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Palbociclib—The First of a New Class of Cell Cycle Inhibitors

  • Marcus Schmidt
  • Martin Sebastian
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 211)

Abstract

During the last decades, much has been learned about with cyclin-dependent kinases (CDK) playing a pivotal role in the cell cycle regulation. CDK4/6 is the key regulator of the G1-S transition. Palbociclib (PD 0332991, Ibrance®) is the first oral CDK4/6 inhibitor showing a substantially improved median progression-free survival (PFS) in advanced estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer. This PFS prolongation was seen both with letrozole as first-line therapy (24.8 vs. 14.5 months [PALOMA 2]) and with fulvestrant in endocrine pretreated patients (9.2 vs. 3.8 months [PALOMA-3]). The main toxicity is neutropenia due to cell cycle arrest which can be easily managed with dose interruption or dose reduction leading to a favorable safety profile with delayed deterioration of global quality of life (QoL). Palbociclib is approved by the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) for ER-positive/HER2-negative advanced breast cancer. Despite the well-understood mode of action of palbociclib, predictive biomarkers are not yet defined. In conclusion, inhibition of CDK4/6 using palbociclib in combination with endocrine therapy is an efficient and well-tolerated treatment option in ER-positive/HER2-negative advanced breast cancer. Ongoing clinical trials are investigating the role of palbociclib in early breast cancer as well as in other types of cancer.

Keywords

Palbocilib Breast cancer Metastatic Advanced Endocrine 

References

  1. Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R, Niesvizky R, Cho H, Ely S, Moore MAS, Chen-Kiang S (2006) A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 66:7661–7667.  https://doi.org/10.1158/0008-5472.CAN-06-1098CrossRefPubMedGoogle Scholar
  2. Bazarov AV, Lee WJ, Bazarov I, Bosire M, Hines WC, Stankovich B, Chicas A, Lowe SW, Yaswen P (2012) The specific role of pRb in p16 (INK4A)-mediated arrest of normal and malignant human breast cells. Cell Cycle 11:1008–1013.  https://doi.org/10.4161/cc.11.5.19492CrossRefPubMedPubMedCentralGoogle Scholar
  3. Cardoso F, Costa A, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Bhattacharyya G, Biganzoli L, Cardoso MJ, Carey L, Corneliussen-James D, Curigliano G, Dieras V, El Saghir N, Eniu A, Fallowfield L, Fenech D, Francis P, Gelmon K, Gennari A, Harbeck N, Hudis C, Kaufman B, Krop I, Mayer M, Meijer H, Mertz S, Ohno S, Pagani O, Papadopoulos E, Peccatori F, Pernault-Llorca F, Piccart MJ, Pierga JY, Rugo H, Shockney L, Sledge G, Swain S, Thomssen C, Tutt A, Vorobiof D, Xu B, Norton L, Winer E (2017) 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol 28:16–33.  https://doi.org/10.1093/annonc/mdw544CrossRefPubMedGoogle Scholar
  4. Chen P, Lee NV, Hu W, Xu M, Ferre RA, Lam H, Bergqvist S, Solowiej J, Diehl W, He Y, Yu X, Nagata A, VanArsdale T, Murray BW (2016) Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther 15:2273–2281.  https://doi.org/10.1158/1535-7163.MCT-16-0300CrossRefPubMedGoogle Scholar
  5. Conyers R, Young S, Thomas DM (2011) Liposarcoma: molecular genetics and therapeutics. Sarcoma 2011:483154.  https://doi.org/10.1155/2011/483154CrossRefPubMedGoogle Scholar
  6. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S, Masuda N, Colleoni M, Demichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425–439.  https://doi.org/10.1016/S1470-2045(15)00613-0CrossRefPubMedGoogle Scholar
  7. Demichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, Lal P, Feldman M, Zhang P, Colameco C, Lewis D, Langer M, Goodman N, Domchek S, Gogineni K, Rosen M, Fox K, O’Dwyer P (2015) CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 21:995–1001.  https://doi.org/10.1158/1078-0432.CCR-14-2258CrossRefPubMedGoogle Scholar
  8. Dhillon S (2015) Palbociclib: first global approval. Drugs 75:543–551.  https://doi.org/10.1007/s40265-015-0379-9CrossRefPubMedGoogle Scholar
  9. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin L, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK (2013) Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 31:2024–2028.  https://doi.org/10.1200/JCO.2012.46.5476CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dickson MA, Schwartz GK, Keohan ML, D’Angelo SP, Gounder MM, Chi P, Antonescu CR, Landa J, Qin L, Crago AM, Singer S, Koff A, Tap WD (2016) Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with cdk4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol 2:937–940.  https://doi.org/10.1001/jamaoncol.2016.0264CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dosil MA, Mirantes C, Eritja N, Felip I, Navaridas R, Gatius S, Santacana M, Colas E, Moiola C, Schoenenberger JA, Encinas M, Gari E, Matias-Guiu X, Dolcet X (2017) Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias. J Pathol 242:152–164.  https://doi.org/10.1002/path.4896CrossRefPubMedGoogle Scholar
  12. Elledge RM, Green S, Pugh R, Allred DC, Clark GM, Hill J, Ravdin P, Martino S, Osborne CK (2000) Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer 89:111–117CrossRefPubMedGoogle Scholar
  13. Elvin JA, Gay LM, Ort R, Shuluk J, Long J, Shelley L, Lee R, Chalmers ZR, Frampton GM, Ali SM, Schrock AB, Miller VA, Stephens PJ, Ross JS, Frank R (2017) Clinical benefit in response to palbociclib treatment in refractory uterine leiomyosarcomas with a common CDKN2A alteration. Oncologist 22:416–421.  https://doi.org/10.1634/theoncologist.2016-0310CrossRefPubMedPubMedCentralGoogle Scholar
  14. Ettl J, Harbeck N (2017) The safety and efficacy of palbociclib in the treatment of metastatic breast cancer. Expert Rev Anticancer Ther 17:661–668.  https://doi.org/10.1080/14737140.2017.1347506CrossRefPubMedGoogle Scholar
  15. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ (2009) 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 11:R77.  https://doi.org/10.1186/bcr2419CrossRefPubMedPubMedCentralGoogle Scholar
  16. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ (2015) 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. Lancet Oncol 16:25–35.  https://doi.org/10.1016/S1470-2045(14)71159-3CrossRefPubMedGoogle Scholar
  17. Finn RS, Crown JP, Ettl J, Schmidt M, Bondarenko IM, Lang I, Pinter T, Boer K, Patel R, Randolph S, Kim ST, Huang X, Schnell P, Nadanaciva S, Bartlett CH, Slamon DJ (2016a) Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res 18:67.  https://doi.org/10.1186/s13058-016-0721-5CrossRefPubMedPubMedCentralGoogle Scholar
  18. Finn RS, Martin M, Rugo HS, Jones S, Im S, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ (2016b) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925–1936.  https://doi.org/10.1056/NEJMoa1607303CrossRefPubMedGoogle Scholar
  19. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK (2012) Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 18:568–576.  https://doi.org/10.1158/1078-0432.CCR-11-0509CrossRefPubMedGoogle Scholar
  20. Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S, Jiang J, Bartlett CH, Koehler M, Dowsett M, Bliss JM, Johnston SRD, Turner NC (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 34:2961–2968.  https://doi.org/10.1200/JCO.2016.67.3061CrossRefPubMedGoogle Scholar
  21. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3:1427–1438PubMedGoogle Scholar
  22. Goldman JW, Shi P, Reck M, Paz-Ares L, Koustenis A, Hurt KC (2016) Treatment rationale and Study design for the JUNIPER study: a randomized phase III study of abemaciclib with best supportive care versus erlotinib with best supportive care in patients with stage IV non-small-cell lung cancer with a detectable KRAS mutation whose disease has progressed after platinum-based chemotherapy. Clin Lung Cancer 17:80–84.  https://doi.org/10.1016/j.cllc.2015.08.003CrossRefPubMedGoogle Scholar
  23. Gopalan PK, Pinder MC, Chiappori A, Ivey AM, Villegas AG, Kaye FJ (2014) A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, advanced non-small cell lung cancer (NSCLC) patients with inactivated CDKN2A. J Clin Oncol 32:5s (suppl; abstr 8077)Google Scholar
  24. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674.  https://doi.org/10.1016/j.cell.2011.02.013CrossRefPubMedPubMedCentralGoogle Scholar
  25. Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, Andre F, Loi S, Verma S, Iwata H, Bhattacharyya H, Puyana Theall K, Bartlett CH, Loibl S (2016) Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol 27:1047–1054.  https://doi.org/10.1093/annonc/mdw139CrossRefPubMedPubMedCentralGoogle Scholar
  26. Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortes J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin L, Turner NC, Serra V (2016) Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 76:2301–2313.  https://doi.org/10.1158/0008-5472.CAN-15-0728CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hu W, Sung T, Jessen BA, Thibault S, Finkelstein MB, Khan NK, Sacaan AI (2016) Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 22:2000–2008.  https://doi.org/10.1158/1078-0432.CCR-15-1421CrossRefPubMedGoogle Scholar
  28. Ingham M, Schwartz GK (2017) Cell-cycle therapeutics come of age. J Clin Oncol 35:2949–2959.  https://doi.org/10.1200/JCO.2016.69.0032CrossRefPubMedPubMedCentralGoogle Scholar
  29. Iwata H, Im S, Masuda N, Im Y, Inoue K, Rai Y, Nakamura R, Kim JH, Hoffman JT, Zhang K, Giorgetti C, Iyer S, Schnell PT, Bartlett CH, Ro J (2017) PALOMA-3: phase III trial of fulvestrant with or without palbociclib in premenopausal and postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer that progressed on prior endocrine therapy-safety and efficacy in asian patients. J Glob Oncol 3:289–303.  https://doi.org/10.1200/JGO.2016.008318CrossRefPubMedPubMedCentralGoogle Scholar
  30. Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, Yang G, Chalukya M, Wang H, Anderson L, Kalli KR, Finn RS, Ginther C, Jones S, Velculescu VE, Riehle D, Cliby WA, Randolph S, Koehler M, Hartmann LC, Slamon DJ (2011) Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 17:1591–1602.  https://doi.org/10.1158/1078-0432.CCR-10-2307CrossRefPubMedPubMedCentralGoogle Scholar
  31. Loibl S, Turner NC, Ro J, Cristofanilli M, Iwata H, Im S, Masuda N, Loi S, Andre F, Harbeck N, Verma S, Folkerd E, Puyana Theall K, Hoffman J, Zhang K, Bartlett CH, Dowsett M (2017) Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist 22:1028–1038.  https://doi.org/10.1634/theoncologist.2017-0072CrossRefPubMedPubMedCentralGoogle Scholar
  32. Malorni L, Piazza S, Ciani Y, Guarducci C, Bonechi M, Biagioni C, Hart CD, Verardo R, Di Leo A, Migliaccio I (2016) A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 7:68012–68022.  https://doi.org/10.18632/oncotarget.12010CrossRefPubMedPubMedCentralGoogle Scholar
  33. Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1:222–231.  https://doi.org/10.1038/35106065CrossRefPubMedGoogle Scholar
  34. Menu E, Garcia J, Huang X, Di Liberto M, Toogood PL, Chen I, Vanderkerken K, Chen-Kiang S (2008) A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res 68:5519–5523.  https://doi.org/10.1158/0008-5472.CAN-07-6404CrossRefPubMedGoogle Scholar
  35. Michel L, Ley J, Wildes TM, Schaffer A, Robinson A, Chun S, Lee W, Lewis J Jr, Trinkaus K, Adkins D (2016) Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol 58:41–48  https://doi.org/10.1016/j.oraloncology.2016.05.011
  36. Murphy CG, Dickler MN (2016) Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies. Endocr Relat Cancer 23:R337–R352.  https://doi.org/10.1530/ERC-16-0121CrossRefPubMedGoogle Scholar
  37. Narayan V, Hwang W, Lal P, Rosen MA, Gallagher M, O’Dwyer PJ, Vaughn DJ (2016) Cyclin-dependent kinase 4/6 inhibition for the treatment of unresectable mature teratoma: long-term follow-up of a phase II study. Clin Genitourin Cancer 14:504–510.  https://doi.org/10.1016/j.clgc.2016.03.010CrossRefPubMedGoogle Scholar
  38. Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA, Haideri NA, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan AA, Raab MS, Tarantolo S, Vij R, Zonder JA, Huang X, Jayabalan D, Di Liberto M, Huang X, Jiang Y, Kim ST, Randolph S, Chen-Kiang S (2015) Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma 56:3320–3328.  https://doi.org/10.3109/10428194.2015.1030641CrossRefPubMedGoogle Scholar
  39. O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13:417–430.  https://doi.org/10.1038/nrclinonc.2016.26CrossRefPubMedGoogle Scholar
  40. Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Heidel FH, Kramer A, Root DE, Barbie DA, Krivtsov AV, Armstrong SA, Hahn WC, Huntly BJ, Sykes SM, Milsom MD, Scholl C, Frohling S (2014) Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 124:13–23.  https://doi.org/10.1182/blood-2014-02-558114CrossRefPubMedPubMedCentralGoogle Scholar
  41. Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, Zamboni WC, Wong K, Perou CM, Sharpless NE (2012) Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst 104:476–487.  https://doi.org/10.1093/jnci/djs002CrossRefPubMedPubMedCentralGoogle Scholar
  42. Schmidt M (2016) Palbociclib—from Bench to Bedside and Beyond. Breast Care (Basel) 11:177–181.  https://doi.org/10.1159/000447001CrossRefGoogle Scholar
  43. Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O’Dwyer PJ (2011) Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer 104:1862–1868.  https://doi.org/10.1038/bjc.2011.177CrossRefPubMedPubMedCentralGoogle Scholar
  44. Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24:1770–1783.  https://doi.org/10.1200/JCO.2005.03.7689CrossRefPubMedGoogle Scholar
  45. Sun W, O’Dwyer PJ, Finn RS, Ruiz-Garcia A, Shapiro GI, Schwartz GK, Demichele A, Wang D (2017) Characterization of neutropenia in advanced cancer patients following palbociclib treatment using a population pharmacokinetic-pharmacodynamic modeling and simulation approach. J Clin Pharmacol 57:1159–1173.  https://doi.org/10.1002/jcph.902CrossRefPubMedGoogle Scholar
  46. Tanaka T, Terai Y, Ashihara K, Fujiwara S, Tanaka Y, Sasaki H, Tsunetoh S, Ohmichi M (2017) The efficacy of the cyclin-dependent kinase 4/6 inhibitor in endometrial cancer. PLoS ONE 12:e0177019.  https://doi.org/10.1371/journal.pone.0177019CrossRefPubMedPubMedCentralGoogle Scholar
  47. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M (2015) Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209–219.  https://doi.org/10.1056/NEJMoa1505270CrossRefPubMedGoogle Scholar
  48. Uras IZ, Walter GJ, Scheicher R, Bellutti F, Prchal-Murphy M, Tigan AS, Valent P, Heidel FH, Kubicek S, Scholl C, Frohling S, Sexl V (2016) Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood 127:2890–2902.  https://doi.org/10.1182/blood-2015-11-683581CrossRefPubMedPubMedCentralGoogle Scholar
  49. Vaughn DJ, Hwang W, Lal P, Rosen MA, Gallagher M, O’Dwyer PJ (2015) Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors. Cancer 121:1463–1468.  https://doi.org/10.1002/cncr.29213CrossRefPubMedGoogle Scholar
  50. Verma S, Bartlett CH, Schnell P, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Cristofanilli M, Zhang K, Thiele A, Turner NC, Rugo HS (2016) Palbociclib in combination with fulvestrant in women with hormone receptor-positive/her2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist 21:1165–1175.  https://doi.org/10.1634/theoncologist.2016-0097CrossRefPubMedPubMedCentralGoogle Scholar
  51. Wilson FR, Varu A, Mitra D, Cameron C, Iyer S (2017) Systematic review and network meta-analysis comparing palbociclib with chemotherapy agents for the treatment of postmenopausal women with HR-positive and HER2-negative advanced/metastatic breast cancer. Breast Cancer Res Treat 166:167–177.  https://doi.org/10.1007/s10549-017-4404-4CrossRefPubMedPubMedCentralGoogle Scholar
  52. Yu Y, Loi C, Hoffman J, Wang D (2017) Physiologically based pharmacokinetic modeling of palbociclib. J Clin Pharmacol 57:173–184.  https://doi.org/10.1002/jcph.792CrossRefPubMedGoogle Scholar
  53. Zardavas D, Phillips WA, Loi S (2014) PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res 16:201.  https://doi.org/10.1186/bcr3605CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyUniversity Medical Center MainzMainzGermany
  2. 2.Department of Hematology/Oncology, Rheumatology, HIVJ.W. Goethe UniversityFrankfurtGermany

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