Impact of sequence order of anthracyclines and taxanes in neoadjuvant chemotherapy on pathologic complete response rate in HER2-negative breast cancer patients

Abstract

Purpose

Data exploring optimal sequencing of anthracyclines and taxanes as neoadjuvant chemotherapy (NACT) for breast cancer are limited and inconsistent. The objective of this study was to assess the real-world impact of sequence order on pathologic complete response (pCR) and clinical outcomes from NACT.

Methods

Patients with HER2-negative breast cancer treated with NACT from May 2012 to April 2020 were identified from a prospectively collected institutional database. The primary endpoint was to compare rates of pCR (ypT0/isN0) between patients who received anthracyclines followed by taxanes (AC-T) to those who received taxanes followed by anthracyclines (T-AC). Additional endpoints of interest included clinical complete response, downstaging, Neo-Bioscore, conversion to breast-conserving surgery eligibility, relapse-free survival, and overall survival between groups.

Results

Of the 283 patients who met eligibility criteria, 187 (66%) received AC-T and 96 (34%) received T-AC. Sequence order did not influence the primary endpoint of pCR rate (19% for AC-T vs. 21% for T-AC, p = 0.752). There were also no significant differences in secondary NACT efficacy outcomes between groups. In the overall cohort, pCR rate was higher in patients with triple-negative breast cancer (TNBC) (32% vs. 13% in hormone-positive cancer, p < 0.001) and grade 3 tumors (31% vs. 12% for grade 1–2 tumors, p < 0.001).

Conclusions

In this real-world analysis of HER2-negative breast cancer patients, there was no differential impact on pCR rate or clinical outcomes from NACT with sequence order of anthracyclines and taxanes. This supports the current variation in prescribing practice.

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References

  1. 1.

    Collaborative EBCT, G, (2018) Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol 19(1):27–39. https://doi.org/10.1016/S1470-2045(17)30777-5

    Article  Google Scholar 

  2. 2.

    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 384(9938):164–172. https://doi.org/10.1016/S0140-6736(13)62422-8

    Article  PubMed  Google Scholar 

  3. 3.

    LeVasseur N, Sun J, Gondara L, Diocee R, Speers C, Lohrisch C, Chia S (2020) Impact of pathologic complete response on survival after neoadjuvant chemotherapy in early-stage breast cancer: a population-based analysis. J Cancer Res Clin Oncol 146(2):529–536. https://doi.org/10.1007/s00432-019-03083-y

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Golshan M, Cirrincione CT, Sikov WM, Berry DA, Jasinski S, Weisberg TF, Somlo G, Hudis C, Winer E, Ollila DW, Alliance for Clinical Trials in O, (2015) Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates surgical results from CALGB 40603 (Alliance). Ann Surg 262(3):434–439. https://doi.org/10.1097/SLA.0000000000001417

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Golshan M, Cirrincione CT, Sikov WM, Carey LA, Berry DA, Overmoyer B, Henry NL, Somlo G, Port E, Burstein HJ, Hudis C, Winer E (2016) Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II-III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance). Breast Cancer Res Treat 160(2):297–304. https://doi.org/10.1007/s10549-016-4006-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M (2017) Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 376(22):2147–2159. https://doi.org/10.1056/NEJMoa1612645

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wulfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr, Investigators K (2019) Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380(7):617–628. https://doi.org/10.1056/NEJMoa1814017

    Article  Google Scholar 

  8. 8.

    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 26(5):778–785. https://doi.org/10.1200/JCO.2007.15.0235

    Article  PubMed  Google Scholar 

  9. 9.

    von Minckwitz G, Raab G, Caputo A, Schutte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 23(12):2676–2685. https://doi.org/10.1200/JCO.2005.05.078

    CAS  Article  Google Scholar 

  10. 10.

    Hutcheon AW, Heys SD, Sarkar TK, Aberdeen Breast G (2003) Neoadjuvant docetaxel in locally advanced breast cancer. Breast Cancer Res Treat 79(Suppl 1):S19-24

    CAS  Article  Google Scholar 

  11. 11.

    Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK, Eggleton SP, Ogston KN (2002) Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20(6):1456–1466. https://doi.org/10.1200/JCO.2002.20.6.1456

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C, Neo-tAnGo I (2014) 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, 2x2 factorial randomised phase 3 trial. Lancet Oncol 15(2):201–212. https://doi.org/10.1016/S1470-2045(13)70554-0

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Guo B, Villeneuve DJ, Hembruff SL, Kirwan AF, Blais DE, Bonin M, Parissenti AM (2004) 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(1):31–51. https://doi.org/10.1023/B:BREA.0000021046.29834.12

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Taghian AG, Abi-Raad R, Assaad SI, Casty A, Ancukiewicz M, Yeh E, Molokhia P, Attia K, Sullivan T, Kuter I, Boucher Y, Powell SN (2005) Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol 23(9):1951–1961. https://doi.org/10.1200/JCO.2005.08.119

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Zaheed M, Wilcken N, Willson ML, O’Connell DL, Goodwin A (2019) Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for early breast cancer. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD012873.pub2

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kummel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G, German Breast G, Arbeitsgemeinschaft Gynakologische Onkologie-Breast I (2016) Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 17(3):345–356. https://doi.org/10.1016/S1470-2045(15)00542-2

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Loibl S, O’Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr (2018) 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(4):497–509. https://doi.org/10.1016/S1470-2045(18)30111-6

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Schmid P, Cortes J, Pusztai L, McArthur H, Kummel 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, Investigators K (2020) Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 382(9):810–821. https://doi.org/10.1056/NEJMoa1910549

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Mittendorf EA, Vila J, Tucker SL, Chavez-MacGregor M, Smith BD, Symmans WF, Sahin AA, Hortobagyi GN, Hunt KK (2016) The neo-bioscore update for staging breast cancer treated with neoadjuvant chemotherapy: incorporation of prognostic biologic factors into staging after treatment. JAMA Oncol 2(7):929–936. https://doi.org/10.1001/jamaoncol.2015.6478

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, Smith BL, Alexander B, Moy B, Isakoff SJ, Parmigiani G, Trippa L, Bardia A (2020) Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin Cancer Res 26(12):2838–2848. https://doi.org/10.1158/1078-0432.CCR-19-3492

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bergquist JR, Murphy BL, Storlie CB, Habermann EB, Boughey JC (2017) Incorporation of treatment response, tumor grade and receptor status improves staging quality in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol 24(12):3510–3517. https://doi.org/10.1245/s10434-017-6010-4

    Article  PubMed  Google Scholar 

  22. 22.

    Bines J, Earl H, Buzaid AC, Saad ED (2014) Anthracyclines and taxanes in the neo/adjuvant treatment of breast cancer: does the sequence matter? Ann Oncol 25(6):1079–1085. https://doi.org/10.1093/annonc/mdu007

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK, American College of Surgeons Oncology Group i (2013) 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(13):1317–1325. https://doi.org/10.1016/S1470-2045(13)70502-3

    CAS  Article  Google Scholar 

  24. 24.

    Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK (2019) Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol 5(1):45–50. https://doi.org/10.1001/jamaoncol.2018.3691

    Article  PubMed  Google Scholar 

  25. 25.

    Bines J, Small IA, Sarmento R, Kestelman F, Silva S, Rodrigues FR, Faroni L, Goncalves A, Ebecken E, Maroun P, Millen E, Bonamino M (2020) Does the Sequence of Anthracycline and Taxane Matter? Oncologist, The NeoSAMBA Trial. https://doi.org/10.1634/theoncologist.2019-0805

    Google Scholar 

  26. 26.

    Pachmann K, Camara O, Pachmann U (2004) Influence of primary tumor chemotherapy in breast cancer on circulating tumor cells. Indications for massive cell release into circulation concurrent with tumor size reduction. Breast Cancer Research and Treatment 88

  27. 27.

    Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E (2012) Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 48(18):3342–3354. https://doi.org/10.1016/j.ejca.2012.05.023

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804. https://doi.org/10.1200/JCO.2011.38.8595

    Article  Google Scholar 

  29. 29.

    Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP (2015) Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33(1):13–21. https://doi.org/10.1200/JCO.2014.57.0572

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, Zahm DM, Kummel S, Eidtmann H, Klare P, Huober J, Costa S, Tesch H, Hanusch C, Hilfrich J, Khandan F, Fasching PA, Sinn BV, Engels K, Mehta K, Nekljudova V, Untch M (2014) Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15(7):747–756. https://doi.org/10.1016/S1470-2045(14)70160-3

    CAS  Article  Google Scholar 

  31. 31.

    Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN (2015) SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33(1):58–64. https://doi.org/10.1200/JCO.2014.56.3296

    Article  PubMed  Google Scholar 

  32. 32.

    Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358(16):1663–1671. https://doi.org/10.1056/NEJMoa0707056

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2015) Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer. J Clin Oncol 33(21):2353–2360. https://doi.org/10.1200/JCO.2015.60.9271

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV (1997) Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15(7):2483–2493. https://doi.org/10.1200/JCO.1997.15.7.2483

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Lovedeep Gondara for assistance with statistical analysis.

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Correspondence to N. LeVasseur.

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M.T. has no disclosures to declare. N.L. reports participation in advisory boards for Pfizer, Novartis, Lilly, and TerSera and grants from Genomic Health and Abbvie. S.C. reports participation in advisory boards for Novartis, honoraria from Novartis, Hoffmann LaRoche, Pfizer, Eli Lilly, Genomic Health, Merck, and AstraZeneca and grants from Novartis, Hoffmann LaRoche, Genomic Health, AstraZeneca, Genentech, Celgene, Merck, Sanofi, and PUMA. C.S. reports honoraria from Mylan, Sandoz, Lilly, Novartis, Roche, and Pfizer and grants from Pfizer, Roche, Merck, Lilly, Novartis, and Amgen.

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Tesch, M.E., Chia, S.K., Simmons, C.E. et al. Impact of sequence order of anthracyclines and taxanes in neoadjuvant chemotherapy on pathologic complete response rate in HER2-negative breast cancer patients. Breast Cancer Res Treat (2021). https://doi.org/10.1007/s10549-021-06110-0

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Keywords

  • Neoadjuvant
  • Breast cancer
  • Taxanes
  • Pre-operative
  • Chemotherapy