between luminal ILC and NST (33.8 vs 35.4 months (mo); HR 1.0, 95% CI 0.91-1.3). No mOS difference was seen between Lum A ILC and NST (47.4 vs 50.5 mo; HR 1.0, 0.84-1.43), while Lum B ILC had worse mOS than NST (27.4 vs 35.3 mo; HR 1.3, 1.1-1.6). Conclusions: This study represents the largest cohort to date with multi-omic characterization of metastatic ILC, revealing distinct genomic, transcriptomic, and immune features compared to NST. These findings highlight the unique biology of ILC and may inform future subtype-specific therapeutic strategies. Citation Format: G. Nader-Marta, S. Kumar Deshmukh, K. Fanucci, P. Tarantino, S. Schnitt, A. Lee, S. Oesterreich, S. Wu, J. Xiu, P. Advani, M. Lustberg, N. Lin, S. Tolaney, E. Mayer, O. Metzger, G. Sledge Jr., R. Jeselsohn. The Genomic, Transcriptomic, and Immune Hallmarks of Metastatic Lobular Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD9-07.