Abstract 2036: Transcriptomic immune signatures and reconstructed immune cell types associated with pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer

Abstract Background: Pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) is positively correlated with long-term event-free survival and overall survival in patients with triple-negative breast cancer (TNBC). However, the molecular subtypes of TNBC associated with pCR remain to be elucidated. Methods: We conducted a transcriptomic and clinical outcome analysis of 28 TNBC patients who underwent surgery following NAC at Hokkaido University Hospital and Hokkaido Cancer Center in Japan between 2017 and 2022. The research protocol was approved by the Internal Review Board at the medical institutes and BostonGene (023-0109). We used an internally developed algorithm (Breast Cancer Classifier, BCC) to classify tumors into 5 intrinsic subtypes: Basal, Luminal A (LumA), Luminal B (LumB), HER2 high, and HER2-low. Using methods described by Bagaev et. al. (Cancer Cell, 2021), we selected 21 functional gene expression signatures to identify tumor microenvironment (TME) subtypes. Next, we used deconvolution by Kassandra algorithm for precise reconstruction of TME. The Mann-Whitney U test and chi-square test with Benjamini-Hochberg correction were used for statistical analysis. Results: Twelve patients achieved pCR, with a median age of 53 years, while 16 were non-pCR with a median age of 63 years. The clinical stages at diagnosis in the pCR group were stage I (n=3), stage II (n=7), and stage Ill (n=2), while the non-pCR group included stage II (n=7), and stage Ill (n=9). Anthracycline followed by taxane regimens were administered to 8 pCR and 13 non-pCR patients, and the remainder received investigational regimens as clinical trials. HER2 scores of 0, 1+ and 2+ were observed in 14, 5, and 9 patients, respectively. BCC revealed 54% (15/28) of patients had basal-like and 25% (7/28) had HER2-low TNBC. It also classified 12% (3/28) as having LumA and another 12% (3/28) as having LumB TNBC. The pCR rates across these subtypes were 53%, 43%, 33%, and 66%, respectively. Kassandra identified 4 TME subtypes: Immune-Enriched, Fibrotic (IE/F); Immune-Enriched, Non-Fibrotic (IE); Fibrotic (F); and Immune-Desert (D). Notably, 11 of 12 pCR patients exhibited the IE subtype, while the non-pCR group displayed a heterogeneous distribution of TME subtypes. Gene signatures of tertiary lymphoid structures were upregulated in pCR patients. Kassandra revealed increased infiltration of T cells, B cells, and NK cells in the TME of pCR patients, corroborated by the presence of lymphocyte clusters in hematoxylin and eosin staining. Conclusion: Our study demonstrates that BostonGene’s TME subtyping and Kassandra can accurately identify TNBC patients likely to achieve pCR after NAC. These findings warrant further prospective evaluation to establish the utility of these approaches in predicting treatment response in TNBC. Citation Format: Tomohiro Oshino, Takuro Noguchi, Nobumoto Tomioka, Kanako.C Hatanaka, Anastasiya Evdokimova, Polina Turova, Vladimir Kushnarev, Nikita Kotlov, Konstantin Chernyshov, Zlata Polyakova, Kirill Kryukov, Anastasiya Makarova, Mitsuchika Hosoda, Shin Ariga, Rika Moku, Yukimasa Shiotsu, Yutaka Hatanaka, Ichiro Kinoshita, Masato Takahashi. Transcriptomic immune signatures and reconstructed immune cell types associated with pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2036.