Associations of steroid-specific immunological phenotypes with tumor cell proliferation in breast cancer patients: CART analysis

Aim. To study the associations between IgA and IgG autoan tibodies against estradiol and progesterone (IgA1-E2 and IgA1 Pg; IgG1-E2 and IgG1-Pg) and the corresponding anti-idiotyp ic IgG autoantibodies (IgG2-E2 and IgG2-Pg) with tumor Ki-67 expression in breast cancer patients. Materials and Methods. Idiotypic and anti-idiotypic antibodies specific to steroid hor mones were studied in the sera of 1,115 postmenopausal women with breast cancer (stage I: 525 patients, stages II–IV: 590 pa tients) prior to treatment by enzyme-linked immunosorbent as say. Tumor Ki-67 expression was determined by an immunohis tochemical staining. Associations were analyzed using CART (Classification and Regression Tree) analysis. Results. Among patients with stage II–IV breast cancer, six groups with distinct individual combinations of antibody levels (immunological phe notypes) were identified, each associated with Ki-67 expression in tumors. High levels of Ki-67-positive cells in tumors (> 20 %) were found in: 1) 53.3 % patients with IgG₂-Pg ≤ 1.9+ IgA₁-Pg ≤ 2.2 + IgG2-E2 ≤ 4.1; 2) 85,0 % patients with IgG₂-Pg ≤ 1.9 + IgA₁-Pg ≤ 2.2 + IgG₂-E2 > 4.1 (p = 0.011 vs 1 group); 3) 87.2 % patients with IgG₂-Pg ≤ 1.9 + IgA₁-Pg > 2.2; 4) 82.7 % patients with IgG₂-Pg > 1.9 + IgA₁-Pg < 0.7; 5) 58.5 % patients with IgG₂-Pg = 1,9–4,1 + IgA₁-Pg > 0,7 (p = 0.012 vs 4 group); 6) 39.7 % patients with IgG₂-Pg > 4.1 + IgA₁-Pg > 0.7 (p = 0.008 vs 5 group). An increased proportion of patients with Ki-67 > 20 % at stages II–IV compared with stage I (p < 0.001) was ob served in groups 2, 3, 4, and 5. Suppression of tumor cell prolif eration was seen in groups 1 and 6. Conclusion. Enzyme-linked immunosorbent assay measurements of IgG₂-Pg, IgA₁-Pg, and IgG1-E2 may be useful for predicting tumor proliferative activ ity in stage I breast cancer patients during further disease pro gression.

1. Nielsen TO, Leung SCY, Rimm DL, Dodson A, Acs B, Badve S, et al. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst. 2021;113(7):808–819. https://doi.org/10.1093/jnci/djaa201

2. Kreipe H, Harbeck N, Christgen M. Clinical validity and clinical utility of Ki67 in early breast cancer. Ther Adv Med Oncol. 2022;14:1–10. https://doi.org/10.1177/17588359221122725

3. Zhang A, Wang X, Fan C, Mao X. The Role of Ki67 in Evaluating Neoadjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer. Front Endocrinol (Lausanne). 2021;12:687244. https://doi.org/10.3389/fendo.2021.687244

4. Hacking SM, Wang Y. Practical Issues of Ki-67 Evaluation in Breast Cancer Clinical Practice. J Clin Transl Pathol. 2022;2(2):53–56. https://doi.org/10.14218/jctp.2022.00012

5. Maselli A, Capoccia S, Pugliese P, Raggi C, Cirulli F, Fabi A, et al. Autoantibodies specific to estrogen receptor alpha act as estrogen agonists and their level correlate with breast cancer cell proliferation. Oncoimmunology. 2016;5(2):e1074375. http://dx.doi.org/10.1080/216240 2X.2015.1074375

6. Maselli A, Parlato S, Puglisi R, Raggi C, Spada M, Macchia D, et al. Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer. Cells. 2019;8(7):750. https://doi.org/10.3390/cells8070750

7. Glushkov AN, Polenok EG, Gordeeva LA, Mun SA, Kostyanko MV, Antonov AV, et al. Influence of autoantibodies to estradiol and progesterone on the blood serum hormones concentrations in postmenopausal healthy women and breast cancer patients. Asian Pac J Cancer Biol. 2022;7(2):115 120. https://doi.org/10.31557/APJCB.2022.7.2.115

8. Jerne NK. Idiotypic networks and other preconceived ideas. Immunol Rev. 1984;79:5–24. https://doi.org/10.1111/j.1600-065x.1984.tb00484.x

9. Glushkov AN, Polenok EG, Gordeeva LA, Bayramov PV, Verzhbitskaya NE, Antonov AV, et al. Antibodies and anti-antibodies specific to estradiol and progesterone and tumor proliferation in breast cancer patients. Siberian journal of oncology. 2024;23(3):73–85 (In Russ). https://doi.org/10.21294/1814-4861-2024-23-3-73-85

10. Spurgeon SE, Hsieh YC, Rivadinera A, Beer TM, Mori M, Garzotto M. Classification and regression tree analysis for the prediction of aggressive prostate cancer on biopsy. J Urol. 2006;175(3 Pt 1):918–922. https://doi.org/10.1016/S0022-5347(05)00353-8

11. Kong AL, Pezzin LE, Nattinger AB. Identifying patterns of breast cancer care provided at high-volume hospitals: a classification and regression tree analysis. Breast Cancer Res Treat. 2015;153(3):689–698. https://doi.org/10.1007/s10549-015-3561-6

12. Early Breast Cancer Trialists’ Collaborative group (EBCTCG). Trastuzum ab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139–1150. https://doi.org/10.1016/S1470-2045(21)00288-6.