Abstract PS1-01-05: Pneumonitis but not other immune related adverse events (irAEs) associate with pre-treatment immune signatures in early-stage breast cancer patients receiving neoadjuvant immunotherapy (IO): results from 5 IO arms in I-SPY2

Abstract Background Neoadjuvant immunotherapy has become standard of care for triple negative (TN) breast cancer; and I-SPY2 and other trials have shown efficacy of IO in HR+HER2-, especially in immune+ subsets. However, IO agents carry risk of immune-related toxicities, some long-term. Previously we developed Imprint, an IDE-enabled immune classifier predicting response to IO now being used in I-SPY2.2 as part of the Response Predictive Subtypes. Here we pool irAE data from 5 IO arms in I-SPY2, where both TN and HR+HER2- patients enrolled, to assess whether irAE development may be predicted by gene expression signatures in pre-treatment tumor biopsies. Long-term, the goal is to develop clinical decision support tools to help balance likelihood of response to IO with likelihood of irAE development. Methods 356 patients (206 HR+HER2- and 150 TN) across 5 IO arms (69 pembrolizumab (Pembro), 76 Pembro/SD101, 73 durvalumab/olaparib, 62 cemiplimab (Cemi), and 78 Cemi/LAG3) with irAE and pCR data were analyzed. irAEs considered included adrenal insufficiency (10%; n=36), colitis (2.3%; n=8), diabetes mellitus (0.3%; n=1), hyperthyroidism (4.2%; n=15), hypothyroidism (15%; n=53), hypophysitis (1% ; n=4), pneumotitis (5.3%; n=19), and thyroiditis (1.4%; n=5) (unresolved grade 1 or grades 2/3). 32 mostly-immune (7 immune checkpoints, 14 immune cells, 3 TcClassII, 4 chemokine/cytokine, 1 interferon, 1 TGFB, 1 ESR1/PGR, and 1 proliferation) genes/signatures were evaluated from pre-treatment mRNA from Agilent 44K arrays for 344 patients. Associations between irAEs (overall/any and individual) and signatures were assessed using logistic regression, overall and within HR+HER2-, TN, and ImPrint+/- subsets. P-values were adjusted for multiple hypothesis testing using the Benjamini-Hochberg method (significance BH p<0.05). Results 31% (109/356) patients over the 5 IO arms had at least one irAE; and some patients had 2 (7%; 24/356), 3 (2%; 7/356), or 4 irAEs (1/356) (150 irAEs were distributed over 109 patients). irAE prevalence ranged from 19% to 44% by IO arm, with the highest prevalence in dual-IO arms. Prevalence of irAEs did not differ significantly between HR+HER2- and TN (OR=1.2 [0.7-2]); nor between ImPrint- and ImPrint+ (OR=1.01 [0.6-1.7]). irAEs (any: yes/no) also did not differ between responders and non-responders (OR=1.14 [0.7-1.84]). Pneumonitis, but not other irAEs nor the composite irAE vector, significantly associated with multiple signatures. 19/32 signatures, all immune, significantly associated with pneumonitis in the population as a whole (BH p<0.05). These include higher levels of immune checkpoints (e.g., CD274 (PDL1) and PDCD1 (PD1)), cell populations (e.g., T-cells and B-cells), TcClassII (e.g., ICS5 and Module4_Immune), and chemokine/cytokine signatures (CK12, TIS, and Geparsixto); and lower levels of TGFB (all BH p<0.05). Subset analysis revealed these associations to be subtype specific, restricted to patients with ImPrint+ tumors (38%). PD1 mRNA levels predict pneumonitis in this group; with an AUC=0.84, sensitivity=67% and specificity=91%. For patients with ImPrint- tumors, there were no associations between irAEs and any tested signatures. Conclusion ∼30% of patients treated with neoadjuvant IO and standard chemotherapy developed an irAE. irAEs did not associate with subtype or IO response. Pneumonitis, but no other irAE, associated with pre-treatment immune signatures. This association was observed exclusively in patients with ImPrint+ tumors, where PD1 mRNA levels predicted pneumonitis. mRNA signatures may help enable early identification and treatment of IO patients likely to develop pneumonitis. Citation Format: D. M. Wolf, H. Rugo, R. Nanda, S. Umashankar, C. Yau, M. Campbell, R. Sayaman, M. Magbanua, L. Brown-Swigart, G. Hirst, A. Glas, I-SPY Investigators, L. Huppert, F. Symmans, S. Borowsky, P. Pohlmann, A. Clark, E. Stringer-Reasor, M. Liu, H. Han, H. Soliman, J. Chien, R. Shatsky, C. Isaacs, D. Yee, A. DeMichele, J. Perlmutter, L. Pusztai, Z. Quandt, R. Cohen, L. van 't Veer, L. Esserman, A. Basu. Pneumonitis but not other immune related adverse events (irAEs) associate with pre-treatment immune signatures in early-stage breast cancer patients receiving neoadjuvant immunotherapy (IO): results from 5 IO arms in I-SPY2 [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 PS1-01-05.