Analysis of the clinical efficacy of the cyclin- dependent kinase inhibitor 4/6 Abemaciclib on the clinical case of a male with hormonereceptor- positive breast cancer

The treatment of advanced hormone- receptor-positive (HR+) breast cancer (BC) is a rather difficult task due to the emergence of resistance to the standard treatment regimen – endocrine therapy. This circumstance has led to the investigation of the role of the tumor microenvironment in the tumor response and the realization of the treatment efficiency. A new class of antitumor drugs – inhibitors of cyclin- dependent kinases 4/6 (CDK 4/6) in combination with endocrine therapy demonstrates the efficiency in prolonging the progression free survival and significantly delays the time of cytotoxic therapy administration. In this case,an additional mechanism of tumor regression, besides inhibition of cell cycle of tumor cells is the influence on the cellular component of the tumor microenvironment. Thus, according to preclinical data and results of clinical studies, an increase in the immunogenicity of the tumor and the activation of the antitumor immune response was established. This unique mechanism can be used as a strategy to increase the efficiency of antitumor drugs prescribed in later lines, as well as to increase sensitivity to immune checkpoint inhibitors. The article presents an analysis of the clinical efficiency of an aromatase inhibitor in combination with a CDK 4/6 - inhibitor Abemaciclib in male with HR-positive breast cancer. At the same time, the appointment of aromatase inhibitors in the presented clinical case is very justified due to the possible genetic violation of the metabolism of sex hormones, taking into account the pathophysiological bases of male gynecomastia. Despite the lack of an objective response to combination therapy, the patient has a long-term stabilization. This may be due to an increase in the immunoreactivity of the tumor, a cumulative effect with the development of senescence of tumor cells and subsequent apoptosis. Also, it is very likely that after the use of the CDK 4/6 inhibitor Abemaciclib, cytotoxic chemotherapy drugs will show greater effectiveness due to the actively altered immunoreactivity of the tumor microenvironment. 

1. Pondé N.F., Zardavas D., Piccart M. Progress in Adjuvant Systemic Therapy for Breast Cancer. Nat Rev Clin Oncol. 2019;16(1):27–44. doi: 10.1038/ s41571-018-0089-9.

2. Diaz Bessone M.I., Gattas M.J., Laporte T., Tanaka M., Simian M. The Tumor Microenvironment as a Regulator of Endocrine Resistance in Breast Cancer. Front Endocrinol (Lausanne). 2019;10:547. doi: 10.3389/fendo.2019.00547 .

3. Dickler M.N., Tolaney S.M., Rugo H.S., Cortes J., Dieras V., Patt D. et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, As a Single Agent, in Patients with Refractory HRþ/HER2- Metastatic Breast Cancer. Clin Cancer Res. 2017;23(17):5218–5224. doi: 10.1158/1078-0432.ccr-17-0754.

4. Sledge G.W. Jr., Toi M., Neven P., Sohn J., Inoue K., Pivot X. et al. MONARCH 2: Abemaciclib in Combination with Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clinical Oncology. 2017;35(25):2875–2884. doi: 10.1200/ jco.2017.73.7585.

5. Sledge G.W. Jr., Toi M., Neven P., Sohn J., Inoue K., Pivot X. et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor- Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy- MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2020;6(1):116–124. doi: 10.1001/jamaoncol.2019.4782.

6. Johnston S., Martin M., Di Leo A., Im S.-A., Awada A., Forrester T. et al. MONARCH 3 Final PFS: A Randomized Study of Abemaciclib as Initial Therapy for Advanced Breast Cancer. NPJ Breast Cancer. 2019;5:5. doi: 10.1038/s41523-018-0097-z.

7. Ruffell B., Coussens L.M. Macrophages and Therapeutic Resistance in Cancer. Cancer Cell. 2015;27(4):462–472. doi: 10.1016/j.ccell.2015.02.015.

8. DeNardo D.G., Brennan D.J., Rexhepaj E., Ruffell B., Shiao S.L., Madden S.F. et al. Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to chemotherapy. Cancer Discov. 2011;1(1):54–67. doi: 10.1158/2159-8274.cd-10-0028.

9. Zhang B., Cao M., He Y., Liu Y., Zhang G., Yang C. et al. Increased Circulating M2-Like Monocytes in Patients with Breast Cancer. Tumour Biol. 2017;39(6):1010428317711571. doi: 10.1177/1010428317711571.

10. Miyasato Y., Shiota T., Ohnishi K., Pan C., Yano H., Horlad H. et al. High Density of CD204-Positive Macrophages Predicts Worse Clinical Prognosis in Patients with Breast Cancer. Cancer Sci. 2017;108(8):1693–700. doi: 10.1111/cas.13287 .

11. Ogba N., Manning N.G., Bliesner B.S., Ambler S.K., Haughian J.M., Pinto M.P. et al. Luminal Breast Cancer Metastases and Tumor Arousal from Dormancy Are Promoted by Direct Actions of Estradiol and Progesterone on the Malignant Cells. Breast Cancer Res. 2014;16(6):489. doi: 10.1186/ s13058-014-0489-4.

12. Rugo H.S., Delord J.P, Im S.A, Ott P.A., Piha- Paul S.A., Bedard P.L. et al. Safety and Antitumor Activity of Pembrolizumab in Patients with Estrogen Receptor- Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer. Clin Cancer Res. 2018;24(12):2804–2811. doi: 10.1158/1078-0432.ccr-17-3452.

13. Liu L., Shen Y., Zhu X., Lv R., Li S., Zhang Z. et al. ERα Is a Negative Regulator of PD-L1 Gene Transcription in Breast Cancer. Biochem Biophys Res Commun. 2018;505(1):157–161. doi: 10.1016/j.bbrc.2018.09.005.

14. Joffroy C.M., Buck M.B., Stope M.B., Popp S.L., Pfizenmaier K., Knabbe C. Antiestrogens Induce Transforming Growth Factor beta- Mediated Immunosuppression in Breast Cancer. Cancer Res. 2010;70(4):1314–1322. doi: 10.1158/0008-5472.can-09-3292.

15. Pontiggia O., Sampayo R., Raffo D., Motter A., Xu R., Bissell M.J. et al. The Tumor Microenvironment Modulates Tamoxifen Resistance in Breast Cancer: A Role for Soluble Stromal Factors and Fibronectin Through Beta1 Integrin. Breast Cancer Res Treat. 2012;133(2):459–471. doi: 10.1007/s10549-011-1766-x.

16. Brechbuhl H.M., Finlay- Schultz J., Yamamoto T.M., Gillen A.E., Cittelly D.M., Tan A.C. et al. Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen. Clin Cancer Res. 2017;23(7):1710–1721. doi: 10.1158/1078-0432.ccr-15-2851.

17. Patnaik A., Rosen L.S., Tolaney S.M., Tolcher A.W., Goldman J.W., Gandhi L. et al. Efficacy and Safety of Abemaciclib, An Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non- Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov. 2016;6(7):740–753. doi: 10.1158/2159-8290. cd-16-0095.

18. Torres- Guzmán R., Calsina B., Hermoso A., Baquero C., Alvarez B., Amat J. et al. Preclinical Characterization of Abemaciclib in Hormone Receptor Positive Breast Cancer. Oncotarget. 2017;8(41):69493–69507. doi: 10.18632/oncotarget.17778.

19. Muñoz- Espín D., Serrano M. Cellular Senescence: from Physiology to Pathology. Nat Rev Mol Cell Biol. 2014;15(7):482–496. doi: 10.1038/ nrm3823.

20. Schaer D.A., Beckmann R.P., Dempsey J.A., Huber L., Forest A., Amaladas N. et al. The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade. Cell Rep. 2018;22(11):2978–2994. doi: 10.1016/j.celrep.2018.02.053.

21. Deng T., Wang J., Jenkins E.S., Li R.W., Dries S., Yates R.K. et al. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Disc. 2018;8(2):216–233. doi: 10.1158/2159-8290.cd-17-0915.

22. Goel S., DeCristo M.J., Watt A.C., BrinJones H., Sceneay J., Li B.B. et al. CDK4/6 Inhibition Triggers Anti- Tumour Immunity. Nature. 2017;548(7668):471–475. doi: 10.1038/nature23465.

23. Roulois D., Loo Yau H., Singhania R., Wang Y., Danesh A., Shen S.Y. et al. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell. 2015;162(5):961–973. doi: 10.3410/f.725752342.793510775.

24. Chiappinelli K.B., Strissel P.L., Desrichard A., Li H., Henke C., Akman B. et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell. 2015;162(5):974–986. doi: 10.1016/j.cell.2015.07.011.

25. Obata Y., Furusawa Y., Endo T.A., Sharif J., Takahashi D., Atarashi K. et al. The Epigenetic Regulator Uhrf1 Facilitates the Proliferation and Maturation of Colonic Regulatory T Cells. Nat Immunol. 2014;15(6): 571–579. doi: 10.1038/ni.2886.

26. Finn R.S., Dering J., Conklin D., Kalous O., Cohen D.J., Desai A.J. et al. PD 0332991, A Selective Cyclin D Kinase 4/6 Inhibitor, Preferentially Inhibits Proliferation of Luminal Estrogen Receptor- Positive Human Breast Cancer Cell Lines In Vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.

27. Hammes S.R., Levin E.R. Impact of Estrogens in Males and Androgens in Females. J Clin Invest. 2019;129(5):1818–1826. doi: 10.1172/jci125755.

28. Fukami M., Shozu M., Soneda S., Kato F., Inagaki A., Takagi H. et al. Aromatase Excess Syndrome: Identification of Cryptic Duplications and Deletions Leading to Gain of Function of CYP19A1 and Assessment of Phenotypic Determinants. J Clin Endocrinol Metab. 2011;96(6): E1035–E1043. doi: 10.1210/jc.2011-0145.

29. Coen P., Kulin H., Ballantine T., Zaino R., Frauenhoffer E., Boal D. et al. An Aromatase- Producing Sex- Cord Tumor Resulting in Prepubertal Gynecomastia. N Engl J Med. 1991;324(5):317–322. doi: 10.1056/ nejm199101313240507.

30. Gourgari E., Saloustros E., Stratakis C.A. Large- Cell Calcifying Sertoli Cell Tumors of the Testes in Pediatrics. Curr Opin Pediatr. 2012;24(4):518–522. doi: 10.1097/mop.0b013e328355a279. 31. Song W.C. Biochemistry and reproductive endocrinology of estrogen sulfotransferase. Ann NY Acad Sci. 2001;948:43–50. doi: 10.1111/j.1749-6632.2001.tb03985.x.

31. Cooke P.S., Nanjappa M.K., Ko C., Prins G.S., Hess R.A. Estrogens in Male Physiology. Physiol Rev. 2017;97(3):995–1043. doi: 10.1152/physrev.00018.2016.