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  • Research article
  • Open Access
  • Open Peer Review

Clinical outcomes comparison of 10 years versus 5 years of adjuvant endocrine therapy in patients with early breast cancer

Contributed equally
BMC Cancer201818:977

https://doi.org/10.1186/s12885-018-4878-4

  • Received: 14 May 2018
  • Accepted: 1 October 2018
  • Published:
Open Peer Review reports

Abstract

Background

Adjuvant endocrine therapy undoubtedly prolongs the time to recurrence for patients with hormone-positive early breast cancer. Extended endocrine therapy to 10 years or longer has been expected to bring a greater clinical advantage. However, the related research conclusions are controversial.

Methods

Tamoxifen (TAM), Aromatase Inhibitor (AI), Exemestane, letrozole (LET) and anastrozole were used as key words in the literature search. After the patients completed 5 years of adjuvant endocrine treatment, they were allocated to continue endocrine treatment for 5 years or receive placebo/observation for 5 years. Disease-free survival (DFS) and overall survival (OS) were the end points. Systematic assessment was performed using Stata 12.0.

Results

Twelve trials including 30,848 cases were involved. The overall analysis demonstrated that extended endocrine therapy to 10 years significantly prolonged DFS compared with 5 years of endocrine therapy [hazard ratio (HR) = 0.84, 95% CI: 0.73–0.97]. Subgroup analysis showed that DFS was significant prolonged with TAM 5y - AI 5y treatment versus TAM 5y treatment and with (AI and/or TAM) 5y - LET 5y treatment versus (AI and/or TAM) 5y treatment [(HR = 0.61, 95% CI: 0.50–0.76) and (HR = 0.81, 95% CI: 0.71–0.93), respectively]. However, no significant difference was found in the DFS with TAM 5y - TAM 5y treatment versus TAM 5y treatment (HR = 0.97, 95% CI: 0.81–1.17). Overall and subgroup analysis did not demonstrate an OS benefit of therapy extended to 10 years. A DFS benefit of extended endocrine therapy to 10 years was verified in the lymph node-positive subgroup, postmenopausal subgroup and ER+ and/or PR+ subgroup (HR = 058, 95% CI: 0.45–0.75; HR = 0.70, 95% CI: 0.58–0.80; HR = 0.80, 95% CI: 0.67–0.96).

Conclusions

An extended 10 years of endocrine treatment yields a DFS benefit for patients with early breast cancer; (AI and/or TAM) 5y - AI 5y treatment is the optimal choice. ER+ and/or PR+, postmenopausal and lymph node-positive patients are the most suitable groups.

Keywords

  • Breast cancer
  • Extended endocrine treatment
  • Tamoxifen
  • Aromatase inhibitor
  • Disease-free survival

Background

For patients with hormone-positive early breast cancer, adjuvant endocrine therapy undoubtedly prolongs the time to recurrence [13]. Moreover, 5 years of adjuvant endocrine treatment has been verified to be more effective than 1–2 years of treatment [3]. However, the recurrence rate of patients receiving tamoxifen (TAM) increases from 15% at 5 years to 33% at 15 years, and cancer mortality increases from 8.3% at 5 years to 26% at 15 years [3]. To control the increased recurrence rate and mortality rate even after receiving 5-year adjuvant endocrine treatment, extended endocrine therapy to 10 years or longer is expected to bring more clinical advantage. However, the research conclusions are controversial.

Both TAM and aromatase inhibitors (AIs) are used as extended adjuvant endocrine regimens. In MA.17, NSABP-B42, MA-17R trials, the prolonged application of AI to 10 years significantly reduced the recurrence risk after 5 years of adjuvant TAM and/or AI treatment [46]. However, in the NSABP-B33 trial, prolonged exemestane (EMT) for 5 years did not significantly decrease the recurrence compared with placebo [7]. In the IDEAL (S1–04) trial, prolonged letrozole (LET) for 5 years also did not prolong the disease-free survival (DFS) compared with prolonged LET for 2.5 years [8]. An extended 10 years of adjuvant TAM compared with 5 years TAM showed mixed results. The ATLAS, aTTom, E4181/E5181 trials showed significant recurrence reduction by 10 years of TAM treatment compared with 5 years of TAM treatment; however, the Scottish trial demonstrated no benefit of extended adjuvant TAM [912]. Additionally, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 reported extended TAM by more than 5 years led to a shorter DFS. Furthermore, all extended endocrine treatment did not bring an overall survival (OS) benefit [13].

The real benefit of extended adjuvant endocrine is unclear. The objectives of the present study were to compare the clinical outcomes of extended 10 y versus 5 y of adjuvant endocrine therapy in patients with early breast cancer.

Methods

Literature search strategy

This comprehensive analysis was performed according to the Preferred Reporting Items for Systematic Reviews [14]. PubMed (1966–2017), Embase (1974–2017), the annual meeting abstracts of the European Society of Medical Oncology and American Society of Clinical Oncology were searched. Only prospective studies were permitted to be included in the assessment. The initial search used the following MeSH terms: “Breast cancer OR Breast cancers OR Breast carcinoma” AND “Adjuvant endocrine OR Extended endocrine treatment OR Extended adjuvant endocrine treatment OR Prolonged endocrine treatment OR Prolonged adjuvant endocrine treatment”. We also used the following MeSH terms: “Breast cancer OR Breast cancers OR Breast carcinoma” AND “Tamoxifen OR Aromatase Inhibitor OR Exemestane OR letrozole OR anastrozole” AND “Clinical Trial”. The PRISMA Checklist is described in Additional file 1: Table S1.

Inclusion and exclusion criteria of the trials

All the included studies met the following criteria: 1) All trials were prospective, properly randomized controlled and well matched for factors such as age, gender, tumor stage, performance status, clinical stage, treatment regimen, menopausal status, lymph node status, and hormone status. 2) When the same trial was summed up using different time points, only the trial with complete results and the longest follow-up time was included. 3) The primary endpoint was DFS, and the secondary endpoint was OS. 4) After the patients with early breast cancer had completed 5 years of adjuvant endocrine treatment, they were randomly allocated to continue adjuvant endocrine treatment for 5 years or receive placebo for 5 years (or only undergo observation for 5 years).

The exclusion criteria were as follows. 1) All trials concerning neo-adjuvant endocrine treatment were excluded. 2) Ongoing clinical trials without the results of DFS and OS were excluded. 3) Trials involving concomitant interventions, such as adjuvant chemotherapy or radiotherapy, were excluded.

Data extraction

Three reviewers (Li Li or Bingmei Chang, Xiaoyue Jiang) independently searched the articles. They screened the articles by reading the titles, abstracts or full texts. Any discrepancy was determined by a third reviewer (Shanshan Wu). The hazard ratio (HR) or risk ratio (RR) and 95% confidence interval (CI) of DFS and OS in each trial were extracted. If a trial only provided a Kaplan-Meier curve, the HR and 95% CI were estimated using the Engauge Digitizer V4.1 screenshot tool and a formula proposed by Parmar [15, 16]. Related statistical data were extracted by an expert at the Statistics Center (Shanshan Wu). The following information were also extracted and summarized: journal name, publication year, author’s name, type of clinical trial, follow-up time, previous endocrine treatment regimens, extended endocrine treatment regimens, primary endpoints, second endpoints, lymph node status, estrogen (ER) + and/ or progesterone (PR) status, and menopausal status. The qualities of the enrolled trials were assessed according to the Cochrane Handbook 4.2.6 for Systematic Reviews of Interventions [17].

Statistical analysis

Systematic assessment was performed using Stata version 12.0 software (Stata Corporation, College Station, Texas, USA). HR/RR and 95% CI were collected to estimate the clinical efficacy of DFS and OS. An HR > 1.0 indicated more recurrence risk or death risk in the extended endocrine treatment group. In each systematic review, Cochrane’s χ2 test was used to evaluate the heterogeneity of the included clinical trials. When the P-value of heterogeneity was < 0.05 or I2 was > 50%, the random-effects model (REM) was used; otherwise, the fixed-effects model (FEM) was used. Begg’s and Egger’s tests were used to evaluate the publication bias of these trials [18, 19].

Results

Characteristics of the included trials

Two hundred forty-eight articles were initially identified through searching the PubMed, Embase and abstracts of International Meeting. One hundred seventy-one articles were excluded by checking the titles and abstracts, and 65 articles were excluded after reading the full text. Finally, 12 trials [413, 20] involving 30,848 cases were included in the meta-analysis. The selection flow chart is shown in Fig. 1a, and the design of extended endocrine treatment in all trials is shown in Fig. 1b. The characteristics of the included trials are shown in Table 1. The analysis of Cochrane risk-of-bias showed that the methodological quality of all trials was relatively satisfied and fair.
Fig. 1
Fig. 1

Inclusion of the studies and design of extended endocrine treatments. a 12 articles were included in quantitative analysis (meta-analysis), b The design of extended adjuvant endocrine treatment

Table 1

Common characteristics of the studies

Trial

 

Type

Follow up time (y)

Previous treatment

Extended treatment

N

Menopausal State

Lymph Node (+)

ER+ and/ or PR

Primary endpoint

E4181/E5181 (1996)

NR

Full article

5.6

TAM 5y

TAM 5y

100

Premenopausal /Postmenopausal

100/100

73% ER+

DFS

   

TAM 5y

 

93

93/93

  

NSABP-B14 (2001)

III

Full article

6.8

TAM 5y

TAM 5y

593

Premenopausal /perimenopausal /Postmenopausal

Negative

ER+

DFS

   

TAM 5y

Placebo 5y

579

Negative

ER+

 

Scottish trial (2001)

NR

Full article

15.0

TAM 5y

TAM 5y

173

Premenopausal /Postmenopausal

43/90a

66/173b

DFS

   

TAM 5y

 

169

35/89

66/169

 

ATLAS (2013)

III

Full article

15.0

TAM 5y

TAM 5y

3428

Premenopausal /perimenopausal /Postmenopausal

1474/3428

ER+

DFS

   

TAM 5y

 

3418

1427/3418

ER+

 

aTTom (2013)

III

Abstract

8.6

TAM 5y

TAM 5y

3468

Premenopausal /Postmenopausal

NR

ER+/untested

DFS

   

TAM 5y

 

3485

   

MA.17 (2005)

III

Full article

2.5

TAM 5y

LET 5y

2593

postmenopausal

1171/2583

2516/2583

DFS

   

TAM 5y

Placebo 5y

2594

1189/2587

2519/2587

 

NSABP-B33 (2008)

III

Full article

2.5

TAM 5y

EMT 5y

799

postmenopausal

384/799

775/799

DFS

   

TAM 5y

Placebo 5y

799

384/779

759/799

 

NSABP-B42 (2016)

III

Abstract

6.9

AI 5y

LET 5y

1959

postmenopausal

NR

1959/1959

DFS

   

TAM 3y-AI 2y

Placebo 5y

1964

 

1964/1964

 

MA-17R (2016)

III

Full article

6.3

AI 4.5–6 y

LET 5y

959

postmenopausal

492/959

945/959

DFS

   

TAM-AI 4.5–6 y

Placebo 5y

959

494/959

950/959

 

ABCSG-6a (2007)

III

Full article

5.2

TAM5y

ANA 3y

387

postmenopausal

132/387

371/387

DFS

   

TAM 5y

 

469

146/469

454/469

 

DATA (S1–03) (2016)

III

Abstract

4.1

TAM 2–3y

ANA 6y

931

postmenopausal

561/827

827/827

DFS

   

TAM 2–3y

ANA 3y

929

551/827

833/833

 

IDEAL(S1–04) (2017)

III

Abstract

6.4

(AI/TAM/TAM -AI) 5y

LET 5y

NR

postmenopausal

partial positive

HR+

DFS

   

(AI/TAM/TAM -AI) 5y

LET 2.5y

NR

   

TAM tamoxifen, AI aromatase inhibitor, EMT exemestane, LET letrozole, ANA anastrozole, ER estrogen, HR hormone receptor, DFS disease free survival

DFS and OS of extended versus routinely adjuvant endocrine treatment

As shown in Fig. 2a, twelve trials reported the HR/RR and 95% CIs for DFS and OS. Among them, nine trials compared the prolonged 10 years of endocrine therapy with 5 years of endocrine therapy. Nine trials were divided into three subgroups as follows: subgroup 1 was TAM 5y - TAM 5y versus TAM 5y, subgroup 2 was TAM 5y - AI 5y versus TAM 5y - PLA 5y, subgroup 3 was (AI and/or TAM) 5y - LET 5y versus (AI and/or TAM) 5y - PLA 5y. Three trials compared > 8 y of endocrine therapy with < 8 y of endocrine therapy.
Fig. 2
Fig. 2

DFS analysis of 10-y endocrine therapy versus 5-y endocrine therapy. a PFS: 10y endocrine therapy versus 5y endocrine therapy, b PFS (%) of extended endocrine treatment versus common endocrine treatment

Significant heterogeneity existed among the studies concerning DFS and DFS1; thus, REM was used to analyze the pooled DFS or pooled DFS1 (DFS: I2 = 72.5%, P = 0.000; DFS1: I2 = 74.6%, P = 0.003). There was no significant heterogeneity among the studies concerning DFS2 and DFS3; thus, FEM was used to analyze the pooled DFS2 or pooled DFS3 (DFS2: I2 = 0.0%, P = 0.481; DFS3: I2 = 49.0%, P = 0.162). The overall analysis demonstrated extended endocrine therapy to 10 years of significantly prolonged DFS compared with 5 years of endocrine therapy (HR = 0.84, 95% CI: 0.73–0.97) (Additional file 2: Figure S1A). Subgroup 2 and subgroup 3 analysis showed that TAM 5y - AI 5y and (AI and/or TAM) 5y - LET 5y treatment significantly prolonged DFS compared with TAM 5y and (AI and/or TAM) 5y treatment, respectively (HR = 0.61, 95% CI: 0.50–0.76; HR = 0.81, 95% CI: 0.71–0.93) (Additional file 2: Figure S1C, 1D). However, no significant difference was found in the DFS between the TAM 5y - TAM 5y group and TAM 5y group (HR = 0.97, 95% CI: 0.81–1.17) (Additional file 2: Figure S1B). The DFS rates of 10 years of endocrine therapy in the NSABP-B14 and Scottish trials were significantly lower than those of 5 years of endocrine treatment, whereas the DFS rates of 10 years of endocrine therapy in seven other trials were increased compared with those of 5 years of endocrine treatment (Fig. 2b).

There was significant heterogeneity among the studies concerning OS and OS1; thus, REM was applied to analyze the pooled OS or pooled OS1 (OS: I2 = 55.4%, P = 0.028; OS1: I2 = 64.2%, P = 0.025). No significant heterogeneity was found among the studies concerning OS2 and OS3; thus, FEM was used (OS2: I2 = 0.0%, P = 0.368; OS3: I2 = 0.0%, P = 0.323). (HR = 1.01, 95% CI: 0.90–1.14; HR = 1.02, 95% CI: 0.87–1.19; HR = 0.88, 95% CI: 0.64–1.23; HR = 1.09, 95% CI: 0.93–1.28, respectively) (Fig. 3).
Fig. 3
Fig. 3

OS analysis of 10-y endocrine therapy versus 5-y endocrine therapy

As shown in Additional file 3: Figure S2, three trials reported the HR/RR and 95% CIs for DFS and OS, which compared the efficacy of > 8 y of endocrine therapy with that of < 8 y of endocrine therapy. FEM was used to analyze the pooled DFS and pooled OS. Greater than 8 y of endocrine treatment significantly improved DFS compared with < 8 y of endocrine treatment (HR = 0.78, 95% CI: 0.66–0.94). However, no significant improvement was found in OS between the two groups (HR = 0.95, 95% CI: 0.76–1.19).

DFS analysis in the lymph node-positive subgroup

As shown in Fig. 4a and b, three trials reported the data of HR/RR and 95% CIs for DFS in the lymph node-positive subgroup. No significant heterogeneity was found among the studies, and FEM was used (I2 = 0.00%, P = 0.806). The analysis showed that extended endocrine therapy to 10 years significantly improved DFS compared with 5 years of endocrine therapy in the lymph node-positive subgroup (HR = 0.58, 95% CI: 0.45–0.75). In MA.17, positive results of extended endocrine treatment were seen in both the lymph node-positive and -negative groups.
Fig. 4
Fig. 4

DFS analysis in the lymph node-positive group. a PFS: 10y endocrine therapy versus 5y endocrine therapy in lymph node positive group, b PFS analysis in lymph node positive group and negative group

DFS analysis in the postmenopausal subgroup

As shown in Fig. 5a and b, seven trials reported the data of HR/RR and 95% CIs for DFS in the postmenopausal subgroup. Postmenopausal subgroup analysis showed that extended endocrine therapy to 10 years significantly improved DFS compared with 5 y of endocrine therapy (HR = 0.70, 95% CI: 0.58–0.85). A similar result was observed between > 8 y of endocrine therapy and < 8 y of endocrine therapy (HR = 0.76, 95% CI: 0.62–0.93). In the ATLAS, MA.17, NSABP-B33, NSABP-B42, MA-17R, ABCSG-6a and DATA trials, the recurrences rates in the extended group and non-extended group were 17.7% versus 20.5%, 3.6% versus 6.0%, 4.6% versus 6.5%, 14.9% versus 17.3%, 7.0% versus 10.2%, 7.8% versus 12.2%, and 14.0% versus 17.4%, respectively.
Fig. 5
Fig. 5

DFS analysis in the postmenopausal subgroup. a PFS: 10y endocrine therapy versus 5y endocrine therapy in postmenopausal subgroup, b PFS: >8y endocrine therapy versus < 8y endocrine therapy in postmenopausal subgroup

DFS analysis in the ER+ subgroup and/or PR+ subgroup

As shown in Fig. 6a and b, six trials reported the data of HR/RR and 95% CIs for DFS in the ER+ subgroup and/or PR+ subgroup. There was significant heterogeneity among the studies; thus, REM analysis was conducted (I2 = 76.7%, P = 0.001). ER+ and/or PR+ subgroup analysis showed that extended endocrine therapy to 10 years significantly improved DFS compared with 5 years of endocrine therapy (HR = 0.80, 95% CI: 0.67–0.96). In the NSABP-B14 trial, the recurrence rate in the TAM 5y - TAM 5y group was higher than that of the TAM 5y group (23.5% versus 18.6%, respectively). However, in the ATLAS, MA.17, NSABP-B33, NSABP-B42, and MA-17R trials, the recurrence rates in the extended treatment groups were lower than those in the 5 years of endocrine treatment group (17.8% versus 20.8%, 3.7% versus 6.1%, 4.8% versus 6.9%, 14.9% versus 17.3%, and 7.1% versus 10.3%, respectively).
Fig. 6
Fig. 6

DFS analysis in ER+ and/or PR+ positive subgroup. a PFS: 10y endocrine therapy versus 5y endocrine therapy in ER+ and/or PR+ positive subgroup, b The recurrence rates in ER+ and/or PR+ positive subgroup

Discussion

Five years of adjuvant endocrine therapy has been verified to significantly reduce the recurrence risk and cancer mortality in ER+, early-stage breast cancer [20]. Whether extended endocrine therapies could further increase the clinical benefit has always been a controversial topic. Some trials have shown that extended endocrine therapies could further lower the recurrence risk. However, IDEAL trials demonstrated that (AI/TAM/TAM-AI) 5y - LET 5y did not bring significant prolongation for DFS and OS compared with (AI/TAM/TAM-AI) 5y - LET 2.5y [8]. Additionally, in the Scottish and NSABP-B14 trials, extended TAM to 10 years was confirmed to decrease DFS compared with 5 years of treatment [12, 13]. The optimal time of extended endocrine treatment is a controversial hot topic for oncologists. Our study comprehensively analyzed the related clinical trials, and the results showed that extended 10 years of adjuvant endocrine treatment was more efficacious than “standard” 5 years of endocrine treatment in preventing recurrence. Unfortunately, extended endocrine therapy to 10 years are not verified to improve OS, and this might mainly influenced by the efficacy of multiline therapy after relapse. It should not be overlooked that the overall follow-up time is not long, so a very long term follow-up is needed in these populations to prove OS differences. Considering the difference in the research populations and backgrounds in different trials, clinical application of extended endocrine treatment should be carefully weighed.

The debates concerning extended TAM treatment is obvious. The time of extended endocrine therapy is an important factor affecting the conclusion. The ATLAS and aTTom trials reported that extended adjuvant TAM for more than 10 years provides further protection against recurrence; however, 5–9 years of application did not exert a positive effect [9, 10]. Saphner reported that the mean recurrence rate of 5–10 years was 4.3% per year; 5–9 years of extended endocrine treatment might not be the most advantageous with a lower recurrence risk [21]. With the increase in the recurrence risk after 10 years, extended adjuvant TAM for more than 10 years probably shows significant clinical efficacy. In the process, identifying patients with high-risk recurrence is the key factor to guide treatment.

The difference in drugs in extended endocrine treatment might affect the conclusion. Coombes RC reported that the DFS and OS in the (TAM-EXE) 5y group were significant improved compared with those in the TAM 5y group [22]. The 10-year breast cancer mortality was 12.1% after 5 years of AI treatment, a value that was lower than 14.2% after 5 years of TAM treatment [23], and 5 years of AI showed an advantage over 5 years of TAM in decreasing the 10-year mortality risk. The extended 3 years of ANA after 5 years of TAM showed a significant DFS reduction of 36% (ABCSG-6a) [24], and the extended 5 years of LET after 5 years of TAM showed a significant DFS reduction of 42% [3]. Our subgroup analysis showed that TAM 5y - AI 5y and (AI and/or TAM) 5y - LET 5y significantly prolonged DFS compared with TAM 5y. These data indicated that extended AI treatment is a valid therapeutic option for early breast cancer. However, the conclusions of continuous 10 years of TAM were not consistent. The NSABP-B14, Scottish and E4181/E5181 trials reported that an additional benefit was not observed in the TAM 5y - TAM 5y arms [1113]. However, the ATLAS and aTTom trials reported that a prolonged 10 years of TAM significantly reduced the recurrence risk [9, 10]. Our subgroup analysis verified that continuous 10 years of TAM did not improve DFS compared with 5 years of TAM.

The following factors are closely related to the efficacy of extended endocrine therapy: (1) Hormone receptor status. In hormone receptor-positive patients, 5 years of TAM treatment decreased the 5-y and 10-y breast cancer recurrence rates from 26.1 and 37.7% to 15.4% and 24.8%, respectively; however, the treatment could not decrease the recurrence rates in hormone receptor-negative patients [25]. In 6 ER+ and/or PR+ trials, five trials (ATLAS, MA.17, NSABP-B33, NSABP-B42, MA-17R) showed the superiority of 10 years of endocrine treatment [47, 9], whereas only the NSABP-B14 trial reported an opposite conclusion [13]. Our comprehensive analysis showed that 10 years of endocrine treatment further reduced the breast cancer recurrence rate and significantly improved DFS compared with 5 years of endocrine treatment (HR = 0.80, 95% CI: 0.67–0.96) in ER+ and/or PR+ patients. (2) Menstrual status. The ATLAS stratified study showed that extended TAM treatment seemed to have a beneficial effect in preventing recurrence in postmenopausal women (RR = 0.85, P = 0.05) but has no effect in premenopausal women (RR = 0.81, P = 0.15) [9]. In postmenopausal women, 5y TAM - 5y AI led to significant improvement in DFS; in the MA.17 trial, it led to OS improvement in the high-risk node-positive subset [4]. Our meta-analysis showed that extended endocrine therapy to 10 years significantly improved DFS in postmenopausal women (HR = 0.70, 95% CI: 0.58–0.85). (3) Lymph node status. The late recurrence risk in breast cancer patients with more than three positive nodes was 2.18-fold that in patients without lymph node metastasis after the completion of 5 years of adjuvant endocrine therapy [26]. In theory, the extended endocrine therapy should exert a clinical benefit in these patients with a lymph node-positive status. Unfortunately, the ATLAS trial showed that 10-year TAM treatment could not improve DFS compared 5 years of TAM in lymph node-positive or -negative patients [9]. 5y TAM-5y AI treatment only improved DFS compared with 5y TAM treatment in lymph node-positive patients, and the corresponding results in lymph node-negative patients were uniform [4, 7]. The mode of TAM 5y -AI 5y is worth recommending in lymph node-positive patients.

The clinical efficacy and side effects are two determining factors for extended endocrine treatment. Serious adverse effects will interrupt the persistence of endocrine treatment [27, 28]. The Ideal study reported that 15.7% patients discontinued extended 2.5 years of LET treatment because of toxicities [8]. However, the MA17R trial showed that it was safe and beneficial for women with HR-positive breast cancer to receive AI for another 5 years after initial treatment; the incidence of toxic effects was lower except that bone-related events occurred more frequently than those in the placebo group (14.0% versus 9.0%, respectively) [6]. Moreover, the discontinuation rate of extended AI for 5 years was 6.0% due to bone fracture, a value similar to that for the placebo. Extended AI to 10 years may be recommended when improved DFS is accompanied by a lower incidence rate of toxic effects. The reported ratios of endometrial cancer in the TAM 5y - TAM 5y group were 2.1, 1.7 and 2.2 folds compared with those in the TAM 5y group in the NSABP-B-14, ATLAS and aTTOM trials, respectively [9, 10, 13]. The TMA 5y - TAM 5y strategy may not be recommended with no improvement in DFS and higher incidence rates of endometrial cancer. Sequential treatment with different types of endocrine drugs is also used to maintain the efficacy to a maximum and decrease adverse effects to a minimum.

Conclusion

Based on standard 5-year endocrine treatment, extended endocrine treatment to 10 years could further bring a DFS benefit for patients with early breast cancer, especially in the AI and/or TAM 5y - AI 5y mode, ER+ subgroup and/or PR+ subgroup, postmenopausal subgroup and lymph node-positive subgroup. Of course, the recognition of patients with the highest recurrence risk will help to obtain more clinical benefit from extended endocrine treatment, and gene analysis or molecular markers will be used to guide individualized endocrine therapy.

Notes

Abbreviations

AI: 

Aromatase inhibitor

DFS: 

Disease-free survival

EMT: 

Exemestane

FEM: 

Fixed-effects model

LET: 

Letrozole

NSABP: 

National Surgical Adjuvant Breast and Bowel Project

OS: 

Overall survival

REM: 

Random-effects model

TAM: 

Tamoxifen

Declarations

Acknowledgements

We thank for the help of Statistical Center of Beijing Friendship Hospital.

Funding

This study was funded by the National Natural Science Foundation of China (Grant NO. 81301912), Beijing Municipal Health System High-level Health Person Foundation Project (Grant NO. 2014-3-005), Beijing Municipal Science and Technology Commission Foundation (Capital Features, Z161100000516083, to Qin Li) and Natural Science Foundation of Capital Medical University (to Qin Li). Funding bodies were not involved in the design of the study, collection, analysis, and interpretation of data or in writing the manuscript.

Availability of data and materials

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Authors’ contributions

QL designed the research and was responsible for the integrity of the data and accuracy of the data analysis. LL, BC and XJ contributed to the literature search, studies selection and figures. BC, XF and YL developed methodology. LL drafted the manuscript. TL and SW participated in studies selection and data extraction and statistical analysis. JZ and SK interpreted the results and polished the manuscript. QL reviewed and edited the manuscript extensively. All authors contributed to the review and approved the paper. All authors agreed to be accountable for the content of this paper.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
(2)
Department of Biochemistry and Molecular Biology, Basic Medical College, Shanxi Medical University, Taiyuan, 030001, China
(3)
Gastroenterology Department, JinCheng People’s Hospital, Shanxi, 048000, China
(4)
Biochemistry and Molecular Biology, Basic Medicine College, Shanxi Medical University, Taiyuan, 050001, China
(5)
Statistical Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
(6)
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, 77030, USA
(7)
Molecular and Cellular Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, 77030, USA

References

  1. Ferreira AR, Palha A, Correia L, Filipe P, Rodrigues V, Miranda A, André R, Fernandes J, Gouveia J, Passos-Coelho JL, Moreira A, Brito M, Ribeiro J, Metzger-Filho O, Lin NU, Costa L, Vaz-Luis I. Treatment adoption and relative effectiveness of aromatase inhibitors compared to tamoxifen in early breast cancer: a multi-institutional observational study. Breast. 2018;37:107–13.View ArticleGoogle Scholar
  2. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998;351:1451–67.View ArticleGoogle Scholar
  3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.View ArticleGoogle Scholar
  4. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol. 2007;25:2006–11.View ArticleGoogle Scholar
  5. Mamounas EP, Lembersky B, Jeong JH, Cronin W, Harkins B, Geyer C, Wickerham DL, Paik S, Costantino J, Wolmark N. NSABP B-42: a clinical trial to determine the efficacy of five years of letrozole compared with placebo in patients completing five years of hormonal therapy consisting of an aromatase inhibitor (AI) or tamoxifen followed by an AI in prolonging disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Clin Breast Cancer. 2006;7:416–21.View ArticleGoogle Scholar
  6. Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375:209–19.View ArticleGoogle Scholar
  7. Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26:1965–71.View ArticleGoogle Scholar
  8. Blok EJ, Kroep JR, Meershoek-Klein KE, Duijm-de CM, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers GJ, Nortier JWR, Rutgers EJT, van de Velde CJH. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006-05). J Natl Cancer Inst. 2018;110:djx134.View ArticleGoogle Scholar
  9. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros AVH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381:805–16.View ArticleGoogle Scholar
  10. Azim HA, Saadeldeen A. Commentary on “aTTom”: long-term effects of continuing adjuvant tamoxifen to 10 years. Chin Clin Oncol. 2014;3:7.PubMedGoogle Scholar
  11. Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst. 1996;88:1828–33.View ArticleGoogle Scholar
  12. Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst. 2001;93:456–62.View ArticleGoogle Scholar
  13. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684–90.View ArticleGoogle Scholar
  14. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.View ArticleGoogle Scholar
  15. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34.View ArticleGoogle Scholar
  16. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.View ArticleGoogle Scholar
  17. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.View ArticleGoogle Scholar
  18. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.View ArticleGoogle Scholar
  19. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.View ArticleGoogle Scholar
  20. Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, Peto R, Pritchard KI, Bergh J, Dowsett M, Hayes DF. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377:1836–46.View ArticleGoogle Scholar
  21. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14:2738–46.View ArticleGoogle Scholar
  22. Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del ML, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007;369:559–70.View ArticleGoogle Scholar
  23. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386:1341–52.View ArticleGoogle Scholar
  24. Fisher B, Redmond C, Fisher ER, Caplan R. Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: findings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol. 1988;6:1076–87.View ArticleGoogle Scholar
  25. Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–84.View ArticleGoogle Scholar
  26. Song F, Zhang J, Li S, Wu J, Jin T, Qin J, Wang Y, Wang M, Xu J. ER-positive breast cancer patients with more than three positive nodes or grade 3 tumors are at high risk of late recurrence after 5-year adjuvant endocrine therapy. Onco Targets Ther. 2017;10:4859–67.View ArticleGoogle Scholar
  27. Barron TI, Connolly R, Bennett K, Feely J, Kennedy MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer. 2007;109:832–9.View ArticleGoogle Scholar
  28. Chlebowski RT, Geller ML. Adherence to endocrine therapy for breast cancer. Oncology. 2006;71:1–9.View ArticleGoogle Scholar

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