Efficiency of combined endocrine therapy with CDK4/6 inhibitors in metastatic HR⁺/HER2^- breast cancer: Immunological aspects

Luminal HER2-negative subtypes of breast cancer have always attracted oncologists due to their sensitivity to low-toxicity hormone therapy. The emergence of new inhibitors of cyclin-dependent kinases has allowed hormone therapy to achieve optimal control of tumor growth, being prescribed even for visceral lesions. Recent advances in this area have provided novel mode of hormonal therapy as the first-line standard for extended HR⁺/HER2^- breast cancer. Evaluation of the relationship between tumor progression and immune surveillance was more often associated with the triple-negative subtype characterized by relatively high levels of mutational load and tumor-infiltrating lymphocytes. However, data from some studies suggest a possible relationship between immunity and luminal types of breast cancer. On the basis of these conclusions, the aim of our work was to evaluate different immunological and clinical factors in view of effectiveness of combined endocrine therapy with CDK4/6 inhibitors in metastatic luminal HR⁺/HER2^- breast cancer, primarily in the context of assessing immune deficiency conditions by the levels of T-cell receptor excision circles (TREC) and κ-deletion element of B cells (KREC). The study included 51 patients with luminal HER2-negative breast cancer who received combined endocrine therapy with CDK4/6 inhibitors. The results of the study indicated a decrease in TREC levels with increasing patients’ age. A decrease in the absolute number of TREC was noted in peripheral blood of patients with worse treatment outcomes, i.e., insufficient response to therapy, rapid progression or death, along with significant intercorrelation between lethal outcomes and low levels of B cell κ-deletion element (KREC) thus suggesting an important role of these immune factors in clinical prognosis. Hence, we consider prognostic significance of T cell receptor excision rings in the patients’ peripheral blood. This factor may affect treatment outcomes and survival rates.

1. Davydova N.V., Prodeus A.P., Obraztsov I.V., Kudlay D., Korsunsky I.A. Reference values for TREC and KREC concentrations in adults. Vrach = The Doctor, 2021, Vol. 32, no. 6, pp. 21-28. (In Russ.)

2. Kolyadina I.V. Following in the footsteps of SABCS 2022: top 12 advanced breast cancer studies that could change our clinical practice: A review. Sovremennaya onkologiya = Journal of Modern Oncology, 2023, Vol. 25, no. 1, pp. 46–54. (In Russ.)

3. Kolyadina I.V. Following in the footsteps of SABCS 2022: top 16 early breast cancer studies that could change our clinical practice: A review. Sovremennaya onkologiya = Journal of Modern Oncology, 2023, Vol. 25, no. 1, pp. 35-45. (In Russ.)

4. Kolyadina I.V. Escalation of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer: to whom, when and why? Opukholi zhenskoy reproduktivnoy systemy = Tumors of Female Reproductive System, 2024, Vol. 20, no. 1, pp. 89-103. (In Russ.)

5. Morozov D.A., Kolyadina .V., Poddubnaya I.V., Chumakov P.M., Ganshina I.P., Khokhlova S.V., Kometova V.V., Rodionov V.V. Relationship between TILs in biopsy material and the class of residual tumor load rcb after neoadjuvant chemotherapy in patients with aggressive subtypes of stage II–III breast cancer. Voprosy onkologii = Issues of Oncology, 2022, Vol. 68, no. S3, pp. 370-371. (In Russ.)

6. Novikova E.A., Krokholev V.Y., Kostromina O.V., Demidov S.M., Sazonov S.V. Age-Related Features of the Distribution of the Frequency of Occurrence of Luminal A Molecular-Biological Subtype of Breast Cancer. Vestnik uralskoy meditsinskoy akademicheskoy nauki = Journal of Ural Medical Academic Science, 2021, Vol. 18, no. 1, pp. 35-42. (In Russ.)

7. Semiglazov V.F., Krivorotko P.V., Semiglazova T.Y., Artamonova E.V., Artemyeva A.S., Bagrova S.G., Bolotina L.V., Bit-Sava E.M., Bozhok A.A., Vladimirova L.Yu., Gorbunova V.A., Geokchyan-Kzhdryan A.K., Dengina N.V., Zhukova L.G., Zakiryakhodzhaev A.D., Imyanitov E.N., Kolyadina I.V., Koroleva I.A., Kudaibergenova A.G., Manikhas A.G., Novikov S.N., Orlova R.V., Paltuev R.M., Petrovsky A.V., Parokonnaya A.A., Portnoy S.M., Raskin G.A., Rodionov V.V., Savelov N.A., Semiglazov V.V., Stenina M.B., Smagulova K.K., Stroyakovsky D.L., Topuzov E.E., Trofimova O.P., Frolova M.A., Khodorovich O.S., Shatova Yu.S. I St. Petersburg International Consensus on the Diagnosis and Treatment of Breast Cancer “White Nights 2024”. Voprosy onkologii = Issues of Oncology, Vol. 70, no. 6, pp. 1175-1188. (In Russ.)

8. Sultanbaev A.V., Kolyadina I.V., Nasretdinov A.F., Menshikov K.V., Askarov V.E., Musin S.I., Akhmetgareeva K.T., Sultanbaeva N.I., Zabelin V.M., Ayupov R.T., Izmailov A.A. Palbociclib in real clinical practice: Results of a single-center observational study. Meditsinskiy sovet = Medical Council, 2024, Vol. 18, no. 21, pp. 42-50. (In Russ.)

9. Sultanbaev A.V., Kolyadina I.V., Menshikov K.V., Musin Sh.I., Nasretdinov A.F., Sultanbaeva N.I., Rakhimov R.R., Lipatov D.O., Menshikova I.A., Izmailov A.A., Lipatova E.E. Efficacy and safety of alpelisib in patients with HR+ HER2-negative metastatic breast cancer in real clinical practice: Results of a single-center observational retrospective study. Sovremennaya onkologiya = Journal of Modern Oncology, 2024, Vol. 26, no. 1, pp. 65-72. (In Russ.)

10. Sultanbaev A.V., Tuzankina I.A., Musin Sh.I., Kolyadina I.V., Menshikov K.V., Sultanbaev M.V., Gilyazova I.R., Kudlay D.A. Specific antitumour immunity and mechanisms of tumour escape from immunological surveillance. Onkologiya. Zhurnal im. P.A. Gertsena = P.A. Herzen Journal of Oncology, 2024, Vol. 13, no. 6, pp. 70-77. (In Russ.)

11. Cha S.M., Park J.W., Lee Y.J., Lee H.J., Lee H., Lee I.W., Gong G., Park S.H., Lee H J., Jeong, B.K. SPP1+ macrophages in HR+ breast cancer are associated with tumor-infiltrating lymphocytes. NPJ Breast Cancer, 2024, Vol. 10, no. 1, 83. doi: 10.1038/s41523-024-00695-7.

12. Goel S., DeCristo M.J., Watt A.C., BrinJones H., Sceneay J., Li B.B., Khan N., Ubellacker J.M., Xie S., MetzgerFilho O., Hoog J., Ellis M.J., Ma C.X., Ramm S., Krop I.E., Winer E.P., Roberts T.M., Kim H.J., McAllister S.S., Zhao J.J. CDK4/6 inhibition triggers anti-tumour immunity. Nature, 2017, Vol. 548, no. 7668, pp. 471-475.

13. Goldberg J., Pastorello R.G., Vallius T., Davis J., Cui Y.X., Agudo J., Waks A.G., Keenan T., McAllister S.S., Tolaney S.M., Mittendorf E.A., Guerriero J.L. The Immunology of Hormone Receptor Positive Breast Cancer. Front. Immunol., 2021, Vol. 12, 674192. doi: 10.3389/fimmu.2021.674192.

14. Hoolehan W., Harris J.C., Byrum J.N., Simpson D.A., Rodgers K.K. An updated definition of V(D)J recombination signal sequences revealed by high-throughput recombination assays. Nucleic Acids Res., 2022, Vol. 50, no. 20, pp. 11696-11711.

15. Hrubesz G., Leigh J., Ng T.L. Understanding the relationship between breast cancer, immune checkpoint inhibitors, and gut microbiota: a narrative review. Transl. Breast Cancer Res., 2024, Vol. 5, 31. doi: 10.21037/tbcr24-14.

16. Kwok J.S.Y., Cheung S.K.F., Ho J.C.Y., Tang I.W.H., Chu P.W.K., Leung E.Y.S., Lee P.P.W., Cheuk D.K.L., Lee V., Ip P., Lau Y.L. Establishing Simultaneous T Cell Receptor Excision Circles (TREC) and K-Deleting Recombination Excision Circles (KREC) Quantification Assays and Laboratory Reference Intervals in Healthy Individuals of Different Age Groups in Hong Kong. Front. Immunol., 2020, Vol. 11, 1411. doi: 10.3389/fimmu.2020.01411.

17. Loibl S., Poortmans P., Morrow M., Denkert C., Curigliano G. Breast cancer. Lancet, 2021, Vol. 397, no. 10286, pp. 1750-1769.

18. Masuda J., Sakai H., Tsurutani J., Tanabe Y., Masuda N., Iwasa T., Takahashi M., Futamura M., Matsumoto K., Aogi K., Iwata H., Hosonaga M., Mukohara T., Yoshimura K., Imamura C.K., Miura S., Yamochi T., Kawabata H., Yasojima H., Tomioka N., Takano T. Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial). J. Immunother. Cancer, 2023, Vol. 11, no. 9, e007126. doi: 10.1136/jitc2023-007126.

19. Nanda R., Liu M.C., Yau C., Asare S., Hylton N., Van't Veer L., Perlmutter J., Wallace A.M., Chien A.J., Forero-Torres A., Ellis E., Han H., Clark A.S., Albain K.S., Boughey J.C., Elias A.D., Berry D.A., Yee D., DeMichele A., Esserman L. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2. J. Clin. Oncol., 2017, Vol. 35, no. 15 Suppl., 506. doi: 10.1200/JCO.2017.35.15_suppl.506.

20. Rugo H.S., Kabos P., Beck J.T., Jerusalem G., Wildiers H., Sevillano E., Paz-Ares L., Chisamore M.J., Chapman S.C., Hossain A.M., Chen Y., Tolaney S.M. Abemaciclib in combination with pembrolizumab for HR+, HER2- metastatic breast cancer: Phase 1b study. NPJ Breast Cancer, 2022, Vol. 8, no. 1, 118. doi: 10.1038/s41523-022-00482-2.

21. Savas P., Salgado R., Denkert C., Sotiriou C., Darcy P.K., Smyth M.J., Loi S. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat. Rev. Clin. Oncol., 2016, Vol. 13, no. 4, pp. 228-241.

22. Schaer D.A., Beckmann R.P., Dempsey J.A., Huber L., Forest A., Amaladas N., Li Y., Wang Y.C., Rasmussen E.R., Chin D., Capen A., Carpenito C., Staschke K.A., Chung L.A., Litchfield L.M., Merzoug F.F., Gong X., Iversen P.W., Buchanan S., de Dios A., Novosiadly R.D., Kalos M. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep., 2018, Vol. 22, no. 11, pp. 2978-2994.

23. Stanton S.E., Adams S., Disis M.L. Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review. JAMA Oncol., 2016, Vol. 2, no. 10, pp. 1354-1360.

24. Sultanbaev A.V., Kolyadina I.V., Sultanbaev M., Musin Sh., Menshikov K., Sultanbaeva N., Kudlay D., Tuzankina I. Options for enhancing specific antitumor immunity in patients with melanoma. J. Clin. Oncol., 2024, Vol. 42, no. 16 Suppl., e21547. doi: 10.1200/JCO.2024.42.16_suppl.e21547.