Citations

Abstract Background: Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in breast cancer and other solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated [1]. While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy [2]. A2B395 is an allogeneic, logic-gated, EGFR-targeted, TmodTM CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells (with preserved HLA expression) while allowing activation against tumor cells (with HLA-A*02 loss of heterozygosity [LOH]). This approach is designed to avoid on-target, off-tumor toxicity, a significant limitation to CAR T treatment of solid tumors [3]. To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response [4]. Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy [5]. A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity. Methods: DENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including triple-negative breast, colorectal, non-small cell lung, squamous cell head and neck, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of the phase 1 portion is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm the RP2D and collect and analyze biomarker data. The Phase 2 portion will assess overall response rate per RECIST v1.1. As of 03 July 2025, the first patient dosed with A2B395, who has breast cancer, completed the 28-day safety review period. Dose-escalation is ongoing. Citation Format: J. M. Specht, S. R. Punekar, M. Ulrickson, D. J. Wong, J. R. Hecht, M. Maus, P. M. Grierson, J. B. Sunwoo, J. R. Molina, D. G. Maloney, K. Spencer, H. E. Fuentes Bayne, M. Davila, S. P. Patel, B. Creelan, D. B. Zhen, J. Niu, D. C. Prasad, R. L. Marar, N. A. Bagegni, G. Palluconi, J. Lee, A. Mardiros, W. Bretzlaff, W. J. Langeberg, J. S. Welch, E. Ng, W. Y. Go, K. Kirtane, R. A. Shatsky. Denali-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with triple-negative breast cancer and other EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (LOH) [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 PS5-08-03.

Abstract Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy (ET), freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after breast-conserving surgery (BCS) and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending ET for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen). A “low risk” MammaPrint is permissible if completed as part of usual care prior to screening. Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. As of July 9, 2025, 1,490 pts have been screened and 1,349 randomly assigned. NCT #: NCT04852887 Support: U10 CA180868, -180822, U24 CA196067, UG1 CA189867 Citation Format: J. R. White, R. S. Cecchini, E. E. Harris, E. P. Mamounas, J. G. Bazan, D. G. Stover, P. A. Ganz, R. Jagsi, S. J. Anderson, C. Bergom, V. Théberge, M. B. El-Tamer, R. C. Zellars, D. A. Shumway, G. Chen, T. B. Julian, N. Wolmark. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [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 PS5-08-20.

Abstract Background: Breast cancer (BC) chemoprevention with selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) remains underutilized among high-risk women. Improving knowledge about BC risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this BC risk reduction strategy. Methods: We conducted a cluster randomized controlled trial to evaluate the effectiveness of web-based patient and provider decision support, RealRisks and BNAV, to improve chemoprevention informed choice among women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS). Thirty-one sites, including academic and community practices across the U.S., were randomized to standard patient educational materials alone or combined with RealRisks and BNAV. A total of 412 patients and 210 healthcare providers were enrolled. Patient surveys were administered at baseline, 6 and 12 months. The primary outcome at 6 months was chemoprevention informed choice, defined as adequate chemoprevention knowledge and attitudes congruent with decision. Secondary endpoints included BC risk perceptions, worry, chemoprevention knowledge, decision conflict and chemoprevention decision. Assuming 10% loss to follow up (LTFU), roughly equal accrual across sites, and an intraclass coefficient (ICC) of 0.02, we had 90% power to detect a 15% absolute difference in informed choice if the event rate in the control arm was 10%. Results: Among 24 evaluable sites, 14 were randomized to the intervention arm and 10 to the control arm. Among 210 enrolled providers, median age was 46 (range, 28-83) and 78% were female; 75% physicians and 25% advanced practice providers/nurses; 53% medical oncologists, 29% surgeons, and 10% gynecologists/family practitioners/internists; and 83% had previously prescribed chemoprevention. Among 412 enrolled patients, median age was 53 (range, 35-74), including 77% White, 8% Black, and 10% Asian race, and 14% Hispanic ethnicity. In terms of BC risk factors, 77% had AH and 23% LCIS, 34% had a first-degree family history of BC, and 65% had heterogeneously or extremely dense breasts on mammography. Thirty percent were unevaluable for the primary endpoint (1% ineligible, 26% LTFU, 3% missing data). Among 288 evaluable patients (148 at intervention sites, 140 at control sites), the proportion of patients exercising informed choice at 6 months in the intervention and control arms was 35% vs. 27%, respectively (odds ratio [OR]=1.44, 95% confidence interval [CI]=0.84-2.46, p=0.19; observed ICC=0.006). Compared to patients in the control arm at 6 months, those in the intervention arm were more likely to have accurate BC risk perceptions (OR=1.80, 95% CI=1.11-2.91) and adequate chemoprevention knowledge (OR=1.62, 95% CI=1.00-2.61). We observed no significant differences in BC worry, decision conflict, or chemoprevention decision between study arms. At 6 months, 49% of women in the control arm and 51% in the intervention arm decided to take a SERM or AI for BC chemoprevention (p=0.58), a rate higher than anticipated. Conclusions: We did not observe a significant increase in informed choice among patients and providers assigned to chemoprevention decision support compared to standard educational materials alone. Among women with AH or LCIS seen mainly by breast specialists who prescribed chemoprevention, about half decided to take a SERM or AI. Therefore, relatively high chemoprevention uptake may be achieved among women with high-risk breast lesions managed by breast specialists. Chemoprevention decision support may improve decision antecedents, such as accurate BC risk perceptions and chemoprevention knowledge, but may have a limited role in changing health behaviors. Citation Format: K. D. Crew, G. L. Anderson, K. B. Arnold, A. Michel, M. T. DeLucie, C. W. Law, S. Pruthi, A. C. Sandoval Leon, R. Shirley, M. T. Grosse Perdekamp, S. V. Colonna, S. L. Krisher, T. King, L. D. Yee, T. J. Ballinger, C. Braun-Inglis, D. A. Mangino, K. B. Wisinski, C. A. DeYoung, M. Ross, J. D. Floyd, A. Kaster, L. VanderWalde, T. Saphner, C. Zarwan, S. Lo, C. Graham, A. K. Conlin, K. J. Yost, D. M. Agnese, C. Jernigan, D. L. Hershman, M. L. Neuhouser, J. A. Zell, B. Arun, R. Kukafka. Making informed choices on incorporating chemoprevention into care (MiCHOICE): Cluster randomized controlled trial of decision support for breast cancer chemoprevention, SWOG 1904 [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 PS3-01-15.

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: Metformin may impact tumorigenesis directly, through effects on AMP kinase, and indirectly, through reduction in circulating growth factors such as insulin. To examine the potential preventive effects of metformin, we analyzed MD, a known risk factor for breast cancer, in participants enrolled in the NCIC MA.32 trial, a randomized, placebo-controlled trial investigating the effects of 5 years of metformin on invasive disease-free survival in women with early breast cancer. The primary aim of this companion to MA.32 (Alliance A211201) was to examine the effects of 1 year of metformin vs placebo on MD in women treated for estrogen receptor negative (ER-) breast cancer. Methods: Eligible women were enrolled on MA.32, had ER- breast cancer, had >25% MD at baseline, and had an unaffected contralateral breast. MD was calculated on the contralateral breast using Cumulus software and analyzed at baseline, 1 and 2 years. The aim was to achieve a sample size of 274 (137 per arm), which would have at least 85% power to detect a 4% difference between study arms, i.e., 5% change from baseline to one year of treatment for metformin vs. 1% for placebo, using a two-sided two-sample t-test at a significance level of 5%. The current study was activated in the United States on 8/22/2012. Enrollment was halted on 10/13/2017 with 177 participants enrolled. Results: 146 women were evaluable (66 on metformin and 80 on placebo). The mean age of evaluable women was 53.6 years (standard deviation [SD] 9.4), 88.4% were white, 31.5% had a body mass index greater than or equal to 30 kg/m2, 99.3% of participants received chemotherapy. The proportions of white women and HER2+ participants in the metformin group were higher compared to placebo ([white 92.4% vs. 85.0%] and [HER2+ 21.2% vs. 11.3%], respectively). The mean MD at baseline was 22.7% (SD 14.1%) for the group as a whole (24.5% (SD 14.5%) for the metformin group and 21.2% (SD 13.6%) for the placebo group. This is lower than the eligibility criteria (>25%MD), due to difference in methods of calculation of MD (BIRADs for eligibility and Cumulus for study analysis). At 1 year, MD decreased by 0.7% (SD 7.6%) in the metformin group and 0.2% (SD 7.3%) in the placebo group (p = 0.58). At 2 years, MD decreased by 0.7% (SD 8.0%) in the metformin group and 0.8% (SD 7.1%) in the placebo group (p=0.60). Conclusions: In a cohort of women with early ER- breast cancer, there was no significant difference in the change in MD in women treated with metformin vs. placebo. There was a non-significant trend toward decreased MD while on metformin after 1 year of treatment. The arms were well balanced, though with more white and HER2+ participants in the metformin arm. The sample size for this study was about half of what was intended thus limiting power to detect a significant difference. Additional limitations include low mean MD, which may have limited our ability to detect the benefit in those at the highest risk, and further, the Cumulus method of MD determination can be imprecise. Interestingly, trends toward decreased MD with metformin were seen in Alliance A211102, and it might be reasonable to consider further study of metformin in a select population (highest MD or atypical hyperplasia). Support: UG1CA189823, U10CA180863, CCS 707213; https://acknowledgments.alliancefound.org.Clinicaltrials.gov ID: NCT01666171. Citation Format: M. Wood, M. I. Elsaid, L. J. Grimm, H. Liu, C. Oswold, C. S. Kuzma, I. Bedrosian, J. Ligibel, P. J. Goodwin. Change in mammographic density (MD) with metformin use: Alliance A211201, A companion study to NCIC study MA.32 [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 PS3-01-30.

Abstract IBC Clear: A decentralized multi-center MRD Registry for Inflammatory Breast CancerInflammatory breast cancer is an aggressive subtype of breast cancer with distinct clinical phenotypes, including early recurrence post-tri-modal care (neoadjuvant systemic therapy, surgery, adjuvant radiation). Preliminary data from MDACC have shown a high rate of baseline and serial MRD positivity in IBC patients (35-40% at 6-12 months post-surgery), suggesting that newly diagnosed IBC is an ideal population to test MRD as a standard of care and design adjuvant interventional trials. However, to date, our understanding of the optimal monitoring cadence and interventions following MRD positivity remains limited. IBC Clear is a decentralized protocol developed to collect real-world data from patients treated amongst our IBC Connect network of 19 US-based and three international institutions (7 of whom have expressed interest in participating). Patients who have had, or plan to have Signatera® ordered at the post-chemo/pre-surgery timepoint can self-enroll from the community by emailing IBCClear@mdanderson.org for information on the consent process. Study Design: Eligibility criteria include English-speaking patients > 18 years of age with a clinical diagnosis of IBC, with Signatera testing ordered or planned. The post-chemo/pre-surgery timepoint is the only study-mandated timepoint; however, any additional serial testing conducted before or after this timepoint will also be collected. Patients who have at least one Signatera test ordered and plan to have a pre-surgery/post-chemo collection as standard of care will be enrolled in a central REDCap database. Physicians enrolling patients may act on the results according to their clinical judgment, including imaging assessments and treatment changes. These interventions will be captured in the database. An electronic EORTC QLQ C30 survey will also be administered prior to and after receiving Signatera results to gather information about the impact of testing on the patient's quality of life. A total of 200 patients from all sites will be enrolled over a period of two years. Patients will be followed remotely for up to 2 years from the first Signatera test or until clinical recurrence, whichever comes first. Endpoints: Data collected will include the feasibility of decentralized data collection studies, as well as Signatera and recurrence information. The goals are to gather real-world data regarding the association of MRD positivity with pathologic response in IBC, patient-reported QOL for worry about recurrence, median lead time between the first MRD-positive result and clinical recurrence, and, if possible, whether the adjuvant therapies decrease the amount of MRD in IBC patients (pending optional longitudinal testing). Status of the study: The study was activated in June 2025. As of abstract submission, 2 patients have been enrolled at the lead site. Collaborating sites are being added. Sponsor: The University of Texas MD Anderson Cancer Center Clinicaltrials.gov Accession number: NCT06966050 Citation Format: A. Alexander, M. Kai, K. A. Abou-Hussein, S. Ali, C. Anderson, S. W. Bahadur, Y. C. Cheng, N. T. Ueno, X. Wang, A. Lucci, W. A. Woodward, S. Saleem, MDACC Inflammatory Breast Cancer Team. PS2-02-05: Ibc clear: a decentralized multi-center mrd registry for inflammatory 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 PS2-02-05.

Abstract Background: We have identified two potentially predictive signatures of palbociclib resistance: the RBsig, composed of E2F1/E2F2 dependent genes, which is associated with genetic loss of RB1, and the ratio between the gene expression levels of CCNE1 to RB1 (CCNE1/RB1). Both signatures have been previously analyzed in vitro and in neoadjuvant and metastatic studies with palbociclib. The present analysis aims to explore the role of RBsig and CCNE1/RB1 in the phase III adjuvant PALLAS trial, which randomized patients to palbociclib plus endocrine therapy, versus endocrine therapy alone. Materials and methods: Gene expression data from PALLAS were generated using the HTG EdgeSeq Oncology BM Panel. Of the 87 genes composing RBsig, 46 were available within the EdgeSeq dataset and were used for the analyses; CCNE1 and RB1 were both available. RBsig was calculated as the mean of the Z-score scaled gene expression (log) of the 46 genes; CCNE1/RB1 was computed as the log ratio between the mRNA expression of CCNE1 and RB1. The prognostic/predictive effect of the continuous signatures in terms of invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), and overall survival (OS) was evaluated using Cox proportional hazard models. Results: HTG data were available from 2,587 of 5,748 patients from the entire PALLAS intention-to-treat (ITT) cohort. As RBsig and CCNE1/RB1 levels are affected by pre-surgical treatments, we limited the analyses to 1612 pre-treatment samples (530 core biopsies and 1082 surgical specimens) (analysis population). Compared with the entire PALLAS ITT cohort, the analysis population was significantly enriched for patients with low clinical risk (41.3% vs 59.4%) who did not receive prior chemotherapy (17.5% vs 55.9%). In keeping with the PALLAS ITT cohort, no significant benefit from the addition of palbociclib was observed in the analysis population. Higher baseline RBsig or CCNE/RB1 values were significantly and independently associated with worse IDFS (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.3-2.0; HR 1.22, 95%CI 1.1-1.3, respectively), DRFS (HR 1.94, 95%CI 1.5-2.5; HR 1.26, 95%CI 1.1-1.4, respectively) and OS (HR 1.79, 95% CI 1.3-2.4; HR 1.26, 95%CI 1.1-1.4, respectively) in the analysis population. No predictive effect of palbociclib benefit was observed for either signature in the analysis population, nor according to clinical risk or chemotherapy receipt. Interestingly, higher RBsig was strongly prognostic in patients who did not receive adjuvant chemotherapy (HR 1.83, 95%CI 1.4-2.3) but not in those who received it (HR 1.01, 95%CI 0.6-1.6) (interaction p=0.02) suggesting a potential predictive role of RBsig for chemotherapy benefit. Conclusions: In the PALLAS trial, higher baseline RBsig or CCNE1/RB1 values are associated with worse prognosis, but are not predictive of benefit from palbociclib in the adjuvant setting. RBsig might be associated with differential benefit from chemotherapy. Further study of these biomarkers may strengthen their role in risk stratification.https://acknowledgments.alliancefound.org Citation Format: L. Malorni, D. Hlauschek, E. Mayer, M. Benelli, L. Biganzoli, I. Migliaccio, A. Kermanidis, G. Pfeiler, E. P. Mamounas, A. M. Brufsky, M. Bellet-Ezquerra, K. Clifton, G. Rubovszky, T. Foukakis, M. Goetz, S. Lee, M. Ruiz-Borrego, W. Symmans, K. V. Ballman, F. Liu, J. Machacek-Link, C. Denkert, A. DeMichele, M. Gnant. Prognostic and predictive role of RBsig and CCNE1/RB1 gene-expression signatures for patients with early breast cancer treated with endocrine therapy with or without palbociclib in the PALLAS trial (ABCSG-42, AFT-05, BIG 14-03) [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 PS2-07-13.

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 Background: BTX-9341 is a first-in-class bifunctional degrader of cyclin dependent kinase (CDK)4 and CDK6 that also inhibits the transcription of CDK2 and Cyclin E. Preclinical data highlight its superiority compared with approved CDK4/6 inhibitors (CDK4/6i) in inhibition of phosphorylation of retinoblastoma (p-RB), cell cycle arrest, and in vivo efficacy in breast cancer (BC) xenografts. BTX-9341 is active in CDK4/6i-resistant models with p-RB half-maximal inhibitory concentrations (IC50s) of 1-15 nM and can overcome key mechanisms that drive CDK4/6i resistance. Here we report early monotherapy data from the first-in-human study of BTX-9341 in patients (pts) with advanced and/or metastatic HR+/HER2- BC. Methods: BTX-9341-101 is a multicenter, nonrandomized, open-label trial to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of orally administered BTX-9341 in pts with RB1 wild type advanced and/or metastatic HR+/HER2- BC who received prior CDK4/6i therapy. An accelerated titration and Bayesian Optimal Interval design (BOIN) were used. The primary objective of dose escalation is to determine the maximum tolerated dose (MTD) or maximum evaluable dose (MED) of BTX-9341 monotherapy and in combination with fulvestrant. Secondary objectives include the characterization of BTX-9341 on PK and efficacy; exploratory objectives include the assessment of BTX-9341 on PD and PK/PD relationships. Results: As of June 9, 2025, 12 pts were evaluated at the following BTX-9341 once daily (QD) dose levels: 50 mg (dose level [DL]1), 100 mg (DL2), and 75 mg (DL3) monotherapy, and 50 mg in combination with fulvestrant (DLA). Pts received up to 4 lines of therapy in the metastatic setting prior to enrollment. No dose-limiting toxicities (DLTs) were observed at any dose levels during the 28-day DLT period. The most common adverse events (AEs) during the DLT period were decreased neutrophil and white blood cell counts (Grades 1-4). There were no dose reductions in DL1. The starting dose was reduced in all pts in DL2; DL3 is currently enrolling. At least 2-fold accumulation was observed after QD dosing, and steady-state trough concentrations were in the range of in vitro IC50 values at DL1 and higher dose levels. Serum thymidine kinase activity (sTKa), a clinical biomarker for tumor response to CDK4/6 inhibition, showed >50% reduction at Cycle 2 Day 1 (C2D1) compared with baseline for 7 of 8 evaluable monotherapy pts, with 6 pts below the sTKa detectable level. “On target” PD reductions in CDK4, CDK6, CDK2, and Cyclin E levels were observed in peripheral blood mononuclear cells. Of the 8 evaluable monotherapy pts, the best overall responses in pts with measurable disease included 1 pt with a confirmed partial response (PR) and 3 pts with stable disease ([SD] first assessed at 8 weeks; i.e., the first time point for assessment in the protocol), and in pts with non-measurable disease, 2 pts had non-complete response (CR)/non-progressive disease. For all pts, the longest duration on treatment was 10 cycles. A clinical benefit rate (defined as a best overall response of CR, PR, or SD for pts with measurable disease or non-CR/non-progressive disease for pts with non-measurable disease, per RECIST v1.1 at Week 24) of 66.7% was observed in the completed cohorts (DL1 and DL2). Conclusion: BTX-9341 monotherapy shows a favorable safety profile, with the most common AEs being decreased neutrophil and white blood cell counts, at doses that show encouraging preliminary PK/PD and efficacy, enabling further evaluation of monotherapy and in combination with fulvestrant. The trial is actively enrolling with anticipated completion of dose escalation enrollment by the end of 2025 (Clinical trial: NCT06515470). Citation Format: A. Patnaik, M. Block, M. Cristofanilli, Q. Liu, H. Majeski, A. Shakya, P. Rajagopalan, C. Deshpande, T. Marmon, S. Padam, D. Powell, A. H. Chourasia, R. Urbanski, M. Goetz, R. M. Layman. First-in-human Phase 1 study of BTX-9341, a CDK4/6 bifunctional degrader, as monotherapy and in combination with fulvestrant in patients with advanced and/or metastatic HR+/HER2- breast cancer - first emerging data [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 PS4-06-04.

Abstract Background Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in its estrogen receptor (ER) signaling pathways, response to systemic therapy, and imaging features. We evaluated differences in early change in the proliferation marker Ki67 and features on magnetic resonance imaging (MRI) after novel endocrine based neoadjuvant therapy in lobular versus non-lobular cases on the I-SPY2 EOP Trial. Methods EOP is a prospective, randomized NET trial enriched for patients with ILC. Patients with stage II-III ER positive HER2 negative breast cancer with low molecular risk (Mammaprint low or Mammaprint Hi1 plus high Sensitivity to Endocrine therapy Index) were randomized to one of several endocrine therapy-based arms. Treatment arms include novel oral SERDS with or without CDK4/6 inhibitor, aromatase inhibitors, and SERMs with or without ovarian function suppression in pre-menopausal patients. Patients undergo repeat core needle biopsy with central Ki67 assessment after 3 weeks of treatment and serial breast MRI. Here, we compare endocrine therapy responsiveness as measured by change in Ki67 at 3 weeks and functional tumor volume (FTV) on pre-surgical MRI in lobular versus non-lobular cases. Results We evaluated 253 patients of whom 148 (58.5%) had non-lobular cancer (93.9% IDC), and 105 (41.5%) had lobular cancer (17.1% mixed ILC/IDC). Overall, mean age was 53.3 years, 63.8% of tumors were grade 2, and 86.5% were Mammaprint (MP) Low with the remaining being Hi1, with higher rates of MP Low in the lobular versus non-lobular cohorts (92.4% versus 83.4%, p=0.0358). At baseline, tumors in the lobular cohort had significantly lower mean Ki67 than those in the non-lobular cohort (11.2% [SD 12.8] versus 16.4% [SD 14.4%], p=0.0038). Consistent with this, the proportion with baseline tumor Ki67 <10% was significantly higher in the lobular cohort than the ductal cohort (60.4% versus 39.3%, p=0.001). At 3-week biopsy, mean Ki67 remained lower in the lobular versus non-lobular group (3.4% versus 5.4%, respectively, p=0.0415). The proportion of patients with Ki67 <10% at 3 weeks did not differ significantly between lobular and non-lobular cases (88.6% versus 79.7%, respectively, p=0.08). Among the 40 lobular cases and 88 non-lobular cases with baseline Ki67 ≥10%, week 3 Ki67 decreased to <10% in 90% of lobular cases and 72.7% of non-lobular cases (p=0.07). On MRI, mean FTV at baseline was similar among lobular and non-lobular cases (21 cc3 versus 16.3 cc3). On pre-surgical MRI, patients in the lobular cohort had significantly higher mean residual FTV than those in the non-lobular cohort (5.7 cc3 versus 3.8 cc3, p=0.034). Interestingly, when splitting the lobular cohort into mixed lobular and pure lobular, mean residual MRI FTV was 7.5 cc3 in mixed cases and 3.8 cc3 in pure lobular cases, reflecting that FTV decreased the least in mixed lobular cases (decrease of 51.1% in mixed cases, 69.7% in pure lobular cases, and 73.9% in non-lobular cases, p=0.0255). Conclusions These results highlight differences in lobular versus non-lobular breast cancer. Lobular cases had lower baseline Ki67, and similar rates of decrease in Ki67 after 3 weeks of NET than non-lobular cases. Despite this, mean FTV after completion of 6 months of NET was higher in lobular tumors. These findings may reflect differences in early versus late indicators of response to NET, or differential response patterns by histology. Alternatively, standard response measures such as Ki67 and FTV may need lobular-specific modifications. Ongoing work includes central assessment of Ki67 from surgical specimens, analysis of changes in gene expression signatures, and evaluation of surgical outcomes such as breast conservation rates by histologic subtype. Citation Format: R. Mukhtar, P. Norwood, A. Borowsky, S. Alkhafaji, K. Giridhar, C. Vaklavas, A. Elias, M. Wei, M. Goetz, N. Onishi, O. Olopade, L. Van 't Veer, L. Huppert, W. F. Symmans, L. Brown Swigart, C. Wu, C. Yau, D. Yee, M. Magbanua, E. Price, N. Hylton, L. Esserman, J. Chien. Differential early response to neoadjuvant endocrine therapy in lobular versus non-lobular breast cancer on the Endocrine Optimization Pilot (EOP) of the I-SPY2 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 PS4-02-01.