Citations

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

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

LBA514 Background: Preclinical and clinical data show that antibody-drug conjugates (ADCs) such as T-DXd may synergize with immunotherapy. Rilvegostomig (R) is a monovalent, Fc-reduced, dual checkpoint bispecific IgG1 monoclonal antibody against PD-1 and TIGIT receptors. R + T-DXd was evaluated as neoadjuvant therapy for up to 4 cycles. Methods: I-SPY2.2 is a phase II neoadjuvant trial with three neoadjuvant sequences (Blocks A/B/C). All HER2-negative subtypes were eligible for R + T-DXd in Block A. Predicted responders at the end of Block A or B could undergo surgery; otherwise, they continued to Block B +/- C. Block B pts received paclitaxel +/- carboplatin +/- pembrolizumab and Block C pts doxorubicin + cyclophosphamide (AC) +/- pembrolizumab, HR+ immune+ received IO in Blocks B/C. Results are analyzed by receptor and response predictive subtypes (RPS), that include expression-based immune, and luminal signatures with hormone receptor (HR) and HER2 status. Some pts were randomized to a control regimen (skipping R + T-DXd in block A and starting in block B). To minimize risk of interstitial lung disease (ILD) that could lead to treatment discontinuation, pts underwent pulmonary function tests and high-resolution chest CTs every 6 weeks. Abnormalities were reviewed in real time. The primary endpoint was pathologic complete response (pCR), within each RPS and HR/HER2 signature, with estimated pCR (EpCR) rates compared to subtype-specific block A goal rates and control pts in those groups. Other endpoints included safety and treatment discontinuation. Results: 105 pts were treated with R + T-DXd in block A, while 31 pts were randomized to the control regimen. Block A EpCR rate was 57% in the 12 HR+Immune+ pts vs a pre-specified goal of 15% (posterior probability, PP > .99). In 35 HR-Immune+ pts EpCR was 52% vs a pre-specified goal of 40% (PP = .87). No other groups (Immune-) had a PP > .85 for their respective pCR goal rate. HER2-IHC was 0 (27.6%), 1+ (49.5%) and 2+ (22.9%) in the treatment arm vs. 37.7%, 37.7%, and 24.7% in the control arm, with no difference in distribution between arms in immune subtypes. The most common adverse events in Block A were fatigue (84.8%), nausea (81.0%) and alopecia (58.1%). ILD was the most common adverse event of special interest in Block A and overall, occurring in 12 pts (11.4%; 7G1, 4G2, 1G3) during Block A and in 3 pts (G1, 2.9%) in other Blocks. 8 pts discontinued T-DXd + R due to ILD and proceeded to the next Block. Conclusions: When considering the full treatment strategy including block B and C regimens, experimental strategies had similar EpCR rates vs. controls in immune+ subtypes but block A rates exceeded pre-defined goal thresholds. This infers that treatment beginning with R + T-DXd has equivalent efficacy to standard of care for immune+ pts, but 64% pts with pCR skip chemotherapy (Block B) and 97% avoid AC (Block C). R + T-DXd participants avoided persistent ILD. Clinical trial information: NCT01042379 .

Abstract Background: Stromal tumor infiltrating lymphocytes (sTILs) are associated with improved response to chemotherapy and better overall survival (OS) in triple-negative breast cancer (TNBC). Quantification of sTILs via hematoxylin and eosin (H&E) tumor slides offers a widely available method to define a simple, effective surrogate for host anti-tumor immunity. Digitization of H&E slides has rapidly gained acceptance for use in diagnostic pathology and research, opening the door for image-based computational approaches to enumerate sTILs, among other features. Methods: We describe QuTILs - a multilayer perceptron-based framework to detect/enumerate TILs trained on >700,000 cells via The Cancer Genome Atlas Program (TCGA) slide images, implemented in the widely used open-source QuPath digital pathology suite. QuTILs was applied to digital H&E images using standard computing in primary breast tumors from phase 3 breast cancer clinical trials - CALGB 40502 (testing), CALGB 40601 and 40603 (validation) - in total 1,729 total images from 962 unique patients. The aims of this investigation were: 1) to assess the relationship between TIL patterns with overall or event-free survival outcomes; 2) to benchmark diverse image-based characteristics of TIL abundance and spatial architecture; and 3) to evaluate the association between image-based TIL levels and RNA-seq-based immune deconvolution metrics (CIBERSORT, EPIC, quanTIseq). Results: QuTILs average processing time was 7.9 minutes for whole-slide total TIL count and area density on a standard laptop workstation. In CALGB 40502, there was positive but modest correlation between pathologist TILs and QuTILs total TILs %, higher in the TNBC subgroup of CALGB 40502 (Pearson r = 0.55). In Cox proportional hazards models, the CALGB 40502 TNBC cohort showed significant univariate association for total TILs % with increasing decile (higher total TIL%) associated with reduced hazard (hazard ratio [HR]: 0.712, 95% CI: 0.559-0.906; P = 0.006), which remained significant in multivariable model incorporating age, race, and treatment arm (HR: 0.713, 95% CI: 0.556-0.915; P = 0.008). In validation TNBC clinical trial CALGB 40603, marginal TILs % was significant in the univariable Cox model (HR: 0.786, 95% CI: 0.639-0.966). Evaluation of TILs % by QuTILs with RNAseq-based deconvolution metrics in cohort-stratified and deconvolution method-stratified multivariable models showed that decile total TILs % by QuTILs was shown to significantly predict outcome in the EPIC (HR: 0.668, 95% CI: 0.466-0.957) and quanTIseq (HR: 0.646, 95% CI: 0.446-0.936) sets, with a similar magnitude as in clinical Cox, suggesting that RNA-based deconvolution estimates may not supplement the prognostic power of image-based TIL estimates. Exploratory analyses of pre- versus post-neoadjuvant therapy H&E images in CALGB 40603 and CALGB 40601 revealed a significant decrease in QuTILs total TIL% in CALGB 40603 for all pairs (n = 118 pairs, pre-median=9.52%, post-median=6.33%; Wilcoxon signed rank P < 0.001) but no significant change in QuTILs total TIL% among all pairs in CALGB 40601 (n = 82 pairs, pre-median=15.92%, post-median=15.10%; P = 0.886). Conclusions: QuTILs provides a computationally efficient open-source workflow for sTIL identification from digital H&E images that can be deployed on a standard laptop. We present the first evaluation of digital sTIL enumeration in CALGB 40502, CALGB 40603, and CALGB 40601 phase III breast cancer clinical trials and demonstrate significant prognostic association with QuTIL total TIL % among TNBCs across studies. Citation Format: M. Vater, R. Salgado, E. Blige, H. Lefebvre, A. Strahan, M. Gatti-Mays, H. Rugo, K. Ballman, M. Watson, Y. Wen, R. Leon-Ferre, K. Niazi, W. Symmans, L. Carey, K. AbdulJabbar, Z. Li, D. Stover. Qutils: open-source image-based infiltrating immune cell detection and outcomes in calgb 40502, calgb 40603, and calgb 40601 phase iii breast cancer clinical trials [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 PS2-07-27.

Abstract PURPOSE: CDK4/6 inhibitors (CDK4/6i), used in combination with endocrine therapy (ET), are standard of care for advanced and higher risk early stage hormone receptor-positive (HR+), HER2 negative (HER2-) breast cancer. PALLAS investigated the addition of 2 years (y) of palbociclib to adjuvant ET (ET/P) compared to ET alone in patients (pts) with stage II-III HR+/HER2- breast cancer. We now present overall survival (OS) with 7-y outcomes and impact of post-recurrence therapy. PATIENTS AND METHODS: This global phase III trial randomized pts to ET for at least 5 y with or without 2 y of P. Primary endpoint was iDFS; distant recurrence-free survival (DRFS) and OS were preplanned endpoints. Kaplan Meier estimates and hazard ratios (HR) from Cox and Fine & Gray models were performed. Post-recurrence OS was analyzed as time from first distant recurrence (DR) until death. The post-recurrence OS model adjusted for both clin/path factors (including DR-free y, DR site) and time-dependent post-DR therapy (chemo, CDK4/6i). Results: 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. DR occurred in 781 pts (377 ET/P, 404 ET alone) with balanced pt/disease characteristics between arms. ET/P had more visceral (46% vs. 36%) and fewer non-visceral (61% vs. 68%) DR compared to ET alone (p=0.03). Unadjusted post-recurrence OS was significantly worse for ET/P vs. ET (median 22.6 vs. 27.9 mo, HR 1.21 (95% CI 1.01-1.46, p=0.04). However, receipt of any post-recurrence CDK4/6i was significantly higher on ET vs. ET/P arms (41% vs. 66%) and time to post-progression CDK4/6i initiation was significantly shorter for those in the ET vs. ET/P arms (HR 0.50, 95% CI 0.41-0.61, p<0.001) adjusting for region, bone/visceral DR type, DR-free time and age. Conversely, time to post-progression chemotherapy initiation was significantly longer for ET alone vs. ET/P arms (HR 1.31, 95% CI 1.07-1.61, p=0.01). However, after adjustment for clinical factors and post-DR treatment, the OS difference was no longer seen (HR 1.05, 95% CI 0.85-1.28, p=0.65). 3-mo landmark analysis showed similar effect on OS after adjusting for CDK4/6i initiation within 3 mo from DR (unadjusted HR 1.24, p=0.03 vs. adjusted HR 1.15, p=0.22). CONCLUSION: The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect. SUPPORT: AFT, ABCSG, NRG, PrECOG; Pfizer Citation Format: A. DeMichele, A. Dueck, M. Gnant, D. Hlauschek, M. Martin, A. Wolff, G. Rubovsky, F. Henao, O. Hahn, A. Chan, A. Brusky, P. Morris, H. Burstein, G. Huber, D. Anderson, L. Garcia-Estevez, G. Pfeiler, H. Rugo, N. Zdenkowski, S. Gampenrieder, N. Wolmark, D. Sabanathan, K. Miller, D. Cameron, E. Winer, C. Brunner, E. Gauthier, P. O’Brien, C. Fesl, E. Mayer. Adjuvant Palbociclib for ER+ Breast Cancer in the PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): Post-Recurrence Treatment and Overall Survival [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 RF7-07.

Abstract Background: Advances in oncology, particularly the adoption of immunotherapies and antibody-drug conjugates, are transforming the nature and frequency of adverse events (AEs). These AEs come with both short and long-term symptoms that significantly impact patient quality of life. Monitoring for early onset of symptoms could optimize personalized therapy, maximizing potential efficacy while mitigating toxicity. It is also possible that some toxicities are directly associated with drug sensitivity. We sought to identify symptoms associated with pathologic complete response (pCR) using patient-reported outcomes (PROs) in early-stage high-risk breast cancer patients. Methods: Our study population included 288 stage II/III high-risk breast cancer patients enrolled on the I-SPY2 trial from 2021-2024, who received IO and ADC neoadjuvant therapies ± standard paclitaxel. pCR was defined as tumor absent in breast and nodes at surgery following neoadjuvant treatment. Patients (n = 288) were sent electronic PROs. 33 patient-reported AEs were measured using NCI's Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptom was evaluated using severity, frequency, and interference on a Likert Scale. Presence of early PRO symptoms (cycles 1-3 of treatment) were categorized (at least one of moderate or greater), and odds ratios were computed with pCR as outcome. To assess whether higher grade AEs were enriched in patients that achieved a pCR, we also performed the Wilcoxan Rank Sum test using maximum (worst) symptom severity. Breast tumor volume was measured by MRI at baseline and again at cycle 3 (∼day 21 from treatment start). Functional tumor volume (FTV) was computed from MR images by using enhancement thresholds. and percent change from baseline (ΔFTV) was calculated. Reduction in FTV was defined as a positive change. The Benjamini-Hochberg method was used to adjust for multiple hypothesis testing. Results: Of 288 patients included in our analysis (median age = 48 years, range = 20-78, pCR rate = 29%), 203 (70.5%) were White, 17 (5.9%) were Asian, 33 (11.5%) were Black or African American, and 35 (12.2%) were Hispanic and 89% were administered immunotherapy, 11% ADC. The pCR rate was 29%. PRO analysis revealed that patients that had moderate to severe muscle pain (27% vs 10% OR = 3.15, P < 0.05), joint pain (22% vs 8% OR = 3.23, P < 0.05), headache (27% vs 12.5% OR = 2.59, P < 0.05), or mouth/throat sores (16% vs 5% OR = 3.56, p < 0.05) within weeks 1-3 had higher odds of achieving a pCR. Maximum severity between weeks 1-3 was associated with pCR. Patients that achieved a PCR had higher grade muscle pain (P < 0.05), heart rates of palpitations (P < 0.05), and significantly lower grade numbness and tingling (p = 0.002). Additionally, of the symptoms assessed, frequency, interference, and severity of arm or leg swelling was significantly correlated with reduction in tumor volume (FTV) during weeks 1-3 treatment (Bonferroni corrected P<0.01). Beyond 6 weeks, associations were weak or insignificant. Conclusion: Our study utilizes a computational framework that defined sentinel symptoms such as muscle and joint pain, mouth/throat sores, headache, and swelling, as early as weeks 1-3 that were associated with a favorable tumor response. This may suggest an early immune reaction in patients that eventually respond favorably to treatment, and prioritization to continue these patients on treatment may be warranted. Our work can help provide earlier proactive monitoring to mitigate toxicities, to enhance treatment response, and a potential symptom-based early understanding to personalize treatment efficacy. Citation Format: A. Basu, S. Umashankar, C. Yau, K. J. Ruddy, A. H. Blaes, D. M. Wolf, A. DeMichele, J. Perlmutter, D. Yee, A. B. Olshen, L. J. van't Veer, R. A. Shatsky, C. Isaacs, R. Nanda, H. S. Rugo, M. E. Melisko, N. Hylton, L. J. Esserman, D. L. Hershman, I-SPY Trial Investigators and Patient Advocates.. Early Adverse Symptoms Predict Response to Treatment Among Patients in the I-SPY Trial [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 RF1-04.

Abstract Background: Microtubule inhibitors remain a standard chemotherapy in the management of HER2-negative metastatic breast cancer (MBC). CALGB (Alliance) 40502 was a phase 3 randomized study involving 799 patients with MBC receiving first-line chemotherapy, to determine the optimal chemotherapeutic agent among paclitaxel, nab-paclitaxel, or ixabepilone (with or without bevacizumab). Secondary analysis suggested inferior PFS with nab-paclitaxel specifically among patients with hormone receptor positive (HR+)/HER2-negative breast cancer. Correlative analysis demonstrated significant association of stromal tumor infiltrating lymphocytes (sTILs) with improved progression-free (PFS) and overall survival (OS) in CALGB40502. We hypothesized that immune activation would be associated with differential benefit among distinct microtubule agents. To address this, we evaluated the sTILs and RNA-based immune features association with clinical outcomes, including evaluation of nab-paclitaxel versus paclitaxel. Methods: To limit heterogeneity, analyses focused on pre-treatment primary tumor breast samples with central review/pathologist-enumerated sTILs in accordance with International TILs Working Group methods and RNAseq (n = 280). PAM50 molecular subtypes were assigned based on transcriptomic features. RNAseq data were used to generate immune deconvolution estimates from 5 distinct algorithms (CIBERSORT, xCell, ABIS, ConsensusTME, ImmuCellAI). 1,018 curated breast cancer gene expression signatures GES) were derived from previously published studies. Associations between sTILs and GES were evaluated with sTILs being a categorical variable with the thresholds <5% (low) and (≥5%) high. Results: In the evaluable population, basal-like PAM50 subtype was enriched for high sTILs category (p=1e-4), as anticipated. T-cell and B-cell immune signatures and immune deconvolution estimates were among most highly associated with sTILs. In addition to the expected prognostic association of high T-cell GES, high B-cell-related IgG signature score was also significantly associated with improved overall survival (OS) among triple-negative breast cancer (TNBC) in CALGB 40502 (HR = 0.50,95% CI:0.30-0.86, log-rank p=0.01) but not in HR+/HER2-. In an exploratory analysis of young patients (age at study entry <50 years), high sTILs were associated with improved OS among TNBC patients but worse OS among those with HR+/HER2- MBC (HR = 2.19, 95% CI:1.10-4.36, log-rank p=0.022). High (above median) RNA-based Xcell total immune score was significantly associated with worse OS in both CALGB 40502 and a validation dataset of primary breast cancers, METABRIC (OS HR = 2.12, 95% CI:1.01-4.45, log-rank p=0.042). To further investigate the clinical trial finding of inferior PFS for nab-paclitaxel compared with paclitaxel in patients with HR+/HER2- MBC, there was a significant enrichment of T-cell signatures associated with poor outcome in patients receiving nab-paclitaxel (Fisher exact p<0.001). Conclusion: In this translational analysis of sTILs and RNAseq from a large phase III clinical trial, sTILs and immune signatures were not uniformly associated with better outcome. Rather, high sTILs or immune signatures were associated with worse OS in young patients with HR+/HER2- breast cancer and higher T-cell signatures were associated with inferior PFS with nab-paclitaxel among HR+/HER2- MBC patients. These data reinforce the importance of context/subtype-specific interrogation of the tumor-immune microenvironment Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. Bristol Myers Squibb (BMS); Clinicaltrials.gov Identifier: NCT00785291 Citation Format: E. K. Blige, K. V. Ballman, A. Michmerhuizen, M. Vater, L. A. Carey, A. H. Partridge, W. F. Symmans, M. A. Watson, C. M. Perou, D. G. Stover, H. S. Rugo. Rna-based immune features associated with benefit from distinct microtubule inhibitor therapy for metastatic her2-negative breast cancer: a post hoc analysis of the calgb 40502 (alliance) phase iii randomized clinical trial [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 PS1-13-17.

Abstract The addition of two years (yrs) of adjuvant abemaciclib to ET resulted in statistically significant and clinically meaningful improvement in overall survival (OS) over ET in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. At 7 yrs, abemaciclib+ET demonstrated sustained IDFS and DRFS benefits ([HR=0.73, 95% CI: 0.66, 0.82), and (HR=0.75, 95% CI: 0.66, 0.84)]). Higher nodal involvement (N2 or N3) is an independent prognostic factor for worse outcomes in EBC. However, previous monarchE data highlight that pts with limited nodal disease (1-3 axillary lymph nodes (ALN)) are at high recurrence risk when additional clinical risk factors are present, such as high-grade (G) tumor and/or large tumor size. Here, we show subgroup analyses by ALN.monarchE is a phase 3, open-label, randomized trial in pts with HR+, HER2-, node-positive, high-risk EBC. Pts were randomized (1:1) to receive ET for at least 5 yrs +/- abemaciclib for 2 yrs (treatment (tx) period). High-risk EBC was defined as either 1-3 ALN (N1) with G3 disease and/or tumor ≥5 cm or, ≥4 ALN (N2: 4-9, N3: ≥10) (Cohort 1 (C1)). A smaller group of pts were enrolled with N1, G≤2, tumor size <5 cm, and central Ki-67 ≥20% (C2). IDFS, DRFS and OS were assessed in C1 by ALN (N1, N2, N3) using the Kaplan-Meier (KM) method, and unstratified Cox proportional hazard model including interaction effect between tx arm and ALN. Of 5120 randomized pts in C1, 1761 (34.4%) had N1, 2223 (43.4%) had N2, and 1123 (21.9%) had N3 disease. At this analysis (data cut off:15Jul2025), in the ET arm, a comparable number of patients with N1 and N2 disease had IDFS events at 6 yrs (21.6% and 25.4%), while event no. in the N3 subgroup was notably higher (38.1%). A similar trend was observed in DRFS and OS (Table). With a median follow-up time of 76.8 months in C1, the addition of abemaciclib to ET reduced the risk of developing an IDFS event by 24.8% (N1), 31.5% (N2) and 27.4% (N3) compared to ET. The absolute improvements in IDFS rates at 6 yrs were 4.6% (N1), 6.9% (N2), and 8.1% (N3). Reductions in the risk of developing DRFS events were 25.2% (N1), 31.2% (N2), and 25.7% (N3), with corresponding 6yr absolute benefit of 3.8% (N1), 6.4% (N2), and 6.8% (N3). Abemaciclib+ET consistently reduced the risk of death compared to ET across ALN subgroups by 12.3% (N1), 15.5% (N2), and 26.8% (N3), which resulted in absolute improvements in OS of 1.4% (N1), 1.6% (N2), and 2.7% (N3). Baseline disease characteristics, IDFS and DRFS KM curves by ALN will be presented. In the ET arm, pts with N1 + ≥1 additional risk factor had recurrence and death risks comparable to pts with N2, while pts with N3 had poorer prognosis. The addition of adjuvant abemaciclib to ET led to a clinically meaningful reduction in the risk of recurrence and death regardless of nodal burden, confirming the consistent and sustained benefit of 2 yrs of tx with abemaciclib and supporting its use in eligible pts with node-positive high-risk EBC. Citation Format: J. Cortes, S. R. D. Johnston, M. Martín, S. M. Tolaney, M. Goetz, H. Rugo, J. Sohn, O. Ozyilkan, M. Henriques Abreu, M. Zaiss, K. Maia Vianna, H. Melgaard Nielsen, A. Chan, H. Kalofonos, S. Morales, B. San Antonio, M. Munoz, B. R Grimes, S. Amdur, P. Neven. monarchE: subgroup analysis of adjuvant abemaciclib + endocrine therapy for HR+, HER2-, high-risk early breast cancer by nodal status [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 PS1-08-08.

Abstract Background: Combinations of antibody-drug conjugates and immunotherapy, such as trastuzumab deruxtecan (T-DXd) and rilvegostomig (rilve), respectively, offer promising efficacy but are associated with a heightened risk of drug-induced interstitial lung disease (ILD)/pneumonitis. Early detection and management are critical for optimizing patient safety, yet there are no standard protocols for real-time evaluation. We hypothesized that vigilant monitoring would enable early detection, prevent symptoms, and minimize the chance of treatment delays while testing novel therapeutic combinations that have a potential risk of ILD. Methods: We tested the combination of T-DXd and rilve administered every 3 weeks in the I-SPY2.2 phase 2 platform trial (NCT01042379), which enrolls patients with clinical stage II/III breast cancer commencing neoadjuvant systemic therapy. Given the potential risk of overlapping pulmonary toxicity of these two agents, we added rigorous monitoring with pulmonary function tests (PFTs), six-minute walk test (6MWT), and high-resolution chest CT (HRCT) scanning pretreatment and every 6 weeks thereafter. A real-time safety workflow was implemented, with pre-specified criteria for halting treatment and escalation to the next block of treatment. All abnormal findings reported on chest CT by site radiologist were centrally reviewed in real time by the study pulmonologist (T.K.) and cases of suspected ILD were adjudicated promptly by a safety committee consisting of the pulmonologist and several medical oncologists, enabling early study drug interruption and therapeutic interventions. Toxicity data were evaluated in the first 51 patients treated with T-DXd plus rilve, and a preplanned hold was initiated until safety was ascertained by the data and safety monitoring board. Results: Safety data were evaluated in the first 51 patients receiving T-DXd plus rilve. Eight ILD events were confirmed (15.68% incidence): 5 grade 1, 2 grade 2, and 1 grade 3. One patient had an early chest CT scan because of dyspnea. All cases were identified by HRCT scans; PFTs and 6MWT did not enhance early detection and were subsequently dropped from the monitoring protocol. No patient was symptomatic for more than 24 hours. Radiographic findings resolved within 14-55 days. Patients with grade 2 & 3 ILD were treated with corticosteroids. No cases of ILD required intensive care or escalated therapy beyond steroids. Early treatment escalation to the subsequent block of therapy occurred in 3 patients; all 3 patients were subsequently able to receive appropriate therapy. At the meeting, safety data from all 100 patients treated with this combination will be reported. Conclusion: Real-time, centralized monitoring and adjudication allowed for early detection and prompt management of ILD, which both mitigated severity and supported timely therapeutic management. Among the monitoring tools studied, HRCT scanning performed every 6 weeks proved most effective for early ILD identification; PFT and 6MWT did not enhance early detection. This approach offers a potential framework for future studies assessing pulmonary safety in regimens combining agents that have a known risk for inducing ILD. Citation Format: T. Kulkarni, R. Nanda, H. S. Rugo, C. C. OSullivan, K. M. Kalinsky, J. C. Boughey, P. R. Pohlmann, J. Perlmutter, D. Yee, A. Borowsky, F. Symmans, N. Hylton, L. Van ‘t Veer, C. Yau, L. Esserman. Real-time monitoring for drug-induced interstitial lung disease with Trastuzumab Deruxtecan and Rilvegostomig combination therapy prevents persistent, symptomatic disease: Safety insights from the I-SPY2.2 platform trial [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 PS1-01-09.

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.