Using Anthracycline Again for Triple Negative

Abstract

Background

De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative chest cancer.

Methods

It is a prospective, open up-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June i, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable chest cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), three cycles of cyclophosphamide/epirubicin/fluorouracil followed by three cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for four cycles followed by paclitaxel for 12 weeks (EC-P, due north = 524) as the intention-to-care for population. Of these patients, 94% completed allocated therapy. Difference in illness-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.v%, corresponding to the hazard ratio (Hour) of 1.44 (one-sided α = 0.05), with an causeless 5-year DFS of 89% for EC-P.

Findings

Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-upwards of five.5 years, Hour for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.ix%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.ane% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 agin events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar.

Interpretation

Both TC and CEF-T are not-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a prophylactic regimen that avoids anthracycline-related side effects.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Splendid Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Applied science in Shanghai Hospitals (grant SHDC12010116), the Cooperation Projection of Acquisition Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

Enquiry in context

Evidence earlier this study

Earlier this written report was designed, adjuvant anthracycline-taxane (AT) regimens worked every bit the standard of care. An increasing number of long-term survivors or elderly patients with operable breast cancer develop heart failure or handling-related leukemia. De-escalation of anthracycline-containing regimens is gaining popularity.

The Us Oncology 9735 reported that four cycles of docetaxel and cyclophosphamide (TCx4) was superior to four cycles of doxorubicin and cyclophosphamide (ACx4) in terms of disease-free survival (DFS) and overall survival (OS). No evidence supported the non-inferiority of TCx6 compared with EC followed by weekly paclitaxel (EC-P).

CEF-T was developed independently equally i of the about effective regimens among all AT-containing regimens. This brusk-term anthracycline-based regimen has not been directly compared with in patients with HER2-negative breast cancer.

Added value of this written report

In this study, hazard ratio for TC versus EC-P was ane.05 (5-year DFS: 85.0% vs. 85.9%; xc% confidence interval [CI]: 0.79–1.39, non-inferior p = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.one% vs. 85.ix%; 90% CI: 0.75–1.30, non-inferior p = 0.045). Both TC and CEF-T are not-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer.

Implications of all the bachelor evidence

This trial will provide testify nigh two not-inferior regiments (TC and CEF-T) versus EC-P.

Introduction

Adjuvant chemotherapy improves outcomes of operable breast cancer. Since the landmark report of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (

), there has been an ongoing effort to identify better regimens to improve survival and subtract toxicity. A meta-analysis done by the Early Breast Cancer Trialists' Collaborative Grouping (EBCTCG) showed the effectiveness of vi-months of anthracycline-based adjuvant regimens for patients with operable breast cancer (

). A after EBCTCG meta-analysis validated the advantage of incorporating taxane into anthracycline-based regimens (

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). For the last twenty years, anthracycline and taxane (AT)-based regimens have been the standard adjuvant handling for operable breast cancer.

Even so, adjuvant anthracycline chemotherapy showed long-term side effects. An increasing number of long-term survivors or elderly patients with operable breast cancer develop heart failure or treatment-related leukaemia (

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). Hence, the de-escalation of anthracycline-containing regimens is gaining popularity in clinical trials. The U.s. Oncology 9735 reported that iv cycles of docetaxel and cyclophosphamide (TCx4) was superior to 4 cycles of doxorubicin and cyclophosphamide (ACx4) in terms of disease-free survival (DFS) and overall survival (Bone) (

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). These results promulgated TC every bit an effective alternative. Since ACx4 was considered a weak comparative regimen, stronger comparators such every bit taxane plus Ac (TaxAC) were studied with TC in later trials. The DBCG 07-READ trial provided no clear evidence of overall do good from anthracycline for selected operable breast cancer patients with normal copy numbers of the topoisomerase IIα factor (

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). The West German Study Grouping PlanB trial recently demonstrated the non-inferiority of 6 cycles of TC to a standard TaxAC regimen in clinically high-risk or genomically intermediate- to high-take chances human epidermal growth cistron receptor ii (HER2)-negative patients (

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). All of these promising results encourage researchers to consider switching from anthracycline-based regimens to anthracycline-free regimens in the adjuvant setting of operable breast cancer. Dose-dense anthracycline has been recommended by National Comprehensive Cancer Network (NCCN) guidelines every bit i of the preferred regimens since 2005 based on the CALGB 9741 trial (

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) and the Oxford Overview confirmed a moderate reduction in x-year recurrence risk and decease from breast cancer without increasing the risk of death from other causes past increasing the dose intensity of adjuvant chemotherapy. Notwithstanding, guidelines in China had not recommended the dose-dense AC-P regimen until 2017 due to unbalanced medical resources across China. The dose-dense Ac-P regimen was recommended for partially tolerable patients with triple-negative breast cancer. Thus, EC-P was the standard of intendance in Red china at the fourth dimension when this trial was designed.

Besides, iii cycles of cyclophosphamide, epirubicin, and fluorouracil followed past 3 cycles of docetaxel (CEF-T) (

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) was developed independently every bit one of the most constructive regimens amidst all AT-containing regimens. This short-term anthracycline-based regimen has not been straight compared with EC followed past weekly paclitaxel (EC-P) in patients with HER2-negative breast cancer. However, it'southward worth noting that CEF-T, a preferred regimen when the trial was first designed, is no longer preferred since Del-Mastro et al. (

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) reported no benefit from five-FU since 2015.

This trial, Minus Anthracycline or Due southhort-Ter1000 versus Epirubicin and Cyclophosphamide followed by Paclitaxel Regimen for Adjuvant Chest Cancer Therapy (MASTER), was designed to prospectively examination the hypothesis that vi cycles of TC are not-inferior to standard AT-containing chemotherapy (EC-P, four cycles of epirubicin and cyclophosphamide followed by weekly paclitaxel). A determination was fabricated to appraise, as a secondary outcome, the non-inferiority of brusk-term anthracycline-based regimen CEF-T to EC-P, after demonstrating the non-inferiority of TC.

Methods

Written report design

Information technology is a prospective, open-label, phase 3, non-inferiority randomized trial of patients with HER2-negative operable chest cancer, approved by the institutional ethics commission of Fudan University Shanghai Cancer Center (FUSCC). The trial was done co-ordinate to the International Briefing on harmonization Practiced Clinical Exercise guidelines and ethical principles in the Proclamation of Helsinki. All patients were required to sign an informed consent form earlier enrollment and randomization.

It was designed as a three-arm prospective trial to test the non-inferiority of anthracycline-free brusque-term regimen docetaxel 75 mg/thou² and cyclophosphamide 600 mg/grand² once every 3 weeks for half dozen cycles (TC) or of short-term anthracycline regimen cyclophosphamide 500 mg/mⁱⁱ, epirubicin 100 mg/one thousandⁱⁱ, and fluorouracil 500 mg/grand² every 3 weeks for 3 cycles followed by docetaxel 100 mg/kⁱⁱ every three weeks for 3 cycles (CEF-T), compared with standard long-term AT-containing regimen epirubicin xc mg/one thousand² and cyclophosphamide 600 mg/k^two every 3 weeks for 4 cycles followed by paclitaxel lxxx mg/thousand² weekly for 12 weeks (EC-P) in HER2-negative operable chest cancer.

Assignment to the treatment groups was stratified by age (less than fifty years vs. 50 years and older), pathological tumor stage (pT1 vs. pT2–3), pathological node condition at diagnosis (negative vs. positive), and hormone-receptor status (negative vs. positive).

Study population

Eligible patients were women with histologically confirmed, unilateral operable primary invasive chest cancer with known hormone-receptor status, HER2-negative status, and no evidence of metastatic affliction past standard laboratory and radiologic testing. Key inclusion criteria were pT1–3 and node-positive (pN+) tumours or pT2–3N0 tumours with at least 1 of the following run a risk factors: (

) grade II/3; (

) lymphovascular invasion; (

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) ≤35 years of age; (

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) estrogen receptor (ER) and progesterone receptor (PR) negative. Patients who had received neoadjuvant therapy (including chemotherapy, radiotherapy, or endocrine therapy) were excluded. Patients with serious active infections, astringent organ dysfunction, left ventricular ejection fraction <50%, pregnancy, lactation, or Eastern Cooperative Oncology Grouping operation status ≥2 were excluded. Inclusion and exclusion criteria are in Supplement ane. Upon completion of treatment, patients underwent follow upward surveillance and were scheduled to be seen every three months for the first ii years and every six months afterward that for 10 years.

Prophylactic utilise of granulocyte colony-stimulating factor (G-CSF) was scheduled during the first cycle of docetaxel-containing therapy according to the latest versions of NCCN guidelines (

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). Chemotherapy was administered before radiations therapy if radiation was indicated. Radiotherapy was completed past patients who received chest conservation or with ≥4 involved axillary lymph nodes or those with i–3 involved axillary lymph nodes forth with other high-take chances factors. On completion of chemotherapy and/or radiotherapy, endocrine therapy (tamoxifen for premenopausal and aromatase inhibitor for postmenopausal women) was administered to patients with hormone-receptor-positive tumours for 5 years. Bisphosphonates and other drugs affecting os metabolism were added to patients who are at risk of or have osteoporosis. The trial protocol is included in Supplement 1.

Endpoints

The primary endpoint was DFS, defined as the fourth dimension from randomization to occurrence of a new upshot including local recurrence, regional relapse, distant metastasis, contralateral primary breast cancer, second not-chest invasive cancer (excluding non-melanoma skin cancers), or death from any cause. Patients alive without whatever predefined issue were censored at the time of the concluding follow-up. Secondary endpoints included (

) distant disease-complimentary survival (DDFS), defined every bit the time from randomization to the earliest distant metastasis or death from whatsoever crusade, whichever offset; (

) Bone, divers as the fourth dimension from randomization to decease from any cause (

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); and (

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) prophylactic, which was assessed throughout the study treatment according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

Statistical analysis

These three cohorts that were included in the efficacy analysis were prespecified in a procedure with a fixed hierarchical sequence to adjust for the type I fault rate (

). This trial was designed to assess the not-inferiority of TC versus EC-P first, so to assess the non-inferiority of CEF-T versus EC-P. Both tests were designed with eighty% power at the one-sided alpha of 0.05. The trial assumed a 5-year DFS of 89% for EC-P (

,

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). Non-inferiority was defined as the 5-year DFS of TC or CEF-T existence not worse than an absolute value of 4.5% below EC-P, corresponding to a limiting hazard ratio (Hr) of ane.44. This four.five% non-inferiority margin was set before starting the trial, following consensus from the trial pattern group. Nether these assumptions, the trial target accrual was approximate 1500 patients, with approximate 200 DFS events expected at the concluding assay. HRs were obtained using the Cox proportional hazards model. The upper limit of ninety% confidence interval (CI) less than 1.44 was show to conclude non-inferiority. Non-junior P values were calculated according to Gisela Tunes da Silva et al. (

). No interim analysis and only one final analysis were planned for DFS. Because of this, a single terminal hypothesis test with an alpha of 0.05 is practical to the present trial.

All efficacy analyses were performed in the ITT and PP population. Five-year DFS, DDFS, and OS were calculated using the Kaplan–Meier method and were analyzed by the stratified log-rank test. HRs and associated xc% CIs were obtained with the use of a stratified Cox proportional-hazards model, with the study group and stratification factors as covariates. Tests for interaction based on the Cox regression model (treatment × factor) were used to assess the heterogeneity of treatment effects across different subgroups. Forest plots were used to summarize these results. For exploratory subgroup analysis, no multiple testing correction was performed.

Toxicity was assessed in patients who received at least one dose of chemotherapy. The proportion of patients presenting with class 3 to 4 agin events in each treatment arm was compared with Fisher's exact examination or X² exam, when appropriate.

Meta-analyses

Nosotros used a fixed-effects model based on the logarithm of the HR weighted from individual trials. Cochrane'southward Q statistic was utilized to explore statistical heterogeneity betwixt studies. The I² statistic was used to quantify the consistency. In the event of significant heterogeneity (P value < 0.05), a random-effect model was used. HRs with the corresponding 95% CIs are presented graphically.

Statistical assay was performed using Stata version xvi.0 software (StataCorp, Texas, United states).

Role of the funding source

Funders in this trial had no role in study design, information collection, data analysis, estimation and writing of the report.

Results

Patient characteristics

A total of 1663 patients were registered betwixt June 2010 and June 2017, and 1571 eligible patients were randomly assigned (1:one:1) to one of three arms following surgery: TC (n = 524), CEF-T (northward = 523) or EC-P (northward = 524) equally the intention-to-treat (ITT) population. Of the ITT population, 94% who completed all cycles of allocated chemotherapy were defined as per-protocol (PP) population: TC (n = 495), CEF-T (due north = 489), and EC-P (due north = 493), respectively (Fig. i). Detailed reasons for the exclusion of 92 patients are listed in Table ane in Supplement ii.

Fig. 1 Espoused diagram. Patients registration, exclusions, treatment-arm assignments, and therapy-completion.

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TCx6: docetaxel 75 mg/thou² and cyclophosphamide 600 mg/m² were given once every three weeks for six cycles (TC).

CEFx3-Tx3: cyclophosphamide 500 mg/thou² _, epirubicin 100 mg/m² and fluorouracil 500 mg/m² were given once every 3 weeks for three cycles followed past docetaxel 100 mg/chiliad² in one case every iii weeks for iii cycles (CEF-T).

ECx4-wPx12: epirubicin 90 mg/mⁱⁱ and cyclophosphamide 600 mg/k² were given once every three weeks for 4 cycles followed by paclitaxel 80 mg/m² once every calendar week for twelve times (EC-P).

ITT, intention-to-treat.

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Table i Baseline characteristics of ITT population.

		TC	CEF-T	EC-P
		northward = 524 (%)	due north = 523 (%)	n = 524 (%)
Age	<fifty years	117 (22.iii)	131(25.0)	136 (26.0)
	≥50 years	407 (77.7)	392 (75.0)	388 (74.0)
Menopausal status	Premenopausal	301 (57.4)	289 (55.2)	293 (55.ix)
	Postmenopausal	223 (42.6)	234 (44.8)	231 (44.1)
Subtype	Luminal A-similar	120 (22.9)	100 (19.ane)	117 (22.three)
	Luminal B-similar	364 (69.five)	384 (73.4)	366 (69.9)
	TNBC	40 (7.half-dozen)	39 (7.5)	41 (seven.8)
Histological grade	I-II	350 (66.viii)	346 (66.two)	337 (64.3)
	3	174 (33.2)	177 (33.viii)	187 (35.7)
Ki-67	≤xiv%	125 (23.9)	105 (twenty.one)	120 (22.9)
	>14%	399 (76.1)	418 (79.nine)	404 (77.one)
pT	pT1	231 (44.1)	227 (43.4)	237 (45.ii)
	pT2–3	293 (55.9)	296 (56.6)	287 (54.8)
pN	pN0	220 (42.0)	212 (40.5)	213 (forty.6)
	pN+	304 (58.0)	311 (59.5)	311 (59.4)
Breast surgery	BCS	77 (xiv.vii)	79 (15.1)	72 (thirteen.vii)
	Mastectomy	447 (85.3)	444 (84.9)	452 (86.three)
Axillary surgery	SLNB	155 (29.6)	150 (28.7)	152 (29.0)
	ALND	369 (70.4)	373 (71.iii)	372 (71.0)
Endocrine therapy	TAM only	159 (30.3)	151 (28.9)	148 (28.2)
	AIs ± OFS only	271 (52.9)	284 (54.3)	275 (52.5)
	TAM to AIs	41 (7.8)	xl (vii.half dozen)	45 (8.6)
	None	53 (x.ane)	48 (nine.two)	56 (10.vii)
Radiations therapy	No	302 (57.half-dozen)	299 (57.two)	297 (56.seven)
	Yes	222 (42.4)	224 (42.viii)	227 (43.3)

Abbreviations: AIs, ALND, axillary lymph node dissection; BCS, breast-conserving surgery; CEF-T, cyclophosphamide/epirubicin/fluorouracil followed by docetaxel; EC-P, epirubicin/cyclophosphamide followed by paclitaxel; ITT, intention-to-care for; SLNB, sentinel lymph node biopsy; TC, docetaxel/cyclophosphamide; TNBC, triple-negative breast cancer.

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Patient characteristics and baseline clinicopathologic variables were well counterbalanced for the ITT population between both experimental arms (TC or CEF-T) and the command arm (EC-P) (Tabular array 1). The median age was l years (interquartile range: 45–57 years); 59% of patients had lymph node-positive disease; 34% had poorly differentiated tumours (grade Iii). The majority (92.2%) of patients had an estrogen-receptor-positive disease and but 7.half dozen% had triple-negative breast cancer. This is because another concurrent clinical trial carried out competitive recruitment on triple-negative chest cancer in the same period (ClinicalTrials.gov identifier: NCT01216111). Baseline characteristics were well balanced for the PP population also (Tabular array 2 in Supplement 2).

Table 2 Efficacy in the ITT population.

	Arms	Events	Cases	5-yr rate (%)	HR# (90% CI)	Log-rank P * P values were calculated by the stratified log-rank examination for comparison with the EC-P arm.
DFS	TC	72	524	85.0	1.05 (0.79–one.39)	0.771
	CEF-T	73	523	85.i	0.99 (0.75–ane.30)	0.946
	EC-P	70	524	85.9	–	–
DDFS	TC	38	524	91.6	0.88 (0.61–1.28)	0.572
	CEF-T	39	523	92.four	0.83 (0.57–one.xix)	0.391
	EC-P	43	524	91.4	–	–
Bone	TC	21	524	96.5	0.96 (0.58–1.59)	0.893
	CEF-T	24	523	94.nine	0.84 (0.51–1.37)	0.549
	EC-P	23	524	95.4	–	–

Abbreviations: CEF-T, cyclophosphamide/epirubicin/fluorouracil followed by docetaxel; CI, confidence interval; DDFS, distant affliction-gratuitous survival; DFS, disease-complimentary survival; EC-P, epirubicin/cyclophosphamide followed by paclitaxel; HR, hazard ratio; ITT, intention-to-care for; OS, overall survival; TC, docetaxel/cyclophosphamide; yr.: year.

HRs with 90% CIs were calculated using stratified Cox by age (<50 vs. ≥50 years), pT (pT1 vs. pT2–3), pN (negative vs. positive), and hormone-receptor status (negative vs. positive).

P values were calculated by the stratified log-rank exam for comparison with the EC-P arm.

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Efficacy analysis

The median follow-up time was 5.5 years (interquartile range: 3.5–6.seven years). There were 215 DFS events during the follow-up period, of which 72 (13.7%) were in the TC arm, 73 (14.0%) in the CEF-T arm, and 70 (13.4%) in the EC-P arm, respectively. DFS events are summarized in Tabular array 3 in Supplement 2.

Table 3 Form 3 to 4 adverse events.

			TC	CEF-T	EC-P	TC vs. EC-P	CEF-T vs. EC-P
			Due north = 524	%	N = 523	%	Due north = 524	%	p-value	P-value
Dose reduction	41	seven.ix	53	10.2	59	eleven.2	0.058	0.556
Dose filibuster	2	0.five	ii	0.5	ten	1.9	0.038	0.038
Blood and lymphatic organization disorders
	Neutropenia	290	55.3	279	53.four	284	54.ane	0.710	0.782
	Anemia	4	0.8	5	0.9	7	1.4	0.547	0.773
	Febrile neutropenia	xi	ii.0	9	1.7	10	1.nine	0.826	0.820
	Thrombocytopenia	1	0.2	1	0.2	2	0.3	1.000	1.000
GI disorders
	Diarrhea	18	3.5	38	vii.2	37	7.0	0.008	0.898
	Mucositis/stomatitis	ii	0.3	7	1.4	ix	ane.7	0.064	0.617
	Nausea/vomiting	nineteen	3.6	50	9.v	55	10.5	<0.001	0.614
Cardiac disorders
	Ejection fraction decreased	one	0.2	5	0.ix	6	ane.1	0.124	ane.000
	Ventricular arrhythmia	2	0.iii	v	0.9	7	1.2	0.178	0.773
	Center failure	0	0.0	0	0.0	1	0.2	i.000	1.000
Hepatobiliary disorders
	AST increase	10	1.ix	eleven	2.0	10	i.nine	1.000	0.822
	ALT increment	7	one.3	6	1.1	6	1.1	0.780	1.000
	Hepatic failure	0	0.0	0	0.0	1	0.two	1.000	one.000
General
	Allergy	7	1.3	six	1.1	4	0.eight	0.547	0.547
	Edema	3	0.6	2	0.5	2	0.3	1.000	1.000
	Fatigue	24	4.half dozen	24	4.5	26	5.0	0.772	0.777
	Pain	seven	i.iii	vii	1.four	13	two.5	0.176	0.177
	Fever	2	0.five	ii	0.3	3	0.6	i.000	0.655
	Rash	21	3.9	eighteen	3.iv	8	1.half-dozen	0.014	0.046
Infection
	Wound infection	2	0.5	3	0.6	3	0.half-dozen	one.000	1.000
	Pulmonary infection	two	0.3	2	0.5	3	0.6	1.000	1.000
	Urinary infection	1	0.2	0	0.0	one	0.two	ane.000	1.000
Hand & Pes
	Thrombosis	1	0.2	1	0.2	0	0.0	one.000	0.500
	Peripheral neuropathy	xv	two.eight	four	0.8	iii	0.6	0.007	0.726
Cardiac-related expiry * During follow-up; ALT, alanine transaminase; AST, aspartate transaminase; CEF-T, cyclophosphamide/epirubicin/fluorouracil followed by docetaxel; EC-P, epirubicin/cyclophosphamide followed by paclitaxel; GI: gastrointestinal; TC, docetaxel/cyclophosphamide.	1	0.2	0	0.0	1	0.2	one.000	ane.000
Acute myeloid leukemia * During follow-up; ALT, alanine transaminase; AST, aspartate transaminase; CEF-T, cyclophosphamide/epirubicin/fluorouracil followed by docetaxel; EC-P, epirubicin/cyclophosphamide followed by paclitaxel; GI: gastrointestinal; TC, docetaxel/cyclophosphamide.	0	0.0	0	0.0	1	0.2	1.000	1.000

During follow-upwards; ALT, alanine transaminase; AST, aspartate transaminase; CEF-T, cyclophosphamide/epirubicin/fluorouracil followed by docetaxel; EC-P, epirubicin/cyclophosphamide followed by paclitaxel; GI: gastrointestinal; TC, docetaxel/cyclophosphamide.

• Open table in a new tab

Five-twelvemonth DFS for ITT population treated with TC or EC-P were 85.0% vs. 85.9%, respectively (HR=one.05; 90% CI, 0.79–ane.39; non-junior P = 0.048) (Tabular array 2). Since the prespecified margin for non-inferiority was ane.44, the 90% CI upper limit of 1.39 was conclusive that TC is non-inferior to EC-P. In ER+ population, five-year DFS for TC or EC-P were 85.7% vs. 85.nine% (HR=0.99; 90% CI, 0.74–ane.33) (Tabular array 4, Supplement 2). Since the prespecified margin for not-inferiority was one.44, the 90% CI upper limit of 1.39 was conclusive that TC is non-junior to EC-P.

Then we evaluated the non-inferiority for CEF-T versus EC-P, the 5-year DFS were 85.1% versus 85.9%, respectively (60 minutes=0.99; 90% CI, 0.75–ane.30, non-inferior p = 0.045). The criterion for the not-inferiority of CEF-T to EC-P was achieved every bit well. Moreover, there were no significant differences in DFS, Bone, or DDFS between the two experimental arms (TC and CEF-T) and the control arm (EC-P) (Fig. 2).

Fig. 2 DFS, DDFS and OS in ITT population

Show full caption

In the intention-to-treat (ITT) population, Kaplan–Meier curves for (A) illness-free survival (DFS), (B) distant recurrence-costless survival (DDFS), and (C) overall survival (Bone) of each arm were illustrated. Hazard ratios (Hr) with 90% confidence intervals (CIs) were calculated based on the stratified Cox model. Numbers at risk were as listed below figures.

CEF-T, cyclophosphamide/epirubicin/fluorouracil followed by docetaxel; EC-P, epirubicin, and cyclophosphamide followed by paclitaxel; TC, docetaxel, and cyclophosphamide.

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The PP analysis yielded equivalent results. The 60 minutes for TC versus EC-P was 1.05 (ninety% CI, 0.79–1.39), and for CEF-T versus EC-P, 0.99 (ninety% CI, 0.75–1.30) (Table 5 in Supplement 2). Survival curves can be found in Fig. 1 in Supplement ii.

Fig. three shows a forest plot of the HR with 90% CI for DFS in major subgroups by ITT analysis (60 minutes >1 would favour EC-P). Subgroup analysis showed similar treatment effects past histological class, Ki-67, tumour stage and nodal status, merely suggested differential effects past historic period and chest cancer subtype betwixt EC-P and TC. EC-P appears to be more constructive than TC in patients with triple-negative breast cancer. Also, in a subgroup with age < 50 years, EC-P showed a meliorate effect. A like wood plot by PP assay is illustrated in Fig. two in Supplement 2. Kaplan–Meier curves for each tumour subtype in Fig. 3, Supplement 2.

Fig. 3 Forest plot for DFS risk ratios in subgroups by ITT analysis

Prove full caption

In the intention-to-treat (ITT) population, hazard ratios (HRs) were calculated within each subgroup. (A) TC vs. EC-P, Hour>1 favours EC-P; (B) CEF-T vs. EC-P, 60 minutes>i favours EC-P.

CEF-T, cyclophosphamide/epirubicin/fluorouracil followed past docetaxel; EC-P, epirubicin, and cyclophosphamide followed past paclitaxel; Lum A-like: Luminal-A like; Lum B-like: Luminal-B similar; pN: pathological node condition; pT, pathological neoplasm phase.

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Toxicity

Agin events were recorded on patients who received at to the lowest degree one dose of allocated chemotherapy (Table three). No treatment-related decease occurred during treatment. Compared with the TC arm, the EC-P arm was characterized past significantly more frequent dose delays [TC versus EC-P: 2 (0.5%) versus ten (1.nine%); p = 0.038]. The use of Grand-CSF prophylaxis during the offset bicycle of docetaxel-containing therapy was documented in 83% and 86% of patients in the TC and CEF-T arms, respectively. Incidences of course 3–4 neutropenia, febrile neutropenia and hepatic dysfunctions were similar betwixt artillery. Noteworthy grade 3 or 4 agin events specific to TC were rash (n = 21, iii.9%) and peripheral neuropathy (due north = 15, 2.8%). The charge per unit of peripheral neuropathy is similar to the rates previously reported in the PATTERN trial (

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• Jones S.
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• Crossref
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) and CBCSG-010 trial (

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• Ejlertsen B.
• Tuxen Grand.K.
• Jakobsen E.H.
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• Knoop A.Due south.
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• et al.

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• Crossref
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) in our centre. Besides, WSG Plan B trial reported 0.8–2.two% of grade iii–4 peripheral neuropathy as well. EC-P arm exhibited more than gastrointestinal (GI) disorders, like nausea/vomiting (northward = 55, ten.5%), diarrhea (north = 37, vii.0%), and mucositis/stomatitis (n = ix, ane.7%), which may made patients feel more uncomfortable subjectively. In the CEF-T arm, fewer dose delays, but a significantly higher frequency of grade 3 to 4 rash were observed, compared to the EC-P arm. Cardiac toxicity was infrequent in all arms. Grade iii or four cardiac events for TC, CEF-T, and EC-P included ejection fraction subtract (n = i, 0.2%; n = 5, 0.9%; due north = 6, i.1%), ventricular arrhythmia (due north = 2, 0.iii%; n = 5, 0.9%; north = 7, one.two%), and middle failure (0%; 0%; n = 1, 0.ii%), respectively. During additional follow-up, two deaths (one in TC, i in EC-P arm) were observed as a outcome of center failure. One case of astute myeloid leukaemia was observed in the EC-P arm.

Meta-assay

Nosotros performed a meta-analysis past a stock-still-effects model, which included 8 RCTs that compared TC with anthracycline-containing therapy, namely HORG (

[18]

• Mavroudis D.
• Matikas A.
• Malamos Northward.
• Papakotoulas P.
• Kakolyris S.
• Boukovinas I.
• et al.

Dose-dense FEC followed past docetaxel versus docetaxel plus cyclophosphamide equally adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized written report past the Hellenic Oncology Research Group (HORG).

• Summary
• Total Text
• Full Text PDF
• PubMed
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), ABC (

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Anthracyclines in early breast cancer: the ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).

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), DBCG 07-READ (

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• Ejlertsen B.
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• Knoop A.S.
• Hojris I.
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Adjuvant Cyclophosphamide and Docetaxel with or without Epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-characterization, Phase III, randomized trial.

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), WSG Program B + SUCCESS C combined analysis and this Main trial (eFigure iv in Supplement 2). The total number of patients is 14,312 patients. All the patients were HER2-negative operable breast cancer. Past the fixed effects model, the total result for TC versus A+T regimens was estimated. Overall, a not-statistically significant increase in the hazard of 7% was observed between TC and A+T in DFS, with a 95% conviction interval ranging from a iii% reduction to a nineteen% increase (HR 1.07, 95% CI 0.97–ane.19).

Give-and-take

In this trial, both adjuvant TC and CEF-T met the not-inferior standard to EC-P mainly in patients with ER+/HER2- operable breast cancer. The ninety% upper confidence limit of the HR versus EC-P for TC was one.39 and for CEF-T was 1.30 by ITT analysis, which were both below the not-inferiority boundary of 1.44 with both non-inferior p values less than 0.05. There were fewer cardiac events and fewer side effects with TC, yielding a favourable therapeutic alphabetize for the anthracycline-gratis regimen.

To our noesis, this MASTER trial is the second large randomized non-inferiority written report supporting TC equally a potential anthracycline-complimentary regimen. The PlanB trial demonstrated the not-inferiority of six cycles of TC to EC-T (4 cycles of epirubicin and cyclophosphamide followed by 4 cycles of docetaxel) in clinically high-risk or genomically intermediate- to loftier-risk patients (

[6]

• Nitz U.
• Gluz O.
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• Malter W.
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• Nuding B.
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West High german Study PlanB trial: adjuvant four cycles of Epirubicin and Cyclophosphamide Plus Docetaxel versus 6 cycles of Docetaxel and Cyclophosphamide in HER2-negative early breast Cancer.

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). Baseline characteristics in our accomplice showed a higher node-positive charge per unit and larger neoplasm size compared with that of the PlanB trial. The 5-yr DFS for TC and EC-T in PlanB reached xc%, while in the Master trial, the 5-year DFS for TC and EC-P are slightly lower. In contrast, 2 other randomized trials did not testify that TC is non-inferior to the TaxAC standards. The HORG trial, designed every bit a non-inferiority trial, aimed to compared TCx6 to dose-dumbo CEF-T (

[18]

• Mavroudis D.
• Matikas A.
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• Papakotoulas P.
• Kakolyris S.
• Boukovinas I.
• et al.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide equally adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early chest cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).

• Summary
• Full Text
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). This trial included but 650 patients and used a not-inferiority margin of 7% for a 3-year DFS, which might have inadequate power to show non-inferiority. The ABC pooled analysis as well failed to written report non-inferiority of TCx6 compared to TaxAC (

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• Blum J.L.
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). That trial enrolled more pN+ and triple-negative diseases than our trial. This trial prepare an original non-inferiority margin of HR at one.eighteen. However, the median follow-up was limited to three.iii years. 4-yr DFS rates were 88.ii% for TCx6 and 90.seven% for TaxAC, yielding an Hour of 1.23 (95% CI, i.01–1.50). Explanations for differences between these four studies include baseline characteristics, sample size, and a conservative non-inferiority margin with an unplanned shortened observation period in the ABC trial. A meta-assay has summarized these randomized controlled trials comparing TC versus AT-containing regimens in HER2-negative operable breast cancer and no differences were observed for DFS and OS (

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). We also performed a meta-analysis with the Main trial included. Overall, for TC versus anthracycline-containing therapy, a not-statistically pregnant increase in the hazard was observed. The upper boundary of 95% CI is 1.19, indicating TC as an acceptable regimen for HER2-negative operable breast cancer. Six cycles of TC shorten the treatment term merely prolong the taxane elapsing, which might explain the non-inferiority of TCx6 to TaxAC.

This trial is also the first written report supporting the non-inferiority of CEF-T to EC-P. CEF-T regimen represents a compromise option, with 20% dose reduction and xx% elapsing saving, which offers an alternative anthracycline-based regimen. Patients received CEF-T showed fewer dose filibuster than EC-P, indicating higher compliance during the procedure for a shortened AT-based regimen.

No patients died from handling-related expiry. With routine prophylactic K-CSF handling, the incidence of grade iii or 4 neutropenia and febrile neutropenia is similar for all groups. Equally to the GI toxicity, six cycles of TC regimen exhibited less dose delay, and fewer grade three–4 vomiting and nausea events. TC was easier to be accustomed and finished by patients. Anthracycline-related acute cardiac toxicity includes a higher incidence of decreased ejection fraction in the EC-P arm. Only one case of congestive heart failure was reported in the EC-P arm and none in the TC arm, consequent with previous trials (

[4]

• Jones S.
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• O'Shaughnessy J.
• Blum J.Fifty.
• Vukelja South.J.
• McIntyre Chiliad.J.
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,

[6]

• Nitz U.
• Gluz O.
• Clemens M.
• Malter Due west.
• Reimer T.
• Nuding B.
• et al.

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,

[xix]

• Blum J.50.
• Flynn P.J.
• Yothers G.
• Asmar L.
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• Jacobs S.A.
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). In summary, the acute toxicity profile favours TC. Moreover, though we have not systematically reported long-term cardiac disease, TC showed fewer middle-related disorders than EC-P during treatment. Also, near patients in our centre came from various places across China and received outpatient chemotherapy. Fewer cycles of chemotherapy mean less travelling and accommodation costs. Though dose-dense EC followed by dose-dumbo paclitaxel shortens the chemo to a groovy deal, it is still not routinely operated in China because of lacking plenty supportive intendance.

The post-obit limitations should be considered when interpreting our results. First, this open-characterization written report was performed in a unmarried centre with all patients who were Chinese, although the results of our trial are expected to apply to patients in Western countries. Thus, cautions are needed for ethnic extrapolation. Considering biases might be introduced by open up-characterization studies, several measures were taken, due east.g. setting objective endpoints, following up patients by an independent squad, and cleaning basic data past independent statisticians. 2d, long-term cardiac affliction and handling-related leukaemia are being collected in the long-term follow-up. Limited cases were observed at this time signal. Continuous follow-upwardly has been kept until the preset ten years to follow Bone events likewise as to better summarize long-term side effects. Third, our trial was designed 10 years ago. The 4.5% non-inferiority margin was originally set according to clinical condition and contemporary other trials at that time. For instance, earlier in 2009, the WSG Plan B trial designed their trial with a non-inferiority margin of 4.4% for v-yr DFS. The 4.v% non-inferiority margin seems not as suitable every bit expected for the current status. However, it was complicated to adjust the prespecified non-inferiority boundary subsequently patient inclusion completion. As well, there is a gap between the bodily observed survival rate (85.9%) and the preset survival charge per unit (89%) for the EC-P arm. Fourth, clinical trials about adjuvant treatment require a large sample size and years of observation to draw meaningful conclusions, which often lag innovative diagnostic features and novel therapies. The RxPONDER study (

[21]

• Jasem J.
• Fisher C.M.
• Amini A.
• Shagisultanova E.
• Rabinovitch R.
• Borges V.F.
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) recently demonstrated no need for adjuvant chemotherapy in the genomically low run a risk (recurrence score ≤25) postmenopausal population with 1–3 positive lymph nodes. Future clinical trials in our eye will combine molecular subtyping and mod predictive biomarkers for generating more precise therapeutic guidance and identify those who may gain substantial benefit from anthracycline. Finally, we must admit that though there is keen interest in patients with triple-negative disease, limited cases were identified due to competitive enrollment populations. Though subgroup analysis by tumour subtype showed various results, the subgroup assay is underpowered due to the pocket-sized number of cases. One thing to note is that a big proportion of patients in our cohort are with ER+ breast cancer, thus the conclusion that TC and CEF-T are non-inferior to EC-P is mainly applicable in those with ER+/HER2- breast cancer.

In conclusion, our clinical outcome findings suggest that TC for 6 cycles too every bit CEF-T are effective adjuvant chemotherapy mainly for patients with ER+/HER2- breast cancer.

Contributors

Conception and design: Ke-Da Yu, Lei Fan, Zhi-Ming Shao

Fiscal support: Ke-Da Yu, Zhi-Ming Shao

Provision of study fabric or patients: All authors

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Proclamation of Competing Interest

The authors have declared no conflicts of interest.

Acknowledgeents

We are grateful to Ying Zhou and Xia Yan for data management.

Information sharing statement

Individual participant data that underlie the results reported in this article will be shared after de-identification. Data will be available 3 months subsequently publication. Researchers who provide a methodologically audio proposal might admission the private participant data. Proposals should be directed to [electronic mail protected] To proceeds admission, information requestors will need to sign a data access agreement.

Appendix. Supplementary materials

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Publication History

Published: May 13, 2021

Accustomed: April 14, 2021

Received in revised form: April 4, 2021

Received: February 7, 2021

Identification

DOI: https://doi.org/x.1016/j.lanwpc.2021.100158

Copyright

© 2021 The Author(s). Published by Elsevier Ltd.

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Source: https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065%2821%2900067-5/fulltext

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