Stringer-Reasor, Erica

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Abstract Current genomic assays provide prognostic information and guide chemotherapy decisions in early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer, but limited tissue sampling may incompletely capture tumor heterogeneity. We developed and validated an image-based artificial intelligence (AI) model integrating dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinicopathologic features to predict recurrence risk in early-stage HR+/HER2 − breast cancer. In this retrospective multi-institutional study, the model was trained using pre-treatment imaging and clinicopathologic data from 522 patients and independently validated in 550 additional patients treated between 2010 and 2023. By analyzing spatial tumor characteristics, the model generated individualized recurrence risk scores that outperformed clinicopathologic features alone. In the validation cohort, median age was 53 years (range, 24–90), 15.6% of patients self-identified as African American, 89.7% had clinical T1–T2 disease, and 34.4% had 1–3 positive lymph nodes. Five-year recurrence-free survival was 93.8% (95% CI, 90.0–96.2%) among patients classified as low risk compared with 82.6% (95% CI, 74.8–88.1%) among those classified as high risk, corresponding to an adjusted hazard ratio of 2.28. Prognostic performance was maintained across clinically relevant subgroups, including age and nodal status. These findings support the potential of a noninvasive image-based AI approach for real-time prognostication and treatment personalization in early-stage HR+/HER2 − breast cancer.

1056 Background: Resistance to HER2-directed therapies remains a major challenge in HER2-positiveMBC. In preclinical models, HER2+ tumors overexpress poly (ADP-ribose) polymerase (PARP), and PARP inhibition induces apoptosis through NF-κB suppression even in the absence of pathogenic mutations in BRCA 1/2 . We evaluated the safety, efficacy, and translational correlates of niraparib combined with trastuzumab in patients (pts) with refractory HER2+ MBC. Methods: This open-label Phase 1b/2 trial (NCT03368729) enrolled pts with HER2+ MBC (IHC 3+ and/or FISH amplified), measurable disease, LVEF ≥50%, and progression on ≥1 prior HER2-targeted therapy; stable CNS disease was allowed. Pts with germline BRCA1/2 mutations or prior PARP inhibitor exposure were excluded. Niraparib 300 mg orally was administered on Days 1–21 of a 21-day cycle with trastuzumab 6 mg/kg IV every 3 weeks (loading dose 8 mg/kg on cycle 1). The Phase 2 portion used a Gehan/Simon two-stage design with early stopping for futility (P0=24%); ≥1 response among the first 20 patients triggered expansion to 40 patients. ORR was assessed by RECIST v1.1, meeting the primary endpoint and allowing response rate estimation with <7% standard error and a two-sided 95% exact CI width of 0.28. Gene expression profiling of paired tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed using the NanoString nCounter Tumor Signaling 360 panel at pretreatment compared to cycle 2. Results: Forty-six pts were enrolled (9/2019–2/2025); 41 were evaluable for response. Pts were heavily pretreated (median 3 prior regimens), including trastuzumab deruxtecan in 22 pts; 33% had brain metastases. Treatment-related adverse events were predominantly grade 1–2 and manageable. Clinical benefit rate (CBR) was 44% (18/41) including 1 complete response, 2 partial responses, and 15 stable disease. Eleven patients achieved disease control ≥ 6 months; 1 patient remained on treatment at data cutoff. Tumor profiling revealed enrichment of a B-cell–driven tertiary lymphoid structure signature with reduced hypoxia signaling in responders. Matched PBMC analyses demonstrated coordinated downregulation of interferon signaling, DNA damage response, metabolic activation, angiogenesis, and resistance pathways in clinical responders, whereas non-responders retained signatures of chronic stress and immune exhaustion. Conclusions: Niraparib plus trastuzumab demonstrated a favorable safety profile and durable clinical benefit in heavily pretreated HER2+ MBC. Integrated tumor and blood-based analyses identify immune-organized tumor microenvironments and systemic immune normalization as key correlates of prolonged response, supporting further investigation of PARP inhibition strategies. Clinical trial information: NCT03368729 .

Abstract Background: (Z)-endoxifen (ENDX) is an oral SERM that dually targets ERα (&gt; 5 ng/ml) and PKCβ1 (&gt;500 ng/ml). It has been tested in the endocrine resistant setting at doses of 20-360 mg/day; however, the optimal dose in an endocrine naïve population is not defined. We explored 10 mg/day dose of neoadjuvant ENDX in the Endocrine Optimization Pilot (EOP) of I-SPY2. Methods: EOP eligibility included pts with Stage II/III HR+ HER2- breast cancer, MammaPrint (MP) low. Pts with MP High1 scores were eligible if clinically node-negative. Pts received ENDX 10 mg orally once daily for 6 cycles (each cycle = 28 days). Premenopausal pts started ovarian function suppression on cycle 2, day 1. ENDX was continued until the day prior to surgery. The primary study endpoint was feasibility, defined as &gt;75% of pts completing &gt;75% of ENDX. Baseline (T0), 3-wk (T1) biopsies, and the surgical specimen (T3) were assessed centrally for Ki-67. Rates of modified preoperative endocrine prognostic index (mPEPI) 0 were reported, defined as pT1-2 pN0, Ki67&lt; 2.7%, or pathologic complete response. A genomic index for sensitivity to endocrine therapy (SET) index was done at T0. Breast MRI measurement of functional tumor volume (FTV) was performed at T0, T1, 12 weeks (T2), and pre-operatively (T3). Blood was collected for tumor informed ctDNA at T0, T1, T2, T3 and for pharmacokinetic (PK) steady state concentrations (Css) at T1. Safety data using CTCAE V5 is reported. Results: Between March 2023 and May 2024, 20 pts were enrolled in this arm. The median age was 52.5 years (range 32 -73), 13 (65%) were premenopausal, and 55% had clinically positive lymph nodes. Tumors were MPHigh1 in 3 pts (15%) and SET2,3 index high in 16 pts (80%). The primary endpoint was met with 95% of study participants completing ≥75% of therapy. The T0 median Ki-67 was 10.5% (range 2-60%). At T1 (n=19) and T3 (n=18), median Ki-67 was 5% (range 0-35%) and 5% (range 0-45%), respectively. The 3-week rate of Ki-67 ≤10% at T1 was 61.5% in premenopausal and 71.4% in postmenopausal women. The rate of Ki-67 ≤10% at surgery was 81.8% in premenopausal and 57.1% in postmenopausal women. An mPEPI score of 0 was observed in 1 (5%) of participants. The median T0 FTV was 8.9 ccs (range 0.9 to 251.1). The median T3 FTV was 1.3 ccs (range 0 to 11.2) and the median change in FTV from T0 to T3 was -72.0% (range -88.5% to -61.6%). ctDNA analysis was performed in 17 pts longitudinally across 64 blood samples.10 pts had positive ctDNA at T0, with 7 converting to ctDNA undetectable during treatment with ENDX. 1/7 pts who was ctDNA negative at T0 became positive at T1 and then reverted to undetectable ctDNA. The other 6 pts remained ctDNA negative at all timepoints. The median ENDX T1 Css was 79.3 ng/mL (range 73.6 - 906.4 ng /mL). The most common side effects reported were Grade 1 hot flush (70%), nausea (40%), fatigue (40%), and insomnia (35%). Grade 2 side effects included fatigue (15%) and night sweats (5%). No dose reductions or discontinuations due to toxicity occurred. Conclusions: ENDX at 10 mg was well tolerated and demonstrated reductions in Ki-67, MRI FTV, and ctDNA. The ISPY2 EOP is currently enrolling patients to ENDX 40 mg/day (intended to dually target ERα and PKCβ1) in combination with abemaciclib (with and without OFS). Citation Format: K. V. Giridhar, M. P. Goetz, C. Yau, A. M. Wallace, C. Falkson, J. Boughey, M. Arora, E. Stringer-Reasor, C. Nangia, C. Gallagher, A. Elias, A. Zimmer, M. S. Trivedi, C. Omene, L. van 't Veer, L. Brown Swigart, G. L. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, C. Vakalvas, M. Wei, J. M. Reid, S. Alhafaji, N. Chen, R. M. Mukhtar, L. Huppert, O. Opopade, L. J. Esserman, A. Chein. Low dose (Z)-endoxifen in the I-SPY2 Endocrine Optimization Pilot [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 PS3-07-10.

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 &gt;75% of pts completing &gt;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 &gt; 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.

Abstract Background Immune checkpoint inhibitors can result in serious, long-lasting immune-related adverse events (irAEs). Early identification of symptoms predictive of irAEs could enhance monitoring and timely intervention. This study assessed whether symptoms within the first 8 weeks of treatment could predict subsequent development of immune-related adrenal insufficiency(AI) or hypothyroidism. Methods This retrospective cohort study analyzed prospectively collected data from the I-SPY2 trial, a phase 2 platform trial for high-risk stage II/III breast cancer across 30 U.S. sites. The cohort included 482 women treated with experimental immunotherapy agents concurrent with weekly paclitaxel neoadjuvant chemotherapy. The primary outcomes were grade ≥ 1 hypothyroidism or AI, adjudicated by an independent safety group, up to 1-year post-treatment. Symptoms and irAEs were assessed using the Common Terminology Criteria for Adverse Events. Symptom burden was quantified as area under the curve (AUC) based on symptom grade and duration. Predictive modeling was performed using logistic regression and ROC analysis; symptom enrichment between cases and controls was evaluated using Fisher’s exact tests. Results Among 482 participants, 107 (22.2%) developed irAEs, with hypothyroidism (n = 61, 12.7%) occurring more frequently than AI (n = 38, 7.9%) at medians of 99 and 105 days from treatment initiation, respectively. Symptom enrichment analysis identified early predictive symptoms. Fatigue (17.2% vs 6.8%, p = 0.011) and rash (20.7% vs 7.8%, p = 0.0037) were predictive of hypothyroidism, while diarrhea (45.9% vs 31%, p = 0.048), constipation (5.4% vs 0.2%, p = 0.018), and taste changes (5.4% vs 0.5%, p = 0.034) were associated with AI. A predictive model demonstrated moderate performance (AUC 0.65 for AI, p < 0.0001; AUC 0.61 for hypothyroidism, p = 0.012). Model accuracy in an external validation cohort was 72.8% for AI and 74.7% for hypothyroidism. Conclusions This study presents a predictive framework to identify patients at risk for adrenal insufficiency and hypothyroidism as irAEs, enabling personalized care and proactive intervention to improve treatment outcomes and safety.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.