A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer

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Abstract

Purpose

Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC.

Methods

We randomized patients with stage I–III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2.

Results

We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups ( p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups ( p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years.

Conclusions

Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC.

Trial registration

UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

Electronic supplementary material

The online version of this article (10.1007/s10549-020-05590-w) contains supplementary material, which is available to authorized users.

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Most cited references 10

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Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

Patricia Cortazar, Lijun Zhang, Michael Untch … (2014)

Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. US Food and Drug Administration. Copyright © 2014 Elsevier Ltd. All rights reserved.

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The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27.

Harry Bear, Stewart Anderson, Ann Brown … (2003)

The National Surgical Adjuvant Breast and Bowel Project Protocol B-27 was designed to determine the effect of adding docetaxel after four cycles of preoperative doxorubicin and cyclophosphamide (AC) on clinical and pathological response rates and on disease-free and overall survival of women with operable breast cancer. Women (N = 2,411) with operable primary breast cancer were randomly assigned to receive either four cycles of preoperative AC followed by surgery (group I), or four cycles of AC followed by four cycles of docetaxel, followed by surgery (group II), or four cycles of AC followed by surgery and then four cycles of docetaxel (group III). Clinical and pathologic tumor responses to preoperative therapy were assessed. Mean tumor size (4.5 cm) and other key characteristics were evenly balanced among the three treatment arms. Grade 4 toxicity was observed in 10.3% of 2,400 patients during AC treatment, and in 23.4% of 1584 patients during docetaxel treatment. Compared to preoperative AC alone, preoperative AC followed by docetaxel increased the clinical complete response rate (40.1% v 63.6%; P <.001), the overall clinical response rate (85.5% v 90.7%; P <.001), the pathologic complete response rate (13.7% v 26.1%; P <.001), and the proportion of patients with negative nodes (50.8% v 58.2%; P <.001). Pathologic primary breast tumor response was a significant predictor of pathologic nodal status (P <.001). The addition of four cycles of preoperative docetaxel after four cycles of preoperative AC significantly increased clinical and pathologic response rates for operable breast cancer.

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Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel.

Simon P.K. Payne, Oleg Eremin, Anthony Smith … (2002)

To compare the efficacy of neoadjuvant (NA) docetaxel (DOC) with anthracycline-based therapy and determine the efficacy of NA DOC in patients with breast cancer initially failing to respond to anthracycline-based NA chemotherapy (CT). Patients with large or locally advanced breast cancer received four pulses of cyclophosphamide 1,000 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.5 mg/m(2), and prednisolone 40 mg (4 x CVAP) for 5 days. Clinical tumor response was assessed. Those who responded (complete response [CR] or partial response [PR]) were randomized to receive further 4 x CVAP or 4 x DOC (100 mg/m(2)). All nonresponders received 4 x DOC. One hundred sixty-two patients were enrolled; 145 patients completed eight cycles of NA CT. One hundred two patients (66%) achieved a clinical response (PR or CR) after 4 x CVAP. After randomization, 50 patients received 4 x CVAP and 47 patients received 4 x DOC. In patients who received eight cycles of CT, the clinical CR (cCR) and clinical PR (cPR) (94% v 66%) and pathologic CR (pCR) (34% v 16%) response rates were higher (P =.001 and P =.04) in those who received further DOC. Intention-to-treat analysis demonstrated cCR and cPR (85% v 64%; P =.03) and pCR (31% v 15%; P =.06). Axillary lymph node examination revealed residual tumor in 33% of patients who received 8 x CVAP and 38% of patients who received further DOC. In patients who failed to respond to the initial CVAP, 4 x DOC resulted in a cCR and cPR rate of 55% and a pCR rate of 2%. Forty-four percent of these patients had residual tumor within axillary lymph nodes. NA DOC resulted in substantial improvement in responses to DOC.

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Author and article information

Contributors

Hiroshi Ishiguro:

ORCID: http://orcid.org/0000-0002-9859-5932

hishiguro@iuhw.ac.jp

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res. Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (New York )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 13 March 2020

Publication date PMC-release: 13 March 2020

Publication date (Print): 2020

Volume: 180

Issue: 3

Pages: 715-724

Affiliations

[1 ]GRID grid.411731.1, ISNI 0000 0004 0531 3030, International University of Health and Welfare, ; 4-3 Kozunomori, Narita, 286-8686 Japan

[2 ]GRID grid.416803.8, ISNI 0000 0004 0377 7966, National Hospital Organization Osaka National Hospital, ; Osaka, Japan

[3 ]GRID grid.416203.2, ISNI 0000 0004 0377 8969, Niigata Cancer Center Hospital, ; Niigata, Japan

[4 ]Higaki Breastcare Clinic, Osaka, Japan

[5 ]Yao Municipal Hospital, Osaka, Japan

[6 ]Gunma Prefectural Cancer Center, Maebashi, Japan

[7 ]Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan

[8 ]GRID grid.415270.5, National Hospital Organization Hokkaido Cancer Center, ; Sapporo, Japan

[9 ]GRID grid.470097.d, ISNI 0000 0004 0618 7953, Hiroshima University Hospital, ; Hiroshima, Japan

[10 ]GRID grid.415872.d, ISNI 0000 0004 1781 5521, Shuto General Hospital, ; Yamaguchi, Japan

[11 ]GRID grid.411152.2, ISNI 0000 0004 0407 1295, Kumamoto University Hospital, ; Kumamoto, Japan

[12 ]GRID grid.486756.e, ISNI 0000 0004 0443 165X, Cancer Institute Hospital of JFCR, ; Tokyo, Japan

[13 ]GRID grid.410813.f, ISNI 0000 0004 1764 6940, Toranomon Hospital, ; Tokyo, Japan

[14 ]GRID grid.411217.0, ISNI 0000 0004 0531 2775, Kyoto University Hospital, ; Kyoto, Japan

[15 ]GRID grid.410827.8, ISNI 0000 0000 9747 6806, Shiga University of Medical Science, ; Otsu, Japan

Author information

Hiroshi Ishiguro http://orcid.org/0000-0002-9859-5932

Article

Publisher ID: 5590

DOI: 10.1007/s10549-020-05590-w

PMC ID: 7103001

PubMed ID: 32170634

SO-VID: 3afdeeb3-dd5e-44bf-9cbe-4c0845522002

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 November 2019

Date accepted : 6 March 2020

Funding

Funded by: Sanofi K.K.

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer,randomized clinical trial,doxorubicin,cyclophosphamide,docetaxel,neoadjuvant chemotherapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer, randomized clinical trial, doxorubicin, cyclophosphamide, docetaxel, neoadjuvant chemotherapy

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A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer

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Abstract

Purpose

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Trial registration

Electronic supplementary material

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Karger: Oncology

Most cited references 10

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27.

Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel.

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