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The treatment paradigm of stage II to III triple-negative breast cancer (TNBC) is rapidly evolving, with the recent incorporation of pembrolizumab to neoadjuvant chemotherapy improving disease outcomes. Nevertheless, almost one in five patients with early-stage TNBC will relapse in 5 years, underscoring an urgent need to identify and improve outcomes for those at high risk of recurrence. Novel therapeutic strategies including antibody-drug conjugates, anti-vascular endothelial growth factor therapies, dual immune checkpoint blockade, and locoregional therapies to augment the antitumor immune response are being investigated in clinical trials. Biomarker strategies including tumor infiltrating lymphocytes, immune signatures, and circulating tumor DNA are being explored to identify patients at a high risk of relapse and to predict treatment response. In this article, we review recent advances in the management of stage II to III TNBC, highlight emerging investigational therapies and combinations, and explore novel biomarker strategies aimed at personalizing the care for patients with stage II to III TNBC.

Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 overexpression. Historically, treatment options for TNBC have been limited, because of the absence of actionable targets. The addition of immune checkpoint inhibitors to chemotherapy improved outcomes for a subset of patients with metastatic PD-L1–positive disease; however, a critical need for more effective therapies remains. Antibody-drug conjugates (ADCs) have been a promising advance in the management of advanced TNBC and are reshaping the landscape as they move earlier into the treatment algorithm. A greater understanding of the molecular heterogeneity of TNBC has enabled the pursuit of more targeted and personalized therapeutic strategies. Despite this, TNBC continues to have the least favorable outcomes compared with other breast cancer subtypes. This review highlights current evidence and future challenges in advanced TNBC, including optimizing therapeutic sequencing and the ongoing need for predictive biomarkers and novel agents.

Abstract Background: In MBC, CTC enumeration is highly prognostic for both progression free survival (PFS) and overall survival (OS). Multiparametric technologies enable for expanded phenotypic profiling of CTCs, including ER and HER2 assessment. Limited information is available on the concordance of CTC ER and HER2 levels compared to synchronously obtained tissue. We assessed the prognostic performance of CTC enumeration and phenotypic profiling of ER and HER2 on CTCs. Methods: The prospective, multi-institutional Aurora study enrolled pts with MBC of any subtype either at diagnosis of metastatic disease or at time of progression on any line of systemic therapy. Pts underwent a metastatic site biopsy, consented to archival primary tissue collection and donated blood samples serially every 3-4 months until progression. CTCs, from blood collected at study entry, were identified as nucleated, EpCAM+/ cytokeratin+/ CD45- cells using an automated imaging system (RareCyte, Seattle). ER and HER2 expression levels were measured by mean fluorescence intensity (MFI), with thresholds above 80 (ER) and 160 (HER2) considered positive. Comparisons were made to total RNAseq from paired metastatic tissue biopsies. PFS and OS were calculated from the time of study entry to last follow up or death. Results: Baseline CTC enumeration was performed in 154 pts. The most common clinical subtype was HR+/HER2- (59.7%), followed by HER2-positive (16.8%) and TNBC (15.5%). The median lines of prior therapy were 1 (range 0-10). At least 1 CTC was identified in 68/154 pts (44%), 30 (19%) had ≥ 5 CTCs, and 15 (9.7%) had CTC clusters. The median CTC value was 0 (0-877). The presence of CTCs (≥1 or ≥5) and CTC clusters was adversely associated with PFS and OS (Table 1 Table 1. CTC survival analyses Number Median PFS PFS HR (95% CI) Median OS OS HR (95% CI) Presence of CTC 0 CTC 86 7.37 (0.03 - 43.1) reference 20.72 (0.03 - 50.6) reference ≥ 1 CTC 68 4.7 (0.43 - 19.5) 1.65 (1.16-2.36) 12.04. (0.43-44.1) 2.13 (1.44-3.16) Presence of ≥ 5 CTC <5 CTC 124 7.7 (0.03 - 43.1) reference 19.31 (0.03 - 50.6) reference ≥ 5 CTC 30 2.88 (0.43 - 18.7) 1.77 (1.15 - 2.71) 5.74 (0.43 - 29.3) 3.59 (2.26-5.70) Presence of clusters 0 clusters 139 7.37 (0.03 - 43.1) reference 18.06 (0.03 - 50.6) reference ≥ 1 cluster 15 1.91 (0.43 - 18.7) 2.06 (1.16 - 3.68) 3.42 (0.43 - 18.7) 5.44 (2.94-10.09) ). Across all subtypes, the median CTC ER-MFI across was 36.2 (range 4.2-10,016.6) and the median HER2-MFI was 139.6 (range 4.2-2480.5). We observed high intra-patient heterogeneity of ER-MFI (CV: 0.65 [0.34-1.25]) and HER2-MFI (CV: 0.79 [0.42-1.54]). Clinical metastatic subtype from metastasis at study entry was available in 54/68 pts with CTCs. Pts with clinical ER+ MBC had a higher median ER-MFI compared to clinical TNBC (111.9 vs 68.6, p = 0.02). However, 11 pts (26.8%) with clinical ER+ MBC had all CTCs with an ER-MFI <80. Lower ER expression was observed in CTCs collected after prior exposure to a SERD (median ER-MFI: post-SERD [n=8] 27 vs post-aromatase inhibitor [n=4] 252, p<2.22e-16). No correlations were observed between the median CTC ER-MFI or HER2-MFI and paired tissue ESR1 or ERBB2 RNA expression (n=66). Conclusions: CTCs are strongly predictive of PFS and OS. CTC ER- and HER2-MFI were highly heterogeneous without clear correlation with bulk tissue RNA expression. The clinical impact of discordant clinical receptor status and CTC receptor status warrants further exploration. Citation Format: K. V. Giridhar, W. C. Nenad, H. Ye, G. L. Wheeler, T. Hinoue, A. R. Michmerhuizen, B. M. Felsheim, U. R. Chandran, B. J. Kelly, E. R. Mardis, P. W. Laird, J. M. Balko, A. C. Garrido-Castro, S. Coppens, J. Bowen, R. Nanda, N. U. Lin, C. K. Anders, C. Isaacs, J. J. Tao, J. D. Anampa, N. Jahan, L. Huppert, A. DeMichele, B. H. Park, S. Vinayak, A. L. Delson, M. M. Magbanua, M. Balic, H. A. Parsons, A. V. Lee, L. A. Carey, L. Norton, A. C. Wolff, N. E. Davidson, I. Krop, T. A. King, C. M. Perou, K. A. Hoadley, Aurora US Metastases Network. Characterizing circulating tumor cell (CTC) enumeration and phenotypic profiling in blood with synchronously obtained tissue in metastatic breast cancer (MBC) in TBCRC /AURORA US [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 PS2-07-17.

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: 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.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

Abstract Introduction Understanding the tumor immune microenvironment (TIME) in multiple myeloma (MM) is critical for identifying prognostic biomarkers and therapeutic targets. We hypothesized that specific immune cell populations within the bone marrow TIME are associated with clinical outcomes and could enhance patient stratification. To this end, we conducted the largest CyTOF-based immune profiling study to date in MM, profiling &gt;300 million bone marrow immune cells from patients enrolled in the CoMMpass study. Methods We analyzed &gt;1,000 bone marrow samples from ~700 newly diagnosed MM patients enrolled in the MMRF CoMMpass study (NCT01454297), using a harmonized protocol and 41-antibody CyTOF panel at five academic centers. The majority were baseline samples (n=671), with additional samples spanning up to 3.5 years post-diagnosis (n&gt;300). Each site contributed ~200 samples on average. The cohort included 40% females, with a median age of 63 years and BMI of 27.8. ISS stages were evenly distributed (I: 36%, II: 36%, III: 29%), and 84% had ECOG 0-1. Autologous stem cell transplant was performed in 58% of patients, and 22% received maintenance therapy. Results We profiled 311 million single cells across the cohort, identifying major immune compartments: Neutrophils (36.0%), CD4 T cells (19.7%), NK cells (9.9%), monocytes (7.6%), B cells (5.7%), and CD8 T cells (5.6%). Less abundant populations included dendritic cells, γδ T cells, plasmablasts, and pDCs. In our preliminary analysis with multivariate cox regression modeling, we identified clinical factors including stem cell transplant, ISS stage, and ECOG status, as independent predictors of overall survival (OS). After adjusting for age and sex, higher proportions of naïve B cells, pDCs, and γδ T cells were independently associated with improved OS, while CD4+ T cell abundance was positively associated with prolonged progression-free survival (PFS). In contrast, elevated neutrophil proportions were significantly linked to inferior OS and demonstrated a trend toward shorter PFS. Longitudinal immune profiling in more than 200 patients identified a gradual accumulation of naïve B cells and a pronounced post-treatment rise in CD45+ plasmablasts, highlighting persistent B cell activity as a candidate mechanism for sustained therapeutic efficacy. Conclusion This study presents the largest immune proteomic atlas in MM to date, linking TIME composition to clinical outcomes. A favorable immune landscape was marked by preserved humoral immunity (naïve B cells, plasmablast expansion), enrichment of pDCs and γδ T cells, and lower neutrophil abundance, collectively associated with improved survival outcomes. These findings lay the groundwork for immune-guided prognostication and highlight new opportunities for therapeutic targeting in MM. Ongoing analyses aim to further resolve baseline and longitudinal immune dynamics in relation to treatment response.

ABSTRACT Purpose Abnormal restrictions at myofascial interfaces are a key factor in chronic low back pain (CLBP) with myofascial pain syndrome (MPS), but no established imaging method exists for quantitative assessment. This pilot study evaluated the clinical feasibility of MR elastography (MRE)‐based slip interface imaging (SII) for visualizing myofascial mobility in CLBP‐MPS patients versus age−/sex‐/BMI‐matched healthy participants. A new SII biomarker, maximal normalized displacement discontinuity (), was introduced, and the previously developed normalized octahedral shear strain (NOSS) map was used for comparison. Preliminary assessments of vibration‐frequency effects, repeatability, and group differences in inter‐muscular mobility were conducted. Methods MRE was conducted at 30, 60, and 90 Hz to compare with NOSS for visualizing inter‐muscular slip interfaces at the quadratus lumborum‐erector spinae (QL‐ES) and erector spinae‐multifidus (ES‐M) muscle boundaries at L3‐L4. Repeatability of and NOSS was assessed at 30 Hz (identified as the best‐performing frequency) using within‐subject coefficients of variation and a linear mixed‐effects model from within‐ and between‐day scans. Clinical feasibility was then assessed via Wilcoxon rank‐sum tests in six CLBP‐MPS patients and matched controls. Results at 30 Hz exhibited superior delineation of slip interfaces compared to higher frequencies and NOSS. demonstrated significantly lower variation and better repeatability than NOSS. Healthy participants showed continuous, well‐defined slip interfaces, whereas CLBP‐MPS patients displayed disrupted interfaces with significant mobility reduction at L4 ES‐M. Conclusion SII with lower vibration frequency and map enhances visualization of lower back myofascial mobility and shows potential for assessing differences between healthy individuals and CLBP‐MPS patients.