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CDK inhibitors in hormone receptor positive advanced breast cancer

Year 2015, Special Issue :1 Oncology, 35 - 39, 30.09.2015
https://doi.org/10.5472/mmj.77406

Abstract

Endocrine treatment is the current first line treatment in ER+
advanced breast cancer with a requirement of predictive
biomarkers to the treatment and different approaches for
endocrine resistance risk. Cyclin dependent kinases (CDKs)
are regulating each step of cellular division in mammalian
cell cycle and are hyperactivated in cancer cells causing
cancer progression. Next generation pan-CDK inhibitors are
in clinical development, while clinical trials in breast cancer,
particularly in ER+ subtype where the greatest growth
inhibition has been observed. Here I will review the data
from this new class of drugs.
Keywords: CDK inhibitors, Hormone positive advanced
breast cancer, Targeted therapies, Palbociclib, Endocrine
therapy resistance

References

  • 1. Mayer EL, Targeting breast cancer with CDK inhibitors. Curr Oncol Rep 2015;17:443. doi: 10.1007/s11912- 015-0443-3
  • 2. Gluck S, Extending the clinical benefit of endocrine therapy for women with hormone receptor-positive metastatic breast cancer: differentiating mechanisms of action. Clin Breast Cancer 2014; 14:75-84. doi: 10.1016/j.clbc.2013.10.008
  • 3. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol 2014, 25:1871-88. doi: 10.1093/annonc/mdu385
  • 4. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011; 144(5):646-674. doi: 10.1016/j.cell.2011.02.013.
  • 5. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev Cancer 2009;9:153-66. doi: 10.1038/nrc2602.
  • 6. Sherr CJ. Cancer cell cycles. Science 1996; 274(5293):1672-7.
  • 7. Lim S, Kaldis P, Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013, 140:3079-93. doi: 10.1242/dev.091744
  • 8. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nature Rev Cancer 2001;1:222-31.
  • 9. Rodgers JT, King KY, Brett JO, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 2014; 510:393-96. doi: 10.1038/ nature13255
  • 10. Sherr CJ, D-type cyclins. Trends in Biochemical Sciences 1995; 20:187-90.
  • 11. Diehl JA, Cycling to cancer with cyclin D1. Cancer Biol Ther 2002; 1:226-31.
  • 12. Pavletich NP, Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 1999; 287:821-8.
  • 13. Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991, 65:701- 13.
  • 14. Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 2011; 10:2497-503. doi: 10.4161/cc.10.15.16776
  • 15. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993, 366:704-7.
  • 16. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes and Development 1993, 7:331-42.
  • 17. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994, 14:2066-76.
  • 18. Wang JY, Knudsen ES, Welch PJ. The retinoblastoma tumor suppressor protein. Advances Cancer Research 1994;64:25-85.
  • 19. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Rev Cancer 2008; 8:671-82. doi: 10.1038/nrc2399
  • 20. Dickson MA, Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res 2014; 20:3379-83. doi: 10.1158/1078-0432.CCR-13-1551
  • 21. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptorpositive human breast cancer cell lines in vitro. Breast Cancer Research:BRC 2009;11:R77. doi: 10.1186/ bcr2419.
  • 22. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997;88:405-15.
  • 23. Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993, 8:2127-33.
  • 24. Hui R, Macmillan RD, Kenny FS, Musgrove EA, Blamey RW, Nicholson RI, Robertson JF, Sutherland RL. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res 2000;6:2777-87.
  • 25. Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL, Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 1995; 9:1804-13.
  • 26. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES, Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. EndocrineRelated Cancer 2011; 18:333-45. doi: 10.1530/ERC- 10-0262.
  • 27. Casimiro MC, Velasco-Velazquez M, Aguirre-Alvarado C, Pestell RG, Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Invest Drugs 2014; 23:295-304. doi: 10.1517/13543784.2014.867017
  • 28. Gopalan PK G-VA, Zajac-Kaye M, Kaye FJ, Inhibitory effect of the CDK4/6 inhibitor, PD 0332991, is enhanced by mTOR inhibition in non–small cell lung cancer (NSCLC). In: AACR: 2013 Apr 6–10; Washington, DC. Philadelphia (PA): Cancer Res 2013 Apr 6–10.
  • 29. Wiest T, Schwarz E, Enders C, Flechtenmacher C, Bosch FX. Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 2002,21:1510-17.
  • 30. Jerusalem G, Bachelot T, Barrios C, Neven P, Di Leo A, Janni W, de Boer R: A new era of improving progressionfree survival with dual blockade in postmenopausal HR(+), HER2(-) advanced breast cancer. Cancer Treat Rev 2015;41:94-104. doi: 10.1016/j.ctrv.2014.12.011
  • 31. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. Clin Oncol 2013; 31:2128-35. doi: 10.1200/ JCO.2012.43.7251
  • 32. Lauring J, Park BH, Wolff AC. The phosphoinositide- 3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. NCCN 2013; 11:670-78.
  • 33. Migliaccio I, Di Leo A, Malorni L. Cyclin-dependent kinase 4/6 inhibitors in breast cancer therapy. Curr Opin Oncol 2014; 26:568-75. doi: 10.1097/ CCO.0000000000000129
  • 34. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.NEJM 2012;366:520-9. doi: 10.1056/ NEJMoa1109653
  • 35. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The Lancet Oncology 2015; 16:25-35. doi: 10.1016/S1470-2045(14)71159-3
  • 36. Migliaccio I, Malorni L, Hart CD, Guarducci C, Di Leo A. Endocrine therapy considerations in postmenopausal patients with hormone receptor positive, human epidermal growth factor receptor type 2 negative advanced breast cancers. BMC Medicine 2015;13:46. doi: 10.1186/s12916-015-0280-0
  • 37. Treilleux I, Arnedos M, Cropet C, et al. Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol 2015; 26:120-5. doi: 10.1093/ annonc/mdu497
  • 38. Hortobagyi GNP-GMJ RH, Burris HA, Campone M, Noguchi S, Perez, AT DI, Shtivelband M, Provencher L, Masuda N, Dakhil SR, Anderson I, Chen D, Damask A, Huang A, McDonald R, Taran T, Sahmoud T, Baselga J. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2. In: ASCO Annual Meeting. Chicago, IL: J Clin Oncol 31, 2013.
  • 39. Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev 2014; 40:862-71. doi: 10.1016/j. ctrv.2014.03.004.
  • 40. Krop IJS JS, Mayer IA, Dickler M, Ganju V, ForeroTorres A, Melichar B, Morales S, de Boer R, Gendreau S, Derynck M, Lackner M, Spoerke J, Yeh R-F, Levy G, Ng V, O’Brien C, Savage H, Xiao Y, Wilson T, Lee SC, Petrakova K, Vallentin S, Yardley D, Ellis M, Piccart M, Perez EA, Winer E, Schmid P. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results. In: San Antonio Breast Cancer Symposium. San Antonio, Texas; 2014.
  • 41. Dhillon S: Palbociclib: first global approval. Drugs 2015; 75:543-51. doi: 10.1007/s40265-015-0379-9.
  • 42. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drug 2014; 32:825-37. doi: 10.1007/s10637-014-0120-7.
  • 43. Tate SC, Cai S, Ajamie RT, et al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclindependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 2014; 20:3763-74. doi: 10.1158/1078-0432.CCR-13-2846
  • 44. Infante JR SG, Witteveen P, Gerecitano JF, et al. A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. In: ASCO Annual Meeting. Chicago, IL. J Clin Oncol 2014.
Year 2015, Special Issue :1 Oncology, 35 - 39, 30.09.2015
https://doi.org/10.5472/mmj.77406

Abstract

References

  • 1. Mayer EL, Targeting breast cancer with CDK inhibitors. Curr Oncol Rep 2015;17:443. doi: 10.1007/s11912- 015-0443-3
  • 2. Gluck S, Extending the clinical benefit of endocrine therapy for women with hormone receptor-positive metastatic breast cancer: differentiating mechanisms of action. Clin Breast Cancer 2014; 14:75-84. doi: 10.1016/j.clbc.2013.10.008
  • 3. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol 2014, 25:1871-88. doi: 10.1093/annonc/mdu385
  • 4. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011; 144(5):646-674. doi: 10.1016/j.cell.2011.02.013.
  • 5. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev Cancer 2009;9:153-66. doi: 10.1038/nrc2602.
  • 6. Sherr CJ. Cancer cell cycles. Science 1996; 274(5293):1672-7.
  • 7. Lim S, Kaldis P, Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013, 140:3079-93. doi: 10.1242/dev.091744
  • 8. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nature Rev Cancer 2001;1:222-31.
  • 9. Rodgers JT, King KY, Brett JO, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 2014; 510:393-96. doi: 10.1038/ nature13255
  • 10. Sherr CJ, D-type cyclins. Trends in Biochemical Sciences 1995; 20:187-90.
  • 11. Diehl JA, Cycling to cancer with cyclin D1. Cancer Biol Ther 2002; 1:226-31.
  • 12. Pavletich NP, Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 1999; 287:821-8.
  • 13. Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991, 65:701- 13.
  • 14. Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 2011; 10:2497-503. doi: 10.4161/cc.10.15.16776
  • 15. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993, 366:704-7.
  • 16. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes and Development 1993, 7:331-42.
  • 17. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994, 14:2066-76.
  • 18. Wang JY, Knudsen ES, Welch PJ. The retinoblastoma tumor suppressor protein. Advances Cancer Research 1994;64:25-85.
  • 19. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Rev Cancer 2008; 8:671-82. doi: 10.1038/nrc2399
  • 20. Dickson MA, Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res 2014; 20:3379-83. doi: 10.1158/1078-0432.CCR-13-1551
  • 21. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptorpositive human breast cancer cell lines in vitro. Breast Cancer Research:BRC 2009;11:R77. doi: 10.1186/ bcr2419.
  • 22. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997;88:405-15.
  • 23. Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993, 8:2127-33.
  • 24. Hui R, Macmillan RD, Kenny FS, Musgrove EA, Blamey RW, Nicholson RI, Robertson JF, Sutherland RL. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res 2000;6:2777-87.
  • 25. Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL, Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 1995; 9:1804-13.
  • 26. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES, Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. EndocrineRelated Cancer 2011; 18:333-45. doi: 10.1530/ERC- 10-0262.
  • 27. Casimiro MC, Velasco-Velazquez M, Aguirre-Alvarado C, Pestell RG, Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opin Invest Drugs 2014; 23:295-304. doi: 10.1517/13543784.2014.867017
  • 28. Gopalan PK G-VA, Zajac-Kaye M, Kaye FJ, Inhibitory effect of the CDK4/6 inhibitor, PD 0332991, is enhanced by mTOR inhibition in non–small cell lung cancer (NSCLC). In: AACR: 2013 Apr 6–10; Washington, DC. Philadelphia (PA): Cancer Res 2013 Apr 6–10.
  • 29. Wiest T, Schwarz E, Enders C, Flechtenmacher C, Bosch FX. Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 2002,21:1510-17.
  • 30. Jerusalem G, Bachelot T, Barrios C, Neven P, Di Leo A, Janni W, de Boer R: A new era of improving progressionfree survival with dual blockade in postmenopausal HR(+), HER2(-) advanced breast cancer. Cancer Treat Rev 2015;41:94-104. doi: 10.1016/j.ctrv.2014.12.011
  • 31. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. Clin Oncol 2013; 31:2128-35. doi: 10.1200/ JCO.2012.43.7251
  • 32. Lauring J, Park BH, Wolff AC. The phosphoinositide- 3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. NCCN 2013; 11:670-78.
  • 33. Migliaccio I, Di Leo A, Malorni L. Cyclin-dependent kinase 4/6 inhibitors in breast cancer therapy. Curr Opin Oncol 2014; 26:568-75. doi: 10.1097/ CCO.0000000000000129
  • 34. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.NEJM 2012;366:520-9. doi: 10.1056/ NEJMoa1109653
  • 35. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The Lancet Oncology 2015; 16:25-35. doi: 10.1016/S1470-2045(14)71159-3
  • 36. Migliaccio I, Malorni L, Hart CD, Guarducci C, Di Leo A. Endocrine therapy considerations in postmenopausal patients with hormone receptor positive, human epidermal growth factor receptor type 2 negative advanced breast cancers. BMC Medicine 2015;13:46. doi: 10.1186/s12916-015-0280-0
  • 37. Treilleux I, Arnedos M, Cropet C, et al. Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol 2015; 26:120-5. doi: 10.1093/ annonc/mdu497
  • 38. Hortobagyi GNP-GMJ RH, Burris HA, Campone M, Noguchi S, Perez, AT DI, Shtivelband M, Provencher L, Masuda N, Dakhil SR, Anderson I, Chen D, Damask A, Huang A, McDonald R, Taran T, Sahmoud T, Baselga J. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2. In: ASCO Annual Meeting. Chicago, IL: J Clin Oncol 31, 2013.
  • 39. Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev 2014; 40:862-71. doi: 10.1016/j. ctrv.2014.03.004.
  • 40. Krop IJS JS, Mayer IA, Dickler M, Ganju V, ForeroTorres A, Melichar B, Morales S, de Boer R, Gendreau S, Derynck M, Lackner M, Spoerke J, Yeh R-F, Levy G, Ng V, O’Brien C, Savage H, Xiao Y, Wilson T, Lee SC, Petrakova K, Vallentin S, Yardley D, Ellis M, Piccart M, Perez EA, Winer E, Schmid P. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results. In: San Antonio Breast Cancer Symposium. San Antonio, Texas; 2014.
  • 41. Dhillon S: Palbociclib: first global approval. Drugs 2015; 75:543-51. doi: 10.1007/s40265-015-0379-9.
  • 42. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drug 2014; 32:825-37. doi: 10.1007/s10637-014-0120-7.
  • 43. Tate SC, Cai S, Ajamie RT, et al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclindependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 2014; 20:3763-74. doi: 10.1158/1078-0432.CCR-13-2846
  • 44. Infante JR SG, Witteveen P, Gerecitano JF, et al. A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. In: ASCO Annual Meeting. Chicago, IL. J Clin Oncol 2014.
There are 44 citations in total.

Details

Primary Language English
Journal Section Articles
Authors

Bilge Aktas This is me

Publication Date September 30, 2015
Published in Issue Year 2015 Special Issue :1 Oncology

Cite

APA Aktas, B. (2015). CDK inhibitors in hormone receptor positive advanced breast cancer. Marmara Medical Journal, 28(1), 35-39. https://doi.org/10.5472/mmj.77406
AMA Aktas B. CDK inhibitors in hormone receptor positive advanced breast cancer. Marmara Med J. September 2015;28(1):35-39. doi:10.5472/mmj.77406
Chicago Aktas, Bilge. “CDK Inhibitors in Hormone Receptor Positive Advanced Breast Cancer”. Marmara Medical Journal 28, no. 1 (September 2015): 35-39. https://doi.org/10.5472/mmj.77406.
EndNote Aktas B (September 1, 2015) CDK inhibitors in hormone receptor positive advanced breast cancer. Marmara Medical Journal 28 1 35–39.
IEEE B. Aktas, “CDK inhibitors in hormone receptor positive advanced breast cancer”, Marmara Med J, vol. 28, no. 1, pp. 35–39, 2015, doi: 10.5472/mmj.77406.
ISNAD Aktas, Bilge. “CDK Inhibitors in Hormone Receptor Positive Advanced Breast Cancer”. Marmara Medical Journal 28/1 (September 2015), 35-39. https://doi.org/10.5472/mmj.77406.
JAMA Aktas B. CDK inhibitors in hormone receptor positive advanced breast cancer. Marmara Med J. 2015;28:35–39.
MLA Aktas, Bilge. “CDK Inhibitors in Hormone Receptor Positive Advanced Breast Cancer”. Marmara Medical Journal, vol. 28, no. 1, 2015, pp. 35-39, doi:10.5472/mmj.77406.
Vancouver Aktas B. CDK inhibitors in hormone receptor positive advanced breast cancer. Marmara Med J. 2015;28(1):35-9.