Integrated Immunomorphological and Molecular Profiling Predicts Response to Neoadjuvant Therapy in Breast Cancer

ORIGINAL ARTICLE
S.V. Vtorushin, N.A. Tarabanovskaya, N.V. Krakhmal, S.S. Naumov, N.V. Litviakov

 

For citation: Vtorushin SV, Tarabanovskaya NA, Krakhmal NV, Naumov SS, Litviakov NV. Integrated Immunomorphological and Molecular Profiling Predicts Response to Neoadjuvant Therapy in Breast Cancer. International Journal of Biomedicine. 2026;16(3):346-351. doi:10.21103/Article16(3)_OA3

Originally published September 5, 2026

Abstract: 

Background: To investigate whether integrating assessment of the tumor immune microenvironment with molecular genetic alterations improves prediction of response to neoadjuvant systemic therapy in patients with invasive breast cancer.

Methods and Results: This retrospective study included 23 patients with invasive breast cancer treated at the Cancer Research Institute, Tomsk National Research Medical Center, from 2023 to 2025. All patients received neoadjuvant systemic therapy followed by surgery. Pathological response was assessed using the Residual Cancer Burden (RCB) system. Pretreatment tumor specimens were analyzed for stromal tumor-infiltrating lymphocytes, immune cell subsets and ratios, immune phenotype, immunosuppressive index, and copy number alterations in genes associated with chemotherapy response and drug resistance. Pathologic complete response (pCR; RCB-0) was achieved in 17 patients (73.9%), and a favorable pathological response (RCB-0/I) was observed in 19 patients (82.6%). Individual immune cell populations showed limited predictive value, whereas integrated immune parameters demonstrated stronger associations with treatment response. Patients with a favorable response had significantly higher CD8/FOXP3 ratios (4.07 vs. 1.72, p = 0.0002), lower FOXP3/CD8 ratios (0.25 vs. 0.58, p = 0.002), and lower CD68-positive macrophage infiltration (42 vs. 66.5 cells/HPF, p = 0.023). An inflamed immune phenotype and a low immunosuppressive index were associated with the highest probability of achieving pCR. Although no individual copy number alteration independently predicted treatment response, alterations involving TUBB3, ERBB2, and TOP2A were significantly associated with distinct tumor immune microenvironment characteristics.

Conclusions: Integrated assessment of the tumor immune microenvironment provides greater predictive value for neoadjuvant treatment response than evaluation of individual immune biomarkers alone. The observed associations between genomic alterations and immune microenvironment characteristics suggest that molecular alterations may influence therapeutic sensitivity through immune remodeling. Integrated immunomorphological and molecular profiling represents a promising strategy for predicting treatment response and personalizing neoadjuvant therapy in breast cancer.

Keywords: 
breast cancer • neoadjuvant therapy • pathological complete response • tumor immune microenvironment • immune profiling • copy number alterations • predictive biomarkers • personalized medicine
References: 
  1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024 Jan-Feb;74(1):12-49. doi: 10.3322/caac.21820. PMID: 38230766.
  2. Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet. 2021 May 8;397(10286):1750-1769. doi: 10.1016/S0140-6736(20)32381-3. PMID: 33812473.
  3. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014 Jul 12;384(9938):164-172. doi: 10.1016/S0140-6736(13)62422-8. PMID: 24529560.
  4. Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, Smith BL, Alexander B, Moy B, Isakoff SJ, Parmigiani G, Trippa L, Bardia A. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: A comprehensive meta-analysis. Clin Cancer Res. 2020 Jun 15;26(12):2838-2848. doi: 10.1158/1078-0432.CCR-19-3492. PMID:32046998. PMCID: PMC7299787.
  5. Xia G, Zhang Z, Jiang Q, Wang H, Wang J. Predictive value of stromal tumor-infiltrating lymphocytes in patients with breast cancer treated with neoadjuvant chemotherapy: A meta-analysis. Medicine (Baltimore). 2024 Feb 9;103(6):e36810. doi: 10.1097/MD.0000000000036810. PMID: 38335394.
  6. Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B, Fumoleau P, Ghiringhelli F. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating FOXP3+ regulatory T cells. Clin Cancer Res. 2008 Apr 15;14(8):2413-2420. doi: 10.1158/1078-0432.CCR-07-4491. PMID: 18413832.
  7. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018 May;24(5):541-550. doi: 10.1038/s41591-018-0014-x. PMID: 29686425.
  8. Myers SP, Sevilimedu V, Barrio AV, Tadros AB, Mamtani A, Robson ME, Morrow M, Lee MK. Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers. NPJ Breast Cancer. 2024 Jul 26;10(1):63. doi: 10.1038/s41523-024-00674-y. PMID:39060255.
  9. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-4422. doi: 10.1200/JCO.2007.10.6823. PMID: 17785706.
  10. Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, D’Alfonso TM, Demaria S, Castaneda C, Sanchez J, Badve S, Michiels S, Bossuyt V, Rojo F, Singh B, Nielsen T, Viale G, Kim SR, Hewitt S, Wienert S, Loibl S, Rimm D, Symmans F, Denkert C, Adams S, Loi S, Salgado R; International Immuno-Oncology Biomarker Working Group on Breast Cancer. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol. 2018 Oct;52(Pt 2):16-25. doi: 10.1016/j.semcancer.2017.10.003. PMID: 29024776.
  11. Schlam I, Loi S, Salgado R, Swain SM. Tumor-infiltrating lymphocytes in HER2-positive breast cancer: potential impact and challenges. ESMO Open. 2025 Feb;10(2):104120. doi: 10.1016/j.esmoop.2024.104120. PMID:39826475.

Download Article

Received July 10, 2026.
Accepted August 23, 2026.
© 2026 The Author(s). International Journal of Biomedicine is published by IMRDC. This is an open access article under the CC BY-NC-ND 4.0 license.