Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical Study

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34

British Journal of Cancer volume 124, pages 1795–1802 (2021)Cite this article

Subjects

Abstract

Background

Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences.

Methods

HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint.

Results

No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation.

Conclusion

Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Consort diagram: ABCSG-34 trial overview.
Fig. 2: RCB 0/1 rate and pCR rate in patients with conventional and reverse chemotherapy sequence.
Fig. 3: RCB 0/1 rate and pCR rate in patients with conventional and reverse chemotherapy sequence with or without L-BLP25.

References

  1. Bonadonna, G. Karnofsky memorial lecture. Conceptual and practical advances in the management of breast cancer. J. Clin. Oncol. 7, 1380–1397 (1998).

    Article  Google Scholar 

  2. Kaufmann, M., von Minckwitz, G., Bear, H. D., Buzdar, A., McGale, P., Bonnefoi, H. et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann. Oncol. 18, 1927–1934 (2007).

    Article  CAS  Google Scholar 

  3. Bear, H. D., Anderson, S., Smith, R. E., Geyer, C. E. Jr., Mamounas, E. P., Fisher, B. et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J. Clin. Oncol. 24, 2019–2027 (1999).

  4. von Minckwitz, G., Untch, M., Blohmer, J. U., Costa, S. D., Eidtmann, H., Fasching, P. A. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796–1804 (2012).

    Article  Google Scholar 

  5. Cortazar, P., Zhang, L., Untch, M., Mehta, K., Costantino, J. P., Wolmark, N. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).

    Article  Google Scholar 

  6. Symmans, W. F., Peintinger, F., Hatzis, C., Rajan, R., Kuerer, H., Valero, V. et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414–4422 (2007).

    Article  Google Scholar 

  7. Wildiers, H., Forceville, K., Paridaens, R. & Joensuu, H. Taxanes and anthracyclines in early breast cancer: which first? Lancet Oncol. 11, 219–220 (2010).

    Article  Google Scholar 

  8. Alvarez, R. H., Bianchini, G., Hsu, L., Cristofanilli, M., Esteva, F. J., Pusztai, L. et al. Clinical outcome of two sequences of administering paclitaxel (P) and anthracyclines (A) as primary systemic therapy (PST) and adjuvant chemotherapy (ACT) in breast cancer (BC) patients: a retrospective analysis from the M. D. Anderson Cancer Center (MDACC). Cancer Res. 70(24 Suppl), 384s (2010).

    Google Scholar 

  9. Puhalla, S., Mrozek, E., Young, D., Ottman, S., McVey, A., Kendra, K. et al. Randomized phase II adjuvant trial of dose-dense docetaxel before or after doxorubicin plus cyclophosphamide in axillary node-positive breast cancer. J. Clin. Oncol. 26, 1691–1697 (2008).

    Article  CAS  Google Scholar 

  10. Guo, B., Villeneuve, D. J., Hembruff, S. L., Kirwan, A. F., Blais, D. E., Bonin, M. et al. Cross-resistance studies of isogenic drug-resistant breast tumor cell lines support recent clinical evidence suggesting that sensitivity to paclitaxel may be strongly compromised by prior doxorubicin exposure. Breast Cancer Res. Treat. 85, 31–51 (2004).

    Article  CAS  Google Scholar 

  11. Chang, B. D., Broude, E. V., Dokmanovic, M., Zhu, H., Ruth, A., Xuan, Y. et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 59, 3761–3767 (1999).

    CAS  PubMed  Google Scholar 

  12. Ewald, J. A., Desotelle, J. A., Wilding, G. & Jarrard, D. F. Therapy-induced senescence in cancer. J. Natl Cancer Inst. 102, 1536–1546 (2010).

    Article  CAS  Google Scholar 

  13. Camara, O., Rengsberger, M., Egbe, A., Koch, A., Gajda, M., Hammer, U. et al. The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Ann. Oncol. 18, 1484–1492 (2007).

    Article  CAS  Google Scholar 

  14. Singer, C. F., Pfeiler, G., Hubalek, M., Bartsch, R., Stöger, H., Pichler, A. et al. Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: results from a prospective, randomized, neoadjuvant Phase II Study (ABCSG 34). Eur. J. Cancer 132, 43–52 (2020).

    Article  CAS  Google Scholar 

  15. Sledge, G. W., Neuberg, D., Bernardo, P., Ingle, J. N., Martino, S., Rowinsky, E. K. et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J. Clin. Oncol. 21, 588–592 (2003).

    Article  Google Scholar 

  16. Murtaza, M., Dawson, S. J., Pogrebniak, K., Rueda, O. M., Provenzano, E., Grant, J. et al. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat. Commun. 6, 8760 (2015).

    Article  Google Scholar 

  17. Earl, H. M., Vallier, A. L., Hiller, L., Fenwick, N., Young, J., Iddawela, M. et al. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 15, 201–212 (2014).

    Article  CAS  Google Scholar 

  18. Buzdar, A. U., Suman, V. J., Meric-Bernstam, F., Leitch, A. M., Ellis, M. J., Boughey, J. C. et al. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 14, 1317–1325 (2013).

    Article  CAS  Google Scholar 

  19. Staems, V., Singh, B., Tsangaris, T., Crawford, J. G., Novielli, A., Ellis, M. J. et al. A prospective randomized pilot study to evaluate predictors of response in serial core biopsies to single agent neoadjuvant doxorubicin or paclitaxel for patients with locally advanced breast cancer. Clin. Cancer Res 9, 124–133 (2003).

    Google Scholar 

  20. Taghian, A. G., Abi-Raad, R., Assaad, S. I., Casty, A., Ancukiewicz, M., Yeh, E. et al. Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J. Clin. Oncol. 23, 1951–1961 (2005).

    Article  CAS  Google Scholar 

  21. Miller, K. D., Soule, S. E., Calley, C., Emerson, R. E., Hutchins, G. D., Kopecky, K. et al. Randomized phase II trial of the anti-angiogenic potential of doxorubicin and docetaxel; primary chemotherapy as Biomarker Discovery Laboratory. Breast Cancer Res. Treat. 89, 187–197 (2005).

    Article  CAS  Google Scholar 

  22. Thiery-Vuillemin, A., Llombart-Cussac, A., Chaigneau, L., Villanueva, C., Bazan, F., Montcuquet, P. et al. Sequential taxane and anthracycline-containing neoadjuvant regimens: the sequential order impact. Breast 20, 46–49 (2011).

    Article  CAS  Google Scholar 

  23. Cardoso, F., Ferreira Filho, A. F., Crown, J., Dolci, S., Paesmans, M., Riva, A. et al. Doxorubicin followed by docetaxel versus docetaxel followed by doxorubicin in the adjuvant treatment of node positive breast cancer: results of a feasibility study. Anticancer Res. 21, 789–795 (2001).

    CAS  PubMed  Google Scholar 

  24. Piedbois, P., Serin, D., Priou, F., Laplaige, P., Greget, S., Angellier, E. et al. Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study. Ann. Oncol. 18, 52–57 (2007).

    Article  CAS  Google Scholar 

  25. Wildiers, H., Dirix, L., Neven, P., Prové, A., Clement, P., Squifflet, P. et al. Delivery of adjuvant sequential dose-dense FEC-Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence. Breast Cancer Res. Treat. 114, 103–112 (2009).

    Article  CAS  Google Scholar 

  26. Zaheed, M., Wilcken, N., Willson, M. L., O’Connell, D. L. & Goodwin, A. Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for early breast cancer. Cochrane Database Syst. Rev. CD012873 (2019).

  27. Untch, M., Jackisch, C., Schneeweiss, A., Conrad, B., Aktas, B., Denkert, C. et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 17, 345–356 (2016).

    Article  CAS  Google Scholar 

  28. Loibl, S., O’Shaughnessy, J., Untch, M., Sikov, W. M., Rugo, H. S., McKee, M. D. et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 19, 497–509 (2018).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Martina Putz for her support in preparing the final version of this paper.

Author information

Authors and Affiliations

  1. Department of Medicine 1, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria

    Rupert Bartsch

  2. Department of Gynecology, Medical University of Vienna, Vienna, Austria

    Christian F. Singer, Georg Pfeiler & Tea Maria Muy-Kheng

  3. Breast Center Schwaz, BKH Schwaz, Schwaz, Austria

    Michael Hubalek

  4. Division of Oncology, Department of Internal Medicine and Comprehensive Cancer Center, Medical University of Graz, Graz, Austria

    Herbert Stoeger & Marija Balic

  5. Department of Hemato-Oncology, LKH Hochsteiermark-Leoben, Leoben, Austria

    Angelika Pichler & Christoph Tinchon

  6. Department of Gynecology and Obstetrics, Medical University of Graz, Graz, Austria

    Edgar Petru & Vesna Bjelic-Radisic

  7. Breast Unit, Helios University Hospital Wuppertal, Wuppertal Germany, University Witten/Herdecke, Wuppertal, Germany

    Vesna Bjelic-Radisic

  8. Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Disease, Rheumatology, Oncologic Center, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University, Salzburg, Austria

    Richard Greil

  9. Department of Pathology, Medical University of Vienna, Vienna, Austria

    Margaretha Rudas & Zsuzsanna Bago-Horvath

  10. Breastcenter Carinthia, St. Veit, Austria

    Viktor Wette

  11. Internal Medicine I, Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Barmherzige Schwestern, Elisabethinen, Linz, Austria

    Andreas L. Petzer

  12. Karl Landsteiner Institute for Gynecologic Oncology and Senology, Vienna, Austria

    Paul Sevelda

  13. Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria

    Daniel Egle

  14. Department of Surgery and Breast Health Center of the Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Peter C. Dubsky, Florian Fitzal, Ruth Exner & Raimund Jakesz

  15. Breastcenter St. Anna, Lucerne, Switzerland

    Peter C. Dubsky

  16. Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Martin Filipits

  17. Statistics Department, Austrian Breast & Colorectal Cancer Study Group (ABCSG), Vienna, Austria

    Sophie Frantal

  18. Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

    Michael Gnant

Authors
  1. Rupert Bartsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian F. Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg Pfeiler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Hubalek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Herbert Stoeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angelika Pichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edgar Petru
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vesna Bjelic-Radisic
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard Greil
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Margaretha Rudas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tea Maria Muy-Kheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Viktor Wette
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andreas L. Petzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Paul Sevelda
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Daniel Egle
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Peter C. Dubsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Martin Filipits
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Florian Fitzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ruth Exner
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Raimund Jakesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Marija Balic
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Christoph Tinchon
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Zsuzsanna Bago-Horvath
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Sophie Frantal
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Michael Gnant
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Austrian Breast and Colorectal Cancer Study Group

Contributions

Conception and design: C.S., R.B., P.D., F.F., M.G. and M.H. Development of methodology: V.B.R., P.D., M.F., S.F., M.G., R.G., Z.B.H. and M.R. Acquisition of the data: all authors. Interpretation of the data: all authors. Paper writing: all authors. Paper approval: all authors.

Corresponding author

Correspondence to Marija Balic.

Ethics declarations

Ethics approval and consent to participate

The study was conducted according to the principles of the Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice. The protocol was conducted under EU directive 2001/20/EC and approved by the Ethics Committee of the Medical University of Vienna, Borschkegasse 8b/6, A-1090 Vienna, Austria, as the leading ethics committee. All subjects provided their written informed consent to participate in the study.

Consent to publish

Not applicable.

Data availability

As the regulatory sponsor of this trial, ABCSG has data sovereignty and individual participant data (including de-identified participant data, participant data with identifiers, data dictionary or other specified datasets) will not be shared.

Competing interests

R.B. reports advisory roles at AstraZeneca, Celgene, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, Samsung, lecture honoraria: Accord, AstraZeneca, BMS, Celgene, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, Sandoz and received research support from Daiichi, Novartis and Roche, all outside of the submitted work. M.H. reports honoraria and/or travel support from Amgen, AstraZeneca, Celgene, Eli-Lilly, Pfizer, Novartis, Roche all outside the submitted work. A.L.P. reports honoraria and/or travel support from Abbvie, Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, Eli-Lilly, MSD, Pfizer, Novartis, Roche, Sanofi and Takeda all outside the submitted work. D.E. reports honoraria/travel support from Amgen, AstraZeneca, Celgene, Eli-Lilly, MSD, Novartis, Pfizer, Roche and Myriad all outside of the submitted work. M.F. has received honoraria for advisory boards from AstraZeneca, Bayer, Biomedica, Boehringer Ingelheim, Eli-Lilly, Merck Sharp & Dohme, Myriad Genetics Inc., Pfizer and Roche. M.G. reports personal fees/travel support from Amgen, AstraZeneca, Celgene, Eli-Lilly, Invectys, Pfizer, Novartis, Puma, Nanostring, Roche, Medison, LifeBrain, all outside the submitted work; an immediate family member is employed by Sandoz. Z.B.-H. has advisory roles at Biomedica, Roche and Novartis, received lecture honoraria and travel support from Roche and research support from Boehringer Ingelheim. C.F.S., G.P., H.S., A.P., E.P., V.B.-R., R.G., M.R., M.K.T., V.W., P.S., P.D., F.F., R.E., R.J., M.B., C.T. and S.F. declare no competing interests.

Funding information

This study was supported by Merck KGaA, Darmstadt, Germany. The academic non-profit organisation ABCSG was the regulatory sponsor of this trial. Merck provided financial funding and tecemotide. The study was designed and conducted by ABCSG. Merck was not involved in the collection, management, analysis and interpretation of the data. ABCSG prepared and approved the paper and decided to submit the paper for the publication.

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bartsch, R., Singer, C.F., Pfeiler, G. et al. Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34. Br J Cancer 124, 1795–1802 (2021). https://doi.org/10.1038/s41416-021-01284-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01284-2

Search

Advanced search

Quick links