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CDK4/6 inhibitors in breast cancer

Breast cancer

Read time: 60 mins
Last updated:13th Apr 2022
Published:22nd Apr 2021

Early and advanced breast cancer

Cancer is a leading cause of death and a burden to global life expectancy1,2. Breast cancer (BC) in women accounts for 1 in 4 cancer cases, with an estimated 2.3 million new cases in 20201. The increased incidence rates of BC in women reflects reproductive, hormonal, lifestyle risk factors and improved mammographic screening1.

Gene expression and molecular profiles are used to characterise BC subtypes3,4. Progesterone (PR) signalling may play a role in the progression of early breast cancer (EBC)3; oestrogen (ER) or PR receptors can be prognostic of therapy response; ERα is usually maintained in metastatic breast cancer (mBC)4. Gene expression profiling of triple-negative breast cancer (TNBC) has aided in delineating disease subtypes5.

EBC is disease confined to the breast, with or without regional lymph node involvement, and the absence of distant metastatic disease3. Advanced breast cancer (ABC) includes inoperable locally ABC (LABC) and mBC, and is manageable, though incurable, with currently approved treatments4.

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Breast cancer risk

Women at high risk of breast cancer (BC) are those with3,8,32:

  • a strong family history of breast, ovarian or pancreatic cancer
  • diagnosis of BC before the age of 50 years
  • diagnosis of triple-negative breast cancer (TNBC) before the age of 60 years
  • personal history of ovarian cancer or second BC

Phenotypic markers that identify people who carry pathogenic mutations that increase the risk of BC are not currently known. A family history evaluation is therefore necessary to assess the risk of predisposing genes for BC in a family3,32.

More than 90% of patients with BC are diagnosed with early-stage disease, of whom approximately 70% have cancers that are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-)14.

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Breast cancer stratification

Breast cancer (BC) can be stratified into different entities on the basis of clinical behaviour, histological features, and/or by biological properties. As current anticancer agents target biological mechanisms, detailed molecular stratification is a requirement for clinical management of breast BC3,4.

Assays for risk stratification focus on prediction of the response to existing treatment regimens. Gene-expression profiling shows that BCs can be stratified in so-called intrinsic subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like and normal-like), which mostly corresponds to hormone receptor (HR) and HER2 status, and further stratifies luminal tumours on the basis of proliferation12–14.

Stratification is critical for selecting patients with BC who could benefit from adjuvant therapy3,4,7. This is especially important for patients with early breast cancer (EBC), who comprise the majority of patients, because of widespread uptake of screening mammography3,4,7.

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Breast cancer treatment landscape

Treatment of breast cancer (BC) in specialised breast units or centres, defined as specialised institutions or departments that care for a high volume of BC patients, improves disease-free survival (DFS) and overall survival (OS), daily functioning, and quality of life (QoL)3,4.

Treatment in these units/centres is provided by a multidisciplinary team (MDT) specialised in BC. MDTs provide “consistent, continuous, co-ordinated, and cost-effective care to the patient,”80 and there is evidence to suggest that decisions made by an MDT are more likely to align with evidence-based guidelines81–84. Introduction of multidisciplinary care has been shown to significantly improve outcomes such as mortality85.  

BC MDTs consist of medical oncologists, breast surgeons, radiation oncologists, breast radiologists, breast pathologists and breast nurses. A breast nurse, or a similarly trained and specialised health care practitioner, usually acts as a “patient navigator.” Patients ought to be actively involved in all management decisions3,4.

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CDK4/6 inhibitor overview

Many breast cancers (BCs) are diagnosed at an early stage. These tumours are mostly hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) and are sensitive to endocrine therapies (ETs). However, approximately 20% of patients have cancer recurrence, usually as incurable metastatic disease, despite such treatment130. Ongoing efforts to improve survival in this subgroup include the development of new endocrine agents or extended duration of ET.

HR+/HER2- BC cells often overexpress cyclin D, which activates cell cycle progression through cyclin-dependent kinases 4 and 6 (CDK4/6). Therefore, HR+/HER2- BC cells are sensitive to CDK4/6 inhibitors, such as oral abemaciclib, palbociclib and ribociclib130.

The combination of CDK4/6 inhibitors with endocrine therapy (ET) has been used successfully in the treatment of HR+/HER2- advanced breast cancer (ABC), showing significantly longer progression-free survival (PFS) and overall survival(OS)87,127–139.

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References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209–249.
  2. World Health Organization (WHO). Global Health Estimates : Deaths by Cause, Age, Sex, by Country and by Region, 2000-2019. Who, Globocan 2020. 2020.
  3. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2019;30(8):1194–1220.
  4. Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, André F, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Annals of Oncology. 2020;31(12):1623–1649.
  5. Lehmann BD, Jovanović B, Chen X, Estrada M V., Johnson KN, Shyr Y, et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One. 2016;11(6):e0157368.
  6. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA - Journal of the American Medical Association. 2019;321(3):288–300.
  7. Richman J DM. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nature Reviews Clinical Oncology. 2019;16(5):296–311.
  8. Dowsett M, Turner N. Estimating risk of recurrence for early breast cancer: Integrating clinical and genomic risk. Journal of Clinical Oncology. 2019;37(9):689–692.
  9. Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. New England Journal of Medicine. 2017;377(19):1836–1846.
  10. Dowsett M, Sestak I, Buus R, Lopez-Knowles E, Mallon E, Howell A, et al. Estrogen receptor expression in 21-Gene recurrence score predicts increased late recurrence for estrogen-positive/HER2-Negative breast cancer. Clinical Cancer Research. 2015;21(12):2763–2770.
  11. Alexandre M, Maran-Gonzalez A, Viala M, Firmin N, D’hondt V, Gutowski M, et al. Decision of adjuvant systemic treatment in HR+ HER2-early invasive breast cancer: Which biomarkers could help? Cancer Management and Research. 2019;11:10353–10373.
  12. Makki J. Diversity of breast carcinoma: Histological subtypes and clinical relevance. Clinical Medicine Insights: Pathology. 2015;8(1):23–31.
  13. Tungsukruthai S, Petpiroon N, Chanvorachote P. Molecular mechanisms of breast cancer metastasis and potential anti-metastatic compounds. Anticancer Research. 2018;38(5):2607–2618.
  14. Cardoso F, Spence D, Mertz S, Corneliussen-James D, Sabelko K, Gralow J, et al. Global analysis of advanced/metastatic breast cancer: Decade report (2005–2015). Breast. 2018;39:131–138.
  15. Santa-Maria CA, Park SJ, Jain S, Gradishar WJ. Breast cancer and immunology: Biomarker and therapeutic developments. Expert Review of Anticancer Therapy. 2015;15(10):1215–1222.
  16. Ding Y, Ding K, Yu K, Zou D, Yang H, He X, et al. Prognosis and endocrine therapy selection for patients with low hormone receptor-positive breast cancer following neoadjuvant chemotherapy: A retrospective study of 570 patients in China. Oncology Letters. 2019;18(6):6690–6696.
  17. Shah R, Rosso K, David Nathanson S. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World Journal of Clinical Oncology. 2014;5(3):283–298.
  18. Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Research. 2002;4(5):197–201.
  19. Brisken C. Hormonal control of alveolar development and its implications for breast carcinogenesis. Journal of Mammary Gland Biology and Neoplasia. 2002;7(1):39–48.
  20. Rosen JM. Hormone receptor patterning plays a critical role in normal lobuloalveolar development and breast cancer progression. Breast Disease. 2003;18:3–9.
  21. Saha Roy S, Vadlamudi RK. Role of estrogen receptor signaling in breast cancer metastasis. International Journal of Breast Cancer. 2012;2012:65498.
  22. Daniel AR, Hagan CR, Lange CA. Progesterone receptor action: Defining a role in breast cancer. Expert Review of Endocrinology and Metabolism. 2011;6(3):359–369.
  23. Grimm SL, Hartig SM, Edwards DP. Progesterone Receptor Signaling Mechanisms. Journal of Molecular Biology. 2016;428(19):3831–3849.
  24. Elster N, Collins DM, Toomey S, Crown J, Eustace AJ, Hennessy BT. HER2-family signalling mechanisms, clinical implications and targeting in breast cancer. Breast Cancer Research and Treatment. 2015;149(1):5–15.
  25. Gagliato D de M, Jardim DLF, Marchesi MSP, Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016;7(39):64431–64446.
  26. Morris GJ, Naidu S, Topham AK, Guiles F, Xu Y, McCue P, et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: A single-institution compilation compared with the national cancer institute’s surveillance, epidemiology, and end results database. Cancer. 2007;110(4):876–884.
  27. Rastelli F, Biancanelli S, Falzetta A, Martignetti A, Casi C, Bascioni R, et al. Triple-negative breast cancer: Current state of the art. Tumori. 2010;96(6):875–888.
  28. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clinical Cancer Research. 2007;13(8):2329–2334.
  29. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clinical Cancer Research. 2007;13(15):4429–4434.
  30. Gao R, Davis A, McDonald TO, Sei E, Shi X, Wang Y, et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nature Genetics. 2016;48(10):1119–1130.
  31. Lee A, Djamgoz MBA. Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies. Cancer Treatment Reviews. 2018;62:110–122.
  32. Amir E, Freedman OC, Seruga B, Evans DG. Assessing women at high risk of breast cancer: A review of risk assessment models. J Natl Cancer Inst. 2010;102(10):680–691.
  33. Bradley R, Burrett J, Clarke M, Davies C, Duane F, Evans V, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. The Lancet. 2015;386(10001):1341–1352.
  34. Mamounas EP, Tang G, Paik S, Baehner FL, Liu Q, Jeong JH, Kim SR, Butler SM, Jamshidian F, Cherbavaz DB SAP, Mamounas EP, Tang G, Paik S, Baehner FL, Liu Q, et al. 21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology. Breast Cancer Res Treat. 2018;168(1):69–77.
  35. Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. New England Journal of Medicine. 2016;375(8):717–729.
  36. Nitz U, Gluz O, Christgen M, Kates RE, Clemens M, Malter W, et al. Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial. Breast Cancer Research and Treatment. 2017;165(3):573–583.
  37. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. New England Journal of Medicine. 2018;379(2):111–121.
  38. Petkov VI, Miller DP, Howlader N, Gliner N, Howe W, Schussler N, et al. Breast-cancer-specific mortality in patients treated based on the 21-gene assay: A SEER population-based study. npj Breast Cancer. 2016;2(1):16017.
  39. Esserman LJ, Yau C, Thompson CK, Van ’t Veer LJ, Borowsky AD, Hoadley KA, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. JAMA Oncology. 2017;3(11):1503–1510.
  40. Fallah P, Mulla N, Rose AA. N, Panasci L. Can high Ki67 predict distant recurrence in early stage breast cancer with low oncotype Dx score? Presented at European Society for Medical Oncology (ESMO) Congress 2021, 16–21 September 2021. Virtual. 149P.
  41. Holme SA, Man I, Sharpe JL, Dykes PJ, Lewis-Jones MS, Finlay AY. The children’s dermatology life quality index: Validation of the cartoon version. British Journal of Dermatology. 2003;148(2):285–290.
  42. Wazir U, Mokbel K. Emerging gene-based prognostic tools in early breast cancer: First steps to personalised medicine. World Journal of Clinical Oncology. 2014;5(5):795–799.
  43. Harbeck N, Sotlar K, Wuerstlein R, Doisneau-Sixou S. Molecular and protein markers for clinical decision making in breast cancer: Today and tomorrow. Cancer Treatment Reviews. 2014;40(3):434–444.
  44. Drukker CA, Bueno-De-Mesquita JM, Retèl VP, Van Harten WH, Van Tinteren H, Wesseling J, et al. A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study. International Journal of Cancer. 2013;133(4):929–936.
  45. Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, et al. Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clinical Cancer Research. 2013;19(15):4196–4205.
  46. Hall PS, Smith A, Hulme C, Vargas-Palacios A, Makris A, Hughes-Davies L, et al. Value of Information Analysis of Multiparameter Tests for Chemotherapy in Early Breast Cancer: The OPTIMA Prelim Trial. Value in Health. 2017;20(10):1311–1318.
  47. Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO clinical practice guidelines for cancer prevention and screening. Annals of Oncology. 2016;27(5):v103–v110.
  48. Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, et al. Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: Validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. Journal of Medical Genetics. 2008;45(7):425–431.
  49. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879–1886.
  50. Bondy ML, Lustbader ED, Halabi S, Ross E, Vogel VG. Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst. 1994;86(8):620–625.
  51. Atkins CD. Re: Validation of the gail et al. Model for predicting individual breast cancer risk. J Natl Cancer Inst. 1994;86(17):1350.
  52. Costantino JP, Gail MH, Pee D, Anderson S, Redmond CK, Benichou J, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst. 1999;91(18):1541–1548.
  53. Cummings SR, Tice JA, Bauer S, Browner WS, Cuzick J, Ziv E, et al. Prevention of breast cancer in postmenopausal women: Approaches to estimating and reducing risk. J Natl Cancer Inst. 2009;101(6):384–398.
  54. Jonker MA, Jacobi CE, Hoogendoorn WE, Nagelkerke NJD, De Bock GH, Van Houwelingen JC. Modeling Familial Clustered Breast Cancer Using Published Data. Cancer Epidemiology Biomarkers and Prevention. 2003;12(12):1479–1485.
  55. Van Asperen CJ, Jonker MA, Jacobi CE, Van Diemen-Homan JEM, Bakker E, Breuning MH, et al. Risk Estimation for Healthy Women from Breast Cancer Families: New Insights and New Strategies. Cancer Epidemiology Biomarkers and Prevention. 2004;13(1):87–93.
  56. Antoniou AC, Pharoah PPD, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. British Journal of Cancer. 2004;91(8):1580–1590.
  57. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Statistics in Medicine. 2004;23(7):1111–1130.
  58. McCarthy AM, Guan Z, Welch M, Griffin ME, Sippo DA, Deng Z, et al. Performance of Breast Cancer Risk-Assessment Models in a Large Mammography Cohort. J Natl Cancer Inst. 2020;112(5):489–497.
  59. Vilmun BM, Vejborg I, Lynge E, Lillholm M, Nielsen M, Nielsen MB, et al. Impact of adding breast density to breast cancer risk models: A systematic review. European Journal of Radiology. 2020;127:109019.
  60. Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MWR, Pooley KA, et al. A common coding variant in CASP8 is associated with breast cancer risk. Nature Genetics. 2007;39(3):352–358.
  61. SEER Cancer Statistics Review, 1975–2005. 2008.
  62. Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Altekruse S, et al. SEER Cancer Statistics Review. 2015.
  63. Terry M, Liao Y, Whittemore A, Leoce N, Buchsbaum R, Zeinomar N, et al. 10-year performance of four models of breast cancer risk: a validation study. Lancet Oncology. 2019;20(4):504–517.
  64. Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. The Lancet. 2011;378(9793):771–784.
  65. Abe O, Abe R, Enomoto K, Kikuchi K, Koyama H, Masuda H, et al. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;365(9472):1687–1717.
  66. Ronchi A, Pagliuca F, Zito Marino F, Accardo M, Cozzolino I, Franco R. Current and potential immunohistochemical biomarkers for prognosis and therapeutic stratification of breast carcinoma. Seminars in Cancer Biology. 2021;72:114–122.
  67. Purdie CA, Quinlan P, Jordan LB, Ashfield A, Ogston S, Dewar JA, et al. Progesterone receptor expression is an independent prognostic variable in early breast cancer: A population-based study. British Journal of Cancer. 2014;110(3):565–572.
  68. Yeung C, Hilton J, Clemons M, Mazzarello S, Hutton B, Haggar F, et al. Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours—a review. Cancer and Metastasis Reviews. 2016;35(3):427–437.
  69. Mohsin SK, Weiss H, Havighurst T, Clark GM, Berardo M, Roanh LD, et al. Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: A validation study. Modern Pathology. 2004;17(12):1545–1554.
  70. Kamranzadeh H, Ardekani RM, Kasaeian A, Sadighi S, Maghsudi S, Jahanzad I, et al. Association between Ki-67 expression and clinicopathological features in prognosis of breast cancer: A retrospective cohort study. Journal of Research in Medical Sciences. 2019;24(1):30.
  71. Anderson WF, Rosenberg PS, Katki HA. Tracking and evaluating molecular tumor markers with cancer registry data: HER2 and breast cancer. J Natl Cancer Inst. 2014;106(5). doi:10.1093/jnci/dju093.
  72. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. Journal of Clinical Investigation. 2011;121(7):2750–2767.
  73. Bareche Y, Venet D, Ignatiadis M, Aftimos P, Piccart M, Rothe F, et al. Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis. Annals of Oncology. 2018;29(4):895–902.
  74. Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SAW, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clinical Cancer Research. 2015;21(7):1688–1698.
  75. Stefansson OA, Jonasson JG, Johannsson OT, Olafsdottir K, Steinarsdottir M, Valgeirsdottir S, et al. Correction: Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Research. 2009;11(5):R47.
  76. Karaayvaz M, Cristea S, Gillespie SM, Patel AP, Mylvaganam R, Luo CC, et al. Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nature Communications. 2018;9(1):3588.
  77. Johnston SJ, Cheung K-L. Endocrine therapy for breast cancer: A model of hormonal manipulation. Oncology and Therapy. 2018;6(2):141–156.
  78. Segovia-Mendoza M, González-González ME, Barrera D, Díaz L, García-Becerra R. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of her2-positive breast cancer: Preclinical and clinical evidence. American Journal of Cancer Research. 2015;5(9):2531–2561.
  79. Gluz O, Scheffen I, Degenhardt T, Marschner NW, Christgen M, Kreipe HH, et al. ADAPTlate: A randomized, controlled, open-label, phase III trial on adjuvant dynamic marker—Adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or ge. 2021. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. TPS598. doi:10.1200/jco.2021.39.15_suppl.tps598.
  80. Fleissig A, Jenkins V, Catt S, Fallowfield L. Multidisciplinary teams in cancer care: are they effective in the UK? Lancet Oncology. 2006;7(11):935–943.
  81. Sainsbury R, Haward R, Round C, Rider L, Johnston C. Influence of clinician workload and patterns of treatment on survival from breast cancer. The Lancet. 1995;345(8960):1265–1270.
  82. Chang JH, Vines E, Bertsch H, Fraker DL, Czerniecki BJ, Rosato EF, et al. The impact of a multidisciplinary breast cancer center on recommendations for patient management: The university of Pennsylvania experience. Cancer. 2001;91(7):1231–1237.
  83. Vinod SK, Sidhom MA, Delaney GP. Do multidisciplinary meetings follow guideline-based care? Journal of Oncology Practice. 2010;6(6):276–281.
  84. Saini KS, Taylor C, Ramirez A-J, Palmieri C, Gunnarsson U, Schmoll HJ, et al. Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries. Annals of Oncology. 2012;23(4):853–859.
  85. Kesson EM, Allardice GM, George WD, Burns HJGG, Morrison DS. Effects of multidisciplinary team working on breast cancer survival: Retrospective, comparative, interventional cohort study of 13 722 women. BMJ (Online). 2012;344(7856). doi:10.1136/bmj.e2718.
  86. Harbeck N, Kates RE, Look MP, Meijer-van Gelder ME, Klijn JGM, Krüger A, et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Research. 2002;62(16):4617–4622.
  87. Tutt A, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. . 2021. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. LBA1. doi:10.1200/jco.2021.39.15_suppl.lba1.
  88. Tung NM, Zakalik D, Somerfield MR. Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update. J Clin Oncol. 2021;39(26):2959–2961.
  89. FDA. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer | FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer. Accessed 5 April 2022.
  90. Mohammed AA, Rashied H, Elsayed FM. CDK4/6 inhibitors in advanced breast cancer, what is beyond? Oncology Reviews. 2019;13(2):125–133.
  91. Ma CX, Gao F, Luo J, Northfelt DW, Goetz M, Forero A, et al. NeoPalAna: Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer. Clinical Cancer Research. 2017;23(15):4055–4065.
  92. Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR1, HER22, node-positive, high-risk, early breast cancer (monarchE). Journal of Clinical Oncology. 2020;38(34):3987–3998.
  93. Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. The Lancet Oncology. 2021;22(2):212–222.
  94. NCT01864746. A study of palbociclib in addition to standard endocrine treatment in hormone receptor positive HER2 normal patients with residual disease after neoadjuvant chemotherapy and surgery (PENELOPE-B). 2016.
  95. Pharmaceuticals N. Adjuvant Ribociclib With Endocrine Therapy in Hormone Receptor+/HER2­ Intermediate Risk Early Breast Cancer (EarLEE­2). 2017;2–5.
  96. Slamon DJ, Fasching PA, Patel R, Verma S, Hurvitz SA, Chia SKL, et al. NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC). https://doi.org/101200/JCO20193715_supplTPS597. 2019;37(15_suppl):TPS597–TPS597.
  97. FDA approves abemaciclib with endocrine therapy for early breast cancer | FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer. Accessed 10 March 2022.
  98. Martin M, Hegg R, Kim S, Schenker M, Grecea D, Saenz JAG, et al. Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC). 2021. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 517.
  99. Adjuvant endocrine therapy combined with abemaciclib in monarchE patients with high-risk early breast cancer: Disease characteristics and endocrine... | OncologyPRO. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/adjuvant-endocrine-therapy-combined-with-abemaciclib-in-monarche-patients-with-high-risk-early-breast-cancer-disease-characteristics-and-endocrine. Accessed 28 September 2021.
  100. Loibl S, Marmé F, Martin M, Untch M, Bonnefoi H, Kim SB, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the penelope-B trial. Journal of Clinical Oncology. 2021;39(14):1518–1530.
  101. Marmé F, Martin M, Untch M, Bonnefoi HR, Kim S-B, Bear HD, et al. Palbociclib combined with endocrine treatment in breast cancer patients with high relapse risk after neoadjuvant chemotherapy: Subgroup analyses of premenopausal patients in PENELOPE-B. 2021. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 518. doi:10.1200/jco.2021.39.15_suppl.518.
  102. Denkert C, Marmé F, Martin M, Untch M, Bonnefoi HR, Witkiewicz AK, et al. Subgroup of post-neoadjuvant luminal-B tumors assessed by HTG in PENELOPE-B investigating palbociclib in high risk HER2-/HR+ breast cancer with residual disease. 2021. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 519. doi:10.1200/jco.2021.39.15_suppl.519.
  103. Hattori M, Iwata H. Advances in treatment and care in metastatic breast cancer (MBC): Are there MBC patients who are curable? Chinese Clinical Oncology. 2018;7(3). doi:10.21037/cco.2018.05.01.
  104. O’Shaughnessy J. Extending Survival with Chemotherapy in Metastatic Breast Cancer. The Oncologist. 2005;10(S3):20–29.
  105. Kashaf MS, McGill E. Does shared decision making in cancer treatment improve quality of life? A systematic literature review. Medical Decision Making. 2015;35(8):1037–1048.
  106. Savard M-F, Khan O, Hunt KK, Verma S. Redrawing the lines: The next generation of treatment in metastatic breast cancer. American Society of Clinical Oncology Educational Book. 2019;(39):e8–e21.
  107. Twelves C, Cheeseman S, Sopwith W, Thompson M, Riaz M, Ahat-Donker N, et al. Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: Retrospective analysis from Leeds Cancer Centre. BMC Cancer. 2020;20(1):53.
  108. Matutino A, Joy AA, Brezden-Masley C, Chia S, Verma S. Hormone receptor-positive, HER2-negative metastatic breast cancer: Redrawing the lines. Current Oncology. 2018;25(Suppl 1):S131–S141.
  109. National Comprehensive Cancer Network (NCCN). Breast cancer - Metastatic, 2018. NCCN Guidelines for Patients. 2018. https://www.nccn.org/patients/guidelines/content/PDF/stage_iv_breast-patient.pdf. Accessed 11 May 2020.
  110. Ballinger TJ, Meier JB, Jansen VM. Current landscape of targeted therapies for hormone-receptor positive, HER2 negative metastatic breast cancer. Frontiers in Oncology. 2018;8(AUG):308.
  111. Abemaciclib, Verzenios® Summary of Product Characteristics (SmPC) - (EMC). 2020. https://www.medicines.org.uk/emc/product/9532/smpc. Accessed 15 May 2020.
  112. Palbociclib, IBRANCE® Summary of Product Characteristics (SmPC) - (EMC). 2020. https://www.ema.europa.eu/en/documents/product-information/ibrance-epar-product-information_en.pdf. Accessed 12 May 2020.
  113. Ribociclib, Kisqali® Summary of Product Characteristics (SmPC) - (EMC). 2020. https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf. Accessed 12 May 2020.
  114. Personalized medicine in advanced breast cancer: AI-driven genomic test for CDK4/6 treatment response prediction | OncologyPRO. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/personalized-medicine-in-advanced-breast-cancer-ai-driven-genomic-test-for-cdk4-6-treatment-response-prediction. Accessed 28 September 2021.
  115. Presti D, Quaquarini E. The PI3K/AKT/mTOR and CDK4/6 pathways in endocrine resistant HR+/HER2- metastatic breast cancer: Biological mechanisms and new treatments. Cancers (Basel). 2019;11(9). doi:10.3390/cancers11091242.
  116. Vinayak S, Carlson RW. mTOR inhibitors in the treatment of breast cancer. ONCOLOGY (United States). 2013;27(1).
  117. O’Shaughnessy J, Thaddeus Beck J, Royce M. Everolimus-based combination therapies for HR+, HER2− metastatic breast cancer. Cancer Treatment Reviews. 2018;69:204–214.
  118. Alpelisib PIQRAY prescribing information (FDA). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf. Accessed 14 May 2020.
  119. Vernieri C, Corti F, Nichetti F, Ligorio F, Manglaviti S, Zattarin E, et al. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: Targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications. 2020. BioMed Central Ltd.
  120. PI3K mutation is associated with reduced sensitivity to CDK4/6 inhibitors in metastatic breast cancer | OncologyPRO. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/pi3k-mutation-is-associated-with-reduced-sensitivity-to-cdk4-6-inhibitors-in-metastatic-breast-cancer. Accessed 29 September 2021.
  121. Schedin TB, Borges VF, Shagisultanova E. Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition. International Journal of Breast Cancer. 2018;2018. doi:10.1155/2018/7835095.
  122. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2. New England Journal of Medicine. 2001;344(11):783–792.
  123. Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Therapeutic Advances in Medical Oncology. 2019;11. doi:10.1177/1758835919833519.
  124. National Institute for Health and Care Excellence (NICE). Managing advanced breast cancer - NICE Pathways. 2020;(May):1–24.
  125. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LAG, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055.
  126. Azim HA, Ghosn M, Oualla K, Kassem L. Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020. The Breast Journal. 2020;26(1):69–80.
  127. Li CH, Karantza V, Aktan G, Lala M. Current treatment landscape for patients with locally recurrent inoperable or metastatic triple-negative breast cancer: A systematic literature review. Breast Cancer Research. 2019;21(1):143.
  128. atezolizumab (Tecentriq) prescribing information 2019. 2019. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf. Accessed 14 May 2020.
  129. Curigliano G. CDK4/6 inhibitors for HR+HER2− early stage breast cancer — when to escalate treatment? Nature Reviews Clinical Oncology. 2021;18(2):67–68.
  130. Dickler MN, Tolaney SM, Rugo HS, 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, n patients with refractory HR+/HER2- metastatic breast cancer. Clinical Cancer Research. 2017;23(17):5218–5224.
  131. Sledge GW, 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. Journal of Clinical Oncology. 2017;35(25):2875–2884.
  132. Slamon DJ, Neven P, Chia S, Fasching PA, de Laurentiis M, Im S-A, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. New England Journal of Medicine. 2020;382(6):514–524.
  133. Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. The Lancet Oncology. 2018;19(7):904–915.
  134. Xu QQ, Pan B, Wang CJ, Zhou YD, Mao F, Lin Y, et al. HER2 amplification level is not a prognostic factor for HER2-positive breast cancer with trastuzumab-based adjuvant treatment: A systematic review and meta-analysis. Oncotarget. 2016;7(39):63571–63582.
  135. Im S-A, Lu Y-S, Bardia A, Harbeck N, Colleoni M, Franke F, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. New England Journal of Medicine. 2019;381(4):307–316.
  136. Sledge GW, 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 Oncology. 2020;6(1):116–124.
  137. Goetz MP, Toi M, Campone M, Trédan O, Bourayou N, Sohn J, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. Journal of Clinical Oncology. 2017;35(32):3638–3646.
  138. Johnston S, Martin M, di Leo A, Im SA, 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(1):1–8.
  139. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: A changing paradigm. 2009. Nature Publishing Group.
  140. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. 2016. BioMed Central Ltd.
  141. Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Research and Treatment. 2019;174(3):719–729.
  142. Murphy CG, Dickler MN. The role of CDK4/6 inhibition in breast cancer. The Oncologist. 2015;20(5):483–490.
  143. Iwata H. Clinical development of CDK4/6 inhibitor for breast cancer. Breast Cancer. 2018;25(4):402–406.
  144. Xu H, Yu S, Liu Q, Yuan X, Mani S, Pestell RG, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. Journal of Hematology and Oncology. 2017;10(1):97.
  145. Abemaciclib, VERZENIOTM Highlights of Prescribing Information (FDA, CDER). .
  146. Palbociclib, IBRANCE® Highlights of Prescribing Information (FDA, CDER). 2019 www.fda.gov/medwatch. Accessed 15 May 2020.
  147. Ribociclib, Kisqali® Highlights of Prescribing Information (FDA, CDER). 2020.
  148. Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? npj Breast Cancer. 2019;5(1). doi:10.1038/s41523-019-0121-y.
  149. Klein ME, Kovatcheva M, Davis LE, Tap WD, Koff A. CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought. Cancer Cell. 2018;34(1):9–20.
  150. Wander SA, Zangardi M, Niemierko A, Kambadakone A, Kim LS, Xi J, et al. A multicenter analysis of abemaciclib after progression on palbociclib in patients (pts) with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). Journal of Clinical Oncology. 2019;37(15_suppl):1057–1057.
  151. Mariotti V, Khong HT, Soliman HH, Costa RL, Fisher S, Boulware D, et al. Efficacy of abemaciclib (abema) after palbociclib (palbo) in patients (pts) with metastatic breast cancer (MBC). Journal of Clinical Oncology. 2019;37(15_suppl):e12521–e12521.
  152. Kovatcheva M, Liu DD, Dickson MA, Klein ME, O’Connor R, Wilder FO, et al. MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition. Oncotarget. 2015;6(10):8226–8243.
  153. Kovatcheva M, Liao W, Klein ME, Robine N, Geiger H, Crago AM, et al. ATRX is a regulator of therapy induced senescence in human cells. Nature Communications. 2017;8(1). doi:10.1038/s41467-017-00540-5.
  154. Goel S, Decristo MJ, Watt AC, Brinjones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–475.
  155. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. 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. The Lancet Oncology. 2016;17(4):425–439.
  156. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. New England Journal of Medicine. 2016;375(20):1925–1936.
  157. Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. New England Journal of Medicine. 2016;375(18):1738–1748.
  158. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Annals of Oncology. 2018;29(7):1541–1547.
  159. Slamon DJ, Neven P, Chia S, Fasching PA, de Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. Journal of Clinical Oncology. 2018;36(24):2465–2472.

 

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