Adjuvant capecitabine in combination with docetaxel and cyclophosphamide versus anthracycline plus docetaxel and cyclophosphamide regimen in women with high-risk, HER2-negative breast cancer: An open-label, randomized controlled trial

Abstract

Background: The standard adjuvant chemotherapy for early-stage, high-risk breast cancer includes anthracyclines and taxanes. While anthracycline-based regimens have proven effective in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, their efficacy may be reduced in HER2-negative patients due to the lack of co-amplification of DNA topoisomerase IIα, the primary target of anthracyclines. This study compared the efficacy and safety of the regimen of docetaxel, anthracycline, and cyclophosphamide (TAC) versus a novel regimen consisting of docetaxel, cyclophosphamide, and capecitabine (TCX), hypothesizing that replacement of anthracycline with capecitabine could offer superior outcomes in this patient population.

Methods: In this open-label, randomized controlled trial, 204 patients with pT1-3, node-positive or high-risk node-negative, HER2-negative early-stage breast cancer were enrolled between May 2011 and December 2013 (ClinicalTrials.gov: NCT01354522). Patients were randomized 2:1 to TAC (n = 136) or TCX (n = 68), with treatment administered every 21 days for six cycles. The primary endpoints were disease-free survival (DFS) and overall survival (OS); secondary endpoints included distant disease-free survival (DDFS), disease-specific survival (DSS), and adverse event (AE) rates.

Results: With a median follow-up of 124.4 (range, 19.5-147.8) months, TCX did not significantly improve the 10-year DFS rate over TAC (71.5% ± 5.6% vs. 67.6% ± 4.0%, P = 0.477). However, the 10-year OS rate was significantly higher in the TCX group than in the TAC group (91.0% ± 3.5% vs. 77.2% ± 3.6%, P = 0.009). The TCX group also showed trends toward improved 10-year DDFS rate (82.0% ± 4.7% vs. 69.8% ± 3.9%, P = 0.052) and significantly higher 10-year DSS rate (93.9% ± 3.0% vs. 77.8% ± 3.6%, P = 0.002) compared to the TAC group. Grade 3-4 AEs occurred significantly more often in the TAC group than the TCX group (67.7% vs. 42.7%, P = 0.001).

Conclusion: TCX may provide superior long-term survival and a more favorable safety profile compared to TAC for patients with high-risk HER2-negative breast cancer, warranting further investigation in larger cohorts.

Keywords

adjuvant chemotherapy / capecitabine / disease-free survival / her2-negative breast cancer / overall survival

References

[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263.

[2] Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019; 321(3): 288-300.

[3] Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005; 352(22): 2302-2313.

[4] Saleh Y, Abdelkarim O, Herzallah K, Abela GS. Anthracycline-induced cardiotoxicity: mechanisms of action, incidence, risk factors, prevention, and treatment. Heart Fail Rev. 2021; 26(5): 1159-1173.

[5] Alizadehasl A, Ghadimi N, Kaveh S, Maleki M, Ghavamzadeh A, Noohi F, et al. Prevention of anthracycline-induced cardiotoxicity: a systematic review and network meta-analysis. Int J Clin Pharm. 2021; 43(1): 25-34.

[6] Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, et al. C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994; 330(18): 1260-1266.

[7] Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008; 100(1): 14-20.

[8] Di Leo A, Gancberg D, Larsimont D, Tanner M, Jarvinen T, Rouas G, et al. HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res. 2002; 8(5): 1107-1116.

[9] Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, et al. Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil. J Clin Oncol. 2005; 23(30): 7483-7490.

[10] Layman RM, Thomas DG, Griffith KA, Smerage JB, Helvie MA, Roubidoux MA, et al. Neoadjuvant docetaxel and capecitabine and the use of thymidine phosphorylase as a predictive biomarker in breast cancer. Clin Cancer Res. 2007; 13(14): 4092-4097.

[11] Andreetta C, Puppin C, Minisini A, Valent F, Pegolo E, Damante G, et al. Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer. Ann Oncol. 2009; 20(2): 265-271.

[12] Tolaney SM, Jeong J, Guo H, Brock J, Morganstern D, Come SE, et al. A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer. Cancer Med. 2014; 3(2): 293-299.

[13] Sobrero A, Guglielmi A, Grossi F, Puglisi F, Aschele C. Mechanism of action of fluoropyrimidines: relevance to the new developments in colorectal cancer chemotherapy. Semin Oncol. 2000; 27(5): 72-77.

[14] Puglisi F, Cardellino GG, Crivellari D, Di Loreto C, Magri MD, Minisini AM, et al. Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer. Ann Oncol. 2008; 19(9): 1541-1546.

[15] Zujewski JA, Rubinstein L. CREATE-X a role for capecitabine in early-stage breast cancer: an analysis of available data. NPJ Breast Cancer. 2017; 3: 27.

[16] Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017; 376(22): 2147-2159.

[17] Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, et al. Adjuvant capecitabine for early breast cancer: 15-year overall survival results from a randomized trial. J Clin Oncol. 2022; 40(10): 1051-1058.

[18] Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, et al. Phase III trial of adjuvant capecitabine after standard neo-/adjuvant chemotherapy in patients with early triple-negative breast cancer. J Clin Oncol. 2020; 38(3): 203-213.

[19] Bai J, Yao X, Pu Y, Wang X, Luo X. Capecitabine-based chemotherapy in early-stage triple-negative breast cancer: a meta-analysis. Front Oncol. 2023; 13: 1245650.

[20] Parsons HA, Burstein HJ. Adjuvant Adjuvant capecitabine in triple-negative breast cancer: new strategies for tailoring treatment recommendations. JAMA. 2021; 325(1): 36-38.

[21] Theriault RL, Carlson RW, Allred C, Anderson BO, Burstein HJ, Edge SB, et al. Breast cancer, version 3.2013: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013; 11(7): 753-761.

[22] U.S. Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0. 2009. Available from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf

[23] Schmidt M, Nitz U, Reimer T, Schmatloch S, Graf H, Just M, et al. Adjuvant capecitabine versus nihil in older patients with node-positive/high-risk node-negative early breast cancer receiving ibandronate - the ICE randomized clinical trial. Eur J Cancer. 2023; 194: 113324.

[24] Furukawa T, Tabata S, Yamamoto M, Kawahara K, Shinsato Y, Minami K, et al. Thymidine phosphorylase in cancer aggressiveness and chemoresistance. Pharmacol Res. 2018; 132: 15-20.

[25] Suresh A, Ganju A, Morgan E, Palettas M, Stephens JA, Liu J, et al. Efficacy of different dosing schedules of capecitabine for metastatic breast cancer: a single-institution experience. Investigational New Drugs. 2020; 38(5): 1605-1611.

[26] Nitz U, Gluz O, Clemens M, Malter W, Reimer T, Nuding B, et al. West German study planB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019; 37(10): 799-808.

[27] de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, et al. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022; 126(12): 1715-1724.

[28] Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US oncology research trial 9735. J Clin Oncol. 2009; 27(8): 1177-1183.

[29] Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009; 360(20): 2055-2065.

[30] Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, et al. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011; 29(29): 3877-3884.

[31] Miller K, Kreis IA, Gannon MR, Medina J, Clements K, Horgan K, et al. The association between guideline adherence, age and overall survival among women with non-metastatic breast cancer: A systematic review. Cancer Treat Rev. 2022; 104: 102353.

[32] Chirgwin JH, Giobbie-Hurder A, Coates AS, Price KN, Ejlertsen B, Debled M, et al. Treatment adherence and its impact on disease-free survival in the Breast International Group 1-98 trial of tamoxifen and letrozole, alone and in sequence. J Clin Oncol. 2016; 34(21): 2452-2459.

RIGHTS & PERMISSIONS

2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.