Mukhtar, R. M.

Abstract Intro: The 70-gene MammaPrint (MP) assay is prognostic for distant recurrence and predictive of benefit from adjuvant chemotherapy (CT) benefit established on surgical tissue of systemically untreated patients (pts). The MP index range is from -1 to +1 with higher index indicating lower risk of early recurrence. Risk is categorized as MP High Risk, MP Low Risk, and MP UltraLow Risk, and results can guide treatment decisions. Pts with MP index >0 are classified as Low Risk and derive little benefit from CT. There are clinical scenarios in which the only available tissue for MP or other genomic testing has been exposed to neoadjuvant endocrine therapy (NET). Few studies have investigated the impact of ET exposure on MP index. Methods: Pts were identified through the I-SPY Low Risk Registry (LRR), an observational sub-study which enrolled pts with hormone receptor positive (HR+)/HER2-negative early breast cancer ineligible for the I-SPY2 trial due to MP Low Risk or UltraLow Risk status, between 2010-2020. Pts were treated at the discretion of their provider. We conducted a retrospective analysis of MP index from paired tumor tissue obtained from systemically untreated diagnostic core biopsies and surgical specimens after NET. MP categories and index before and after NET were compared. Change in MP index was assessed for an association with changes in clinicopathologic factors obtained through the LRR using the paired-t test. Results: 28 pts with paired tumor samples were included in the analysis. Median age was 48 (range 31-75) and 18 (64%) were premenopausal. At baseline, 13 (46%) were clinically node-positive and 22 (76%) had ductal histology. Tumor grade was 1 in 6 pts (21%), 2 in 20 pts (71%), and 3 in 2 pts (7%). ER expression was >95% in 25 pts (range 60-100%) and PR expression was >90% in 14 pts (range 0-100%). NET regimens included tamoxifen +/- ovarian function suppression (OFS) in 3 pts (10.7%), aromatase inhibitor (AI) +/- OFS in 15 pts (53.6%), tamoxifen followed by or in combination with AI +/- OFS in 8 pts (28.6%), fulvestrant in 1 pt (3.6%) and OFS alone in 1 pt (3.6%). 11 (61%) of premenopausal pts received OFS. 96% (27/28) of pts were classified as Low Risk both pre- and post-NET. Only one pt had MP change from Low Risk to High Risk. Three pts had change from Low Risk to UltraLow Risk or vice versa. As a continuous variable, a small average increase in MP index was observed after NET; but, there was a range of responses. 19 pts (68%) had an increase in MP index after NET, while 9 pts (32%) had a decrease. In those with a decrease in MP index, the average ER expression decreased by -13.6%, whereas in those with an increase in MP index, ER expression was unchanged (-0.18%) (p=0.049). There was no significant difference in changes in PR expression between tumors with increased vs decreased MP indices. At a median follow-up of 35 months, 4 distant recurrences were observed. Of the 9 pts with a decrease in MP index, 3 pts (33%), including the one who changed from Low Risk to High Risk, experienced a distant recurrence. In contrast, in those with an increase in MP index, 1 of 19 (5%) experienced a distant recurrence. Conclusion: In pts with early-stage HR+/HER2- MP Low Risk or UltraLow Risk breast cancer, NET had minimal impact on the tumor MP classification. These data suggest that the MP assay could be used for tissue exposed to NET if untreated tissue is not available. Further investigation in larger cohorts is needed to validate these findings. The observation that there were more distant recurrences in pts with tumors that had an increase in MP after NET is hypothesis generating, and potentially clinically relevant if validated in a larger study. The potential of MP as a dynamic risk marker to stratify recurrence risk following NET is being evaluated in the ongoing I-SPY2 Endocrine Optimization Pilot. Citation Format: S. Jacob, C. Wu, A. Glas, C. Yau, L. Brown-Swigart, G. Hirst, T. Haddad, K. Giridhar, A. Elias, R. Mukhtar, L. Huppert, K. Albain, D. Yee, L. van’t Veer, L. Esserman, J. Chien. Impact of Neoadjuvant Endocrine Therapy on MammaPrint Index in Hormone Receptor-Positive, HER2-Negative MammaPrint Low Risk Early-Stage 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 PS4-05-28.

Abstract BACKGROUND: EOP is an I-SPY2 sub-study designed to test novel endocrine-based strategies in patients (pts) predicted to have modest benefit from chemotherapy. Vepdegestrant is a selective oral PROTAC estrogen receptor (ER) degrader that has demonstrated efficacy in mutant ER+ HER2-negative MBC. METHODS: EOP eligibility included pts with Stage 2/3 HR+ HER2-negative, MammaPrint (MP) Low Risk BC. Patients with MP High1 signatures were eligible if clinically node-negative or SET 2,3 High. Pts were randomized to one of 3 oral treatment (tx) arms: vepdegestrant 200 mg/d (V), vepdegestrant 200 mg/d +letrozole (VL), vepdegestrant 200 mg/d + abemaciclib 150 mg bid (VA). Pts received tx for six 28-day cycles followed by surgery. Premenopausal (PreMN) pts received ovarian function suppression (OFS) starting C1D1 in the VL arm, and C2D1 in the V and VA arms. The primary endpoint was feasibility, defined as >75% of pts completing >75% of study therapy. Breast MRI functional tumor volume (FTV) and ctDNA (tumor-informed assay) were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). Ki67 and ER/PR by IHC were centrally assessed from tumor biopsies at T0, T1, and the surgical specimen. Results: Between 4/2023 and 1/2025, 121 pts were enrolled: 40 in V, 41 in VL, and 40 in VA. Median age was 54 years, 50% preMN. 60% of pts had ductal, 35% lobular, 5% mixed histology. 55% were cN+, and 59% were not breast conservation surgery (BCS) candidates at baseline. Mean baseline Ki67 was 12.5%, 85.1% had MP Low Risk signature, 79.3% were SET 2,3 High. All 3 tx arms met the primary endpoint with 88%, 88%, and 83% completing > 75% study therapy in V, VL, and VA (thus far), respectively. Most common all grade (AG) TRAEs in V and VL arms include fatigue (53% V, 71% VL), hot flashes (48% V, 71% VL), arthralgias (33% V, 49% VL), all G1 or G2 except for 1 G3 fatigue in VL arm. G2 and G3 neutropenia was seen in 1 pt each in V and VL arms. The most common AG TRAEs in VA include diarrhea (80%), fatigue (65%), nausea (58%), hot flashes (50%), neutropenia (43%). High grade TRAEs in VA include neutropenia (23% G3, 5% G4), ovarian cyst requiring surgery (5% G3), diarrhea (15% G3), nausea (3% G3), transaminitis (3% G3), thromboembolic event (8% G3), acute kidney injury (3% G3). Table 1 summarizes key response endpoints by tx arm. CONCLUSION: Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy. Citation Format: J. Chien, R. M. Mukhtar, C. Yau, A. D. Elias, A. M. Wallace, N. Chan, C. Omene, N. Chen, J. Tseng, M. S. Trivedi, E. Stringer-Reasor, D. Yee, A. S. Clark, A. Thomas, H. Han, M. Arora, C. Nangia, K. Albain, C. Falkson, C. Isaacs, A. Zimmer, M. Rozenblit, L. van't Veer, L. Brown Swigart, G. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, S. Alkhafaji, K. V. Giridhar, C. Vaklavas, M. Wei, M. P. Goetz, O. Olopade, L. Huppert, C. Wu, L. J. Esserman. I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) [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 PD10-02.