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Neoadjuvant pegylated liposomal doxorubicin- and epirubicin-based combination therapy regimens for early breast cancer: a multicenter retrospective case–control study

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Abstract

Purpose

This study aimed to compare the effectiveness and safety of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based combination therapy regimen as neoadjuvant therapy for early breast cancer.

Methods

Patients with stage I–III breast cancer who underwent neoadjuvant therapy followed by surgery between January 2018 and December 2019 were retrospectively reviewed. The primary outcome was pathological complete response (pCR) rate. The secondary outcome was radiologic complete response (rCR) rate. Outcomes were compared between treatment groups PLD-cyclophosphamide followed by docetaxel (LC-T group) or epirubicin-cyclophosphamide followed by docetaxel (EC-T group), using both propensity-score matched (matched) and unmatched data.

Results

Data were analyzed from patients who received neoadjuvant LC-T (n = 178) or EC-T (n = 181) treatment. The overall pCR rate and rCR rate were higher in the LC-T group compared with the EC-T group (unmatched pCR: 25.3% vs. 15.5%, p = 0.026; rCR: 14.7% vs. 6.7%, p = 0.016; matched pCR: 26.9% vs. 16.1%, p = 0.034; rCR: 15.5% vs. 7.4%, p = 0.044). Analysis by molecular subtype showed that compared with EC-T treatment, LC-T treatment achieved significantly greater pCR rate in triple-negative subtype and greater rCR rate in Her2 (+) subtype.

Conclusions

Neoadjuvant PLD-based therapy may be a potential option for patients with early-stage breast cancer. The current results warrant further investigation.

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Data availability

All data used in this study are available by contacting the corresponding author upon reasonable request.

Abbreviations

EPR:

Enhanced permeability and retention

Her2:

Anti-human epidermal growth factor receptor 2

LVEF:

Left ventricular ejection fraction

pCR:

Pathological complete response

PLD:

Pegylated liposomal doxorubicin

rCR:

Radiologic complete response

TNBC:

Triple-negative breast cancer

References

  1. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N (2008) Preoperative chemotherapy: updates of National surgical adjuvant breast and bowel project protocols B-18 and B-27. J clin oncol: off J American Soc Clin Oncol 26(5):778–785. https://doi.org/10.1200/jco.2007.15.0235

    Article  Google Scholar 

  2. 1.2021) BCV. National Comprehensive Cancer Network, vol. 2021.

  3. Barrett-Lee PJ, Dixon JM, Farrell C, Jones A, Leonard R, Murray N, Palmieri C, Plummer CJ, Stanley A, Verrill MW (2009) Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Ann oncol: off J European Soc Med Oncol 20(5):816–827. https://doi.org/10.1093/annonc/mdn728

    Article  CAS  Google Scholar 

  4. Cardinale D, Iacopo F, Cipolla CM (2020) Cardiotoxicity of anthracyclines. Front cardiovasc med 7:26. https://doi.org/10.3389/fcvm.2020.00026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gabizon A, Shmeeda H, Grenader T (2012) Pharmacological basis of pegylated liposomal doxorubicin: impact on cancer therapy. European J Pharm sci: off J European Fed Pharm Sci 45(4):388–398. https://doi.org/10.1016/j.ejps.2011.09.006

    Article  CAS  Google Scholar 

  6. Gabizon AA, Lyass O, Berry GJ, Wildgust M (2004) Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer investig 22(5):663–9. https://doi.org/10.1081/cnv-200032899

    Article  CAS  Google Scholar 

  7. Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharm 42(5):419–36. https://doi.org/10.2165/00003088-200342050-00002

    Article  CAS  Google Scholar 

  8. Gabizon AA, Patil Y, La-Beck NM (2016) New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug res updat : rev comment antimicrob anticancer chemother 29:90–106. https://doi.org/10.1016/j.drup.2016.10.003

    Article  Google Scholar 

  9. Liu W, Chen W, Zhang X, Zhao P, Fan Z, Bi L, Wu D, Li S, Yang M, Fu T, Song D, Han B, Zhao G, Du Y, Shi A (2021) Higher efficacy and reduced adverse reactions in neoadjuvant chemotherapy for breast cancer by using pegylated liposomal doxorubicin compared with pirarubicin. Sci rep 11(1):199. https://doi.org/10.1038/s41598-020-80415-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yao J, Pan S, Fan X, Jiang X, Yang Y, Jin J, Liu Y (2020) Pegylated liposomal doxorubicin as neoadjuvant therapy for stage II-III locally advanced breast cancer. J chemother (Florence, Italy) 32(4):202–07. https://doi.org/10.1080/1120009x.2020.1746886

    Article  CAS  Google Scholar 

  11. Hung CC, Yang Y, Tsai IC, Hsu CY, Liu CH, Yang JR (2020) The efficacy of pegylated liposomal doxorubicin-based neoadjuvant chemotherapy in breast cancer: a retrospective case-control study in Taiwan. Biochem Res Int 202:1–9. https://doi.org/10.1155/2020/5729389

    Article  Google Scholar 

  12. Dong M, Luo L, Ying X, Lu X, Shen J, Jiang Z, Wang L (2018) Comparable efficacy and less toxicity of pegylated liposomal doxorubicin versus epirubicin for neoadjuvant chemotherapy of breast cancer: a case-control study. OncoTargets therapy 11:4247–4252. https://doi.org/10.2147/ott.S162003

    Article  PubMed  PubMed Central  Google Scholar 

  13. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet (London, England) 384(9938):164–72. https://doi.org/10.1016/s0140-6736(13)62422-8

    Article  PubMed  Google Scholar 

  14. Cheng M, Song Z, Qi Y, Wang X, Zhang L, Shi J, Wang M (2019) A dose-escalating pilot study (NCT03017404) of pegylated liposomal doxorubicin and cyclophosphamide, followed by docetaxel administration as a neoadjuvant chemotherapy regimen in patients with locally advanced breast cancer. Oncol res treat 42(5):269–74. https://doi.org/10.1159/000498993

    Article  CAS  PubMed  Google Scholar 

  15. Li R, Tian F, Qi Y, Ma L, Zhou T, Li Y, Hui T, Zhang L, Wang S, Song Z (2019) Pegylated liposomal doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy in locally advanced breast cancer (registration number: ChiCTR1900023052). Sci rep 9(1):18135. https://doi.org/10.1038/s41598-019-54387-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gil-Gil MJ, Bellet M, Morales S, Ojeda B, Manso L, Mesia C, Garcia-Martínez E, Martinez-Jáñez N, Melé M, Llombart A, Pernas S, Villagrasa P, Blasco C, Baselga J (2015) Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE study. Breast cancer res treat 151(3):597–606. https://doi.org/10.1007/s10549-015-3415-2

    Article  CAS  PubMed  Google Scholar 

  17. Zhang J, Jiang H, Zhang J, Bao G, Zhang G, Wang H, Wang X (2021) Effectiveness and safety of pegylated liposomal doxorubicin versus epirubicin as neoadjuvant or adjuvant chemotherapy for breast cancer: a real-world study. BMC cancer 21(1):1301. https://doi.org/10.1186/s12885-021-09050-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann oncol: off J European Soc Med Oncol 15(3):440–449. https://doi.org/10.1093/annonc/mdh097

    Article  CAS  Google Scholar 

  19. Tsai IC, Hung CC (2021) Efficacy of pegylated liposomal doxorubicin-based neoadjuvant chemotherapy in breast cancer: a single center experience. Clin Investig Med Med Clin et Exp 44(1):E7-14

    Article  CAS  Google Scholar 

  20. Lien MY, Liu LC, Wang HC, Yeh MH, Chen CJ, Yeh SP, Bai LY, Liao YM, Lin CY, Hsieh CY, Lin CC, Li LY, Lin PH, Chiu CF (2014) Safety and efficacy of pegylated liposomal doxorubicin-based adjuvant chemotherapy in patients with stage I-III triple-negative breast cancer. Anticancer Res 34(12):7319–7326

    CAS  PubMed  Google Scholar 

  21. Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, Grischke EM, Furlanetto J, Tesch H, Hanusch C, Engels K, Rezai M, Jackisch C, Schmitt WD, von Minckwitz G, Thomalla J, Kümmel S, Rautenberg B, Fasching PA, Weber K, Rhiem K, Denkert C, Schneeweiss A (2019) A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann oncol : off J European Soc Med Oncol 30(8):1279–1288. https://doi.org/10.1093/annonc/mdz158

    Article  CAS  Google Scholar 

  22. Bianchini G, Huang C, Egle D, Bermejo B, Zamagni C, Thill M, Anton A, Zambelli S, Russo S, Ciruelos EM, Greil R, Semiglazov V, Colleoni MA, Kelly CM, Mariani G, Mastro LD, Smart C, Valagussa P, Viale G, Gianni L (2020) Tumour infiltrating lymphocytes (TILs), PD-L1 expression and their dynamics in the NeoTRIPaPDL1 trial. Ann Oncol 31:S1142–S215. https://doi.org/10.1016/annonc/annonc325

    Article  Google Scholar 

  23. Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O’Shaughnessy J (2020) Pembrolizumab for early triple-negative. Breast Cancer 382(9):810–821. https://doi.org/10.1056/NEJMoa1910549

    Article  CAS  Google Scholar 

  24. Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N (2020) Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet (London, England) 396(10257):1090–1100. https://doi.org/10.1016/s0140-6736(20)31953-x

    Article  CAS  PubMed  Google Scholar 

  25. Rocca A, Cortesi P, Cortesi L, Gianni L, Matteucci F, Fantini L, Maestri A, Giunchi DC, Cavanna L, Ciani R, Falcini F, Bagni A, Meldoli E, Dall’Agata M, Volpi R, Andreis D, Nanni O, Curcio A, Lucchi L, Amadori D, Fedeli A (2021) Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer. Ther adv med oncol 13:1758835920985632. https://doi.org/10.1177/1758835920985632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shen G, Zhao F, Huo X, Ren D, Du F, Zheng F, Zhao J (2021) Meta-analysis of HER2-enriched subtype predicting the pathological complete response within HER2-positive breast cancer in patients who received neoadjuvant treatment. Front oncol. https://doi.org/10.3389/fonc.2021.632357

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen J, Colosimo M, Lim E (2021) The management of HER2-positive early breast cancer: current and future therapies. Asia-Pacific J clin oncol 17(Suppl 6):3–12. https://doi.org/10.1111/ajco.13655

    Article  Google Scholar 

  28. Thomassin-Naggara I, Tardivon A, Chopier J (2014) Standardized diagnosis and reporting of breast cancer. Diagn interv imagin 95(7–8):759–66. https://doi.org/10.1016/j.diii.2014.06.006

    Article  CAS  Google Scholar 

  29. Wang H, Mao X (2020) Evaluation of the efficacy of neoadjuvant chemotherapy for breast cancer. Drug des, dev ther 14:2423–2433. https://doi.org/10.2147/dddt.S253961

    Article  CAS  Google Scholar 

  30. Gampenrieder SP, Peer A, Weismann C, Meissnitzer M, Rinnerthaler G, Webhofer J, Westphal T, Riedmann M, Meissnitzer T, Egger H, Klaassen Federspiel F, Reitsamer R, Hauser-Kronberger C, Stering K, Hergan K, Mlineritsch B, Greil R (2019) Radiologic complete response (rCR) in contrast-enhanced magnetic resonance imaging (CE-MRI) after neoadjuvant chemotherapy for early breast cancer predicts recurrence-free survival but not pathologic complete response (pCR). Breast Cancer Res 21(1):19. https://doi.org/10.1186/s13058-018-1091-y

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhang X, Wang D, Liu Z, Wang Z, Li Q, Xu H, Zhang B, Liu T, Jin F (2020) The diagnostic accuracy of magnetic resonance imaging in predicting pathologic complete response after neoadjuvant chemotherapy in patients with different molecular subtypes of breast cancer. Quant Imaging Med Surg 10(1):197–210. https://doi.org/10.21037/qims.2019.11.16

    Article  PubMed  PubMed Central  Google Scholar 

  32. Janssen LM, den Dekker BM, Gilhuijs KGA, van Diest PJ, van der Wall E, Elias SG (2022) MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis. NPJ Breast Cancer 8(1):107. https://doi.org/10.1038/s41523-022-00475-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kong X, Moran MS, Zhang N, Haffty B, Yang Q (2011) Meta-analysis confirms achieving pathological complete response after neoadjuvant chemotherapy predicts favourable prognosis for breast cancer patients. Eur J Cancer 47(14):2084–2090. https://doi.org/10.1016/j.ejca.2011.06.014

    Article  PubMed  Google Scholar 

  34. Research CfDEa. Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval, 2020.

  35. Browne R, McAnena P, O’Halloran N, Moloney BM, Crilly E, Kerin MJ, Lowery AJ (2022) Preoperative breast magnetic resonance imaging as a predictor of response to neoadjuvant chemotherapy. Breast Cancer: Basic Clin Res 16:11782234221103504. https://doi.org/10.1177/11782234221103504

    Article  Google Scholar 

  36. Deshpande PP, Biswas S, Torchilin VP (2013) Current trends in the use of liposomes for tumor targeting. Nanomedicine (London, England) 8(9):1509–28. https://doi.org/10.2217/nnm.13.118

    Article  CAS  PubMed  Google Scholar 

  37. Torchilin V (2011) Tumor delivery of macromolecular drugs based on the EPR effect. Adv drug deliv rev 63(3):131–5. https://doi.org/10.1016/j.addr.2010.03.011

    Article  CAS  PubMed  Google Scholar 

  38. Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv drug deliv rev 65(1):71–9. https://doi.org/10.1016/j.addr.2012.10.002

    Article  CAS  PubMed  Google Scholar 

  39. Azzi S, Hebda JK, Gavard J (2013) Vascular permeability and drug delivery in cancers. Front oncol. https://doi.org/10.3389/fonc.2013.00211

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gil-Gil MJ, Bellet M, Bergamino M, Morales S, Barnadas A, Manso L, Saura C, Fernández-Ortega A, Garcia-Martinez E, Martinez-Jañez N, Melé M, Villagrasa P, Celiz P, Perez Martin X, Ciruelos E, Pernas S (2021) Long-term cardiac safety and survival outcomes of neoadjuvant pegylated liposomal doxorubicin in elderly patients or prone to cardiotoxicity and triple negative breast cancer final results of the multicentre phase II CAPRICE study. Front oncol. https://doi.org/10.3389/fonc.2021.645026

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan, ROC

    Jui-Hung Tsai

  2. Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC

    Chung-Liang Li

  3. Breast Medical Center, Cheng Ching Hospital, Taichung, Taiwan, ROC

    Dah-Cherng Yeh

  4. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC

    Chin-Sheng Hung

  5. Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC

    Chin-Sheng Hung

  6. Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 40705, Taiwan, ROC

    Chih-Chiang Hung

  7. Breast Medical Center, Taichung Tzu Chi Hospital, No. 88, Sec. 1, Tanxing Rd, Taichung, 427, Taiwan, ROC

    Chin-Yao Lin

  8. Department of Surgery, National Cheng Kung University, Tainan, Taiwan, ROC

    Yao-Lung Kuo

  9. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

    Yao-Lung Kuo

  10. Breast Medical Center, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

    Yao-Lung Kuo

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Contributions

JHT, DCY, CSH, and CCH: contributed to classification of cohorts and study design. CSH and CCH: contributed to conceptualization. DCY, CSH, and CYL: contributed to study methodology. JHT, CLL, and DCY: contributed to data acquisition and interpretation. CCH, CYL, and YLK: contributed to statistical analysis, data interpretation. CCH, CYL, and YLK: contributed to supervision, review, and editing the draft article. JHT, CCH, CYL, and YLK: contributed to literature review and writing the draft article.

Corresponding authors

Correspondence to Chih-Chiang Hung or Chin-Yao Lin.

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All authors declare that there is no conflict of interest.

Ethical approval

The study protocol was approved by the institutional review board of six hospitals (NCKUH, KMUH, CCH, TCH, VGH-TC and TMUH; IRB number: A-ER-110–177, E(I)-20210297, HP220008, REC110-61, CE21429A and N202112074).

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Tsai, JH., Li, CL., Yeh, DC. et al. Neoadjuvant pegylated liposomal doxorubicin- and epirubicin-based combination therapy regimens for early breast cancer: a multicenter retrospective case–control study. Breast Cancer Res Treat 199, 47–55 (2023). https://doi.org/10.1007/s10549-023-06867-6

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