Rugo, H. S.

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.