Online first
Review paper
Published online: 2024-04-29

open access

Page views 94
Article views/downloads 72
Get Citation

Connect on Social Media

Connect on Social Media

Combination of chemotherapy and endocrine treatment in breast cancer — is it still a taboo?

Piotr J. Wysocki1


For many years, it has been believed that a combination of endocrine therapies with chemotherapeutic agents should not be used in clinical practice as the treatment for either early or advanced breast cancer. These conclusions resulted from clinical trials conducted several decades ago, which combined a selective estrogen receptor modulator (tamoxifen) with polychemotherapy regimens in early breast cancer patients. However, recent results of clinical trials and cohort studies that evaluated combinations of novel chemotherapy regimens with aromatase inhibitors or fulvestrant demonstrated that chemoendocrine therapy is feasible, safe, and active in patients with HR+ breast cancer at various stages of the disease. This article reviews the available data on the safety, activity, and clinical utility of systemic treatment approaches based on the simultaneous administration of endocrine agents with mainly metronomic chemotherapy.

Article available in PDF format

View PDF Download PDF file


  1. Anderson WF, Rosenberg PS, Prat A, et al. How many etiological subtypes of breast cancer: two, three, four, or more? J Natl Cancer Inst. 2014; 106(8).
  2. Cardoso F, Kyriakides S, Ohno S, et al. ESMO Guidelines Committee. Electronic address: Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019; 30(8): 1194–1220.
  3. Jassem J, Krzakowski M, Bobek-Billewicz B, et al. Breast cancer. Oncol Clin Pract. 2020; 16(5): 207–260.
  4. Rugo HS, Rumble RB, Macrae E, et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016; 34(25): 3069–3103.
  5. Wysocki PJ. Wise and skillful utilization of contemporary endocrine therapies for the treatment of ER+/HER2– advanced breast cancer. Oncol Clin Pract. [online first].
  6. Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood. 1997; 89(6): 1845–1853.
  7. Lee YH, Kang BS, Bae YS. Premature senescence in human breast cancer and colon cancer cells by tamoxifen-mediated reactive oxygen species generation. Life Sci. 2014; 97(2): 116–122.
  8. Augusto TV, Amaral C, Almeida CF, et al. Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells. Mol Cell Endocrinol. 2021; 537: 111426.
  9. Amadori D, Volpi A, Maltoni R, et al. Cell proliferation as a predictor of response to chemotherapy in metastatic breast cancer: a prospective study. Breast Cancer Res Treat. 1997; 43(1): 7–14.
  10. Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat. 2007; 105 Suppl 1(Suppl 1): 33–43.
  11. Miller WR, White S, Dixon JM, et al. Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole. Br J Cancer. 2006; 94(7): 1051–1056.
  12. Levine RM, Rubalcaba E, Lippman ME, et al. Effects of Estrogen and Tamoxifen on the Regulation of Dihydrofolate Reductase Gene Expression in a Human Breast Cancer Cell Line. Cancer Res. 1985; 45(4): 1644–1650.
  13. Benz C, Cadman E, Gwin J, et al. Tamoxifen and 5-fluorouracil in breast cancer: cytotoxic synergism in vitro. Cancer Res. 1983; 43(11): 5298–5303.
  14. Goldenberg GJ, Froese EK. Antagonism of the cytocidal activity and uptake of melphalan by tamoxifen in human breast cancer cells in vitro. Biochem Pharmacol. 1985; 34(6): 763–770.
  15. Pico C, Martin M, Jara C, et al. GEICAM Group. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study. Ann Oncol. 2004; 15(1): 79–87.
  16. Bedognetti D, Sertoli MR, Pronzato P, et al. Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial. J Natl Cancer Inst. 2011; 103(20): 1529–1539.
  17. Albain KS, Barlow WE, Ravdin PM, et al. Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009; 374(9707): 2055–2063.
  18. Del Mastro L, Dozin B, Aitini E, et al. GONO-MIG Group. Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: findings from two consecutive trials of Gruppo Oncologico Nord-Ovest-Mammella Intergruppo (GONO-MIG) Group. Ann Oncol. 2008; 19(2): 299–307.
  19. Poggio F, Ceppi M, Lambertini M, et al. Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis. Breast. 2017; 33: 104–108.
  20. Torrisi R, Bagnardi V, Rotmensz N, et al. Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer. Breast Cancer Res Treat. 2011; 126(2): 431–441.
  21. Mohammadianpanah M, Ashouri Y, Hoseini S, et al. The efficacy and safety of neoadjuvant chemotherapy +/- letrozole in postmenopausal women with locally advanced breast cancer: a randomized phase III clinical trial. Breast Cancer Res Treat. 2012; 132(3): 853–861.
  22. Yu KD, Wu SY, Liu GY, et al. Concurrent neoadjuvant chemotherapy and estrogen deprivation in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (CBCSG-036): A randomized, controlled, multicenter trial. Cancer. 2019; 125(13): 2185–2193.
  23. Matsunuma R, Watanabe T, Hozumi Y, et al. Preoperative concurrent endocrine therapy with chemotherapy in luminal B-like breast cancer. Breast Cancer. 2020; 27(5): 819–827.
  24. Rimawi MF, Cecchini RS, Rastogi P, et al. Abstract S3-06: A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52. Cancer Res. 2017; 77(4_Supplement): S3-06-S3–06.
  25. Lambertini M, Guarneri V, Caremoli ER, et al. 95TiP Gruppo Italiano Mammella (GIM) 10 – CONSENT: A phase III randomized study comparing concurrent versus sequential administration of adjuvant chemotherapy (CT) and aromatase inhibitors (AIs) in post-menopausal patients (pts) with hormone receptor-positive (HR+) early breast cancer (EBC). Ann Oncol. 2020; 31: S47.
  26. Gundem G, Van Loo P, Kremeyer B, et al. ICGC Prostate Group. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015; 520(7547): 353–357.
  27. Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 2003; 3(6): 453–458.
  28. Yu T, Wang C, Xie M, et al. Heterogeneity of CTC contributes to the organotropism of breast cancer. Biomed Pharmacother. 2021; 137: 111314.
  29. Hapach LA, Carey SP, Schwager SC, et al. Phenotypic Heterogeneity and Metastasis of Breast Cancer Cells. Cancer Res. 2021; 81(13): 3649–3663.
  30. Savci-Heijink CD, Halfwerk H, Hooijer GKJ, et al. Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res Treat. 2015; 150(3): 547–557.
  31. Schettini F, De Santo I, Rea CG, et al. CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. Front Oncol. 2018; 8: 608.
  32. Knudsen ES, Witkiewicz AK. The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer. 2017; 3(1): 39–55.
  33. Wysocki PJ, Lubas MT, Wysocka ML. Metronomic Chemotherapy in Prostate Cancer. J Clin Med. 2022; 11(10).
  34. Aurilio G, Munzone E, Botteri E, et al. Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report. Breast J. 2012; 18(5): 470–474.
  35. Munzone E, Regan MM, Cinieri S, et al. A Randomized Phase II Trial of Metronomic Oral Vinorelbine plus Cyclophosphamide and Capecitabine (VEX) vs Weekly Paclitaxel (P) as First- or Secon... | OncologyPRO. (17.09.2022).
  36. Kwinta Ł, Wysocki P. Strikingly high activity of metronomic chemotherapy in a patient with locally advanced, life-threatening cutaneous squamous-cell cancer — case report and discussion of the literature. Oncol Clin Pract. 2023; 19(3): 174–177.
  37. Wysocki PJ, Łobacz M, Potocki P, et al. Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer. Cancers (Basel). 2023; 15(4).
  38. Sledge GW, Toi M, Neven P, 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.
  39. Im SA, Lu YS, Bardia A, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019; 381(4): 307–316.
  40. Lu YS, Im SA, Colleoni M, et al. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022; 28(5): 851–859.
  41. Kollmann K, Heller G, Schneckenleithner C, et al. A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis. Cancer Cell. 2013; 24(2): 167–181.
  42. Scirocchi F, Scagnoli S, Botticelli A, et al. Immune effects of CDK4/6 inhibitors in patients with HR/HER2 metastatic breast cancer: Relief from immunosuppression is associated with clinical response. EBioMedicine. 2022; 79: 104010.
  43. Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017; 548(7668): 471–475.
  44. Schaer DA, Beckmann RP, Dempsey JA, 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.
  45. Krzakowski M, Wysocki P. Chemioterapia metronomiczna. Onkol Prakt Klin Edu. 2019; 5(D).
  46. Cazzaniga ME, Munzone E, Bocci G, et al. Pan-European Expert Meeting on the Use of Metronomic Chemotherapy in Advanced Breast Cancer Patients: The PENELOPE Project. Adv Ther. 2019; 36(2): 381–406.
  47. Schwartzberg LS, Wang G, Somer BG, et al. Phase II trial of fulvestrant with metronomic capecitabine for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Breast Cancer. 2014; 14(1): 13–19.
  48. Rashad N, Abdelhamid T, Shouman SA, et al. Capecitabine-Based Chemoendocrine Combination as First-Line Treatment for Metastatic Hormone-Positive Metastatic Breast Cancer: Phase 2 Study. Clin Breast Cancer. 2020; 20(3): 228–237.
  49. Buda-Nowak A, Kwinta Ł, Potocki P, et al. Metronomic Chemo-Endocrine Therapy (FulVEC) as a Salvage Treatment for Patients with Advanced, Treatment-Refractory ER+/HER2-Breast Cancer-A Retrospective Analysis of Consecutive Patients Data. J Clin Med. 2023; 12(4).
  50. Shi W, Wang X, Bi X, et al. Combination of Aromatase Inhibitors with Metronomic Capecitabine: A New Chemoendocrine Treatment for Advanced Breast Cancer. Journal of Cancer Therapy. 2019; 10(02): 146–156.
  51. Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021; 22(2): 212–222.
  52. Loibl S, Marmé F, Martin M, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol. 2021; 39(14): 1518–1530.
  53. Johnston SRD, Harbeck N, Hegg R, et al. monarchE Committee Members and Investigators. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020; 38(34): 3987–3998.
  54. André N, Banavali S, Snihur Y, et al. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 2013; 14(6): e239–e248.
  55. Mo H, sun X, zhai J, et al. Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a bayesian adaptive randomized design. In proceedings of the presented at SABCS 2023. December 5-9, 2023. San antonio, TX. Abstract RF01-06. 2023.