Estrogen receptor, Progesterone receptor, HER2 status and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial

doi:10.1016/j.ejca.2014.02.022

European Journal of Cancer

Volume 50, Issue 8, May 2014, Pages 1412-1421

https://doi.org/10.1016/j.ejca.2014.02.022 Get rights and content

Abstract

Background

The DBCG 77C trial compared one year of tamoxifen in postmenopausal, steroid-receptor unknown, high-risk breast cancer patients to no adjuvant systemic therapy. After a potential follow-up of 30 years we report overall efficacy of the study and results according to subtypes subsequently assessed by immunohistochemistry and fluorescent in situ hybridisation (FISH).

Methods

Between 1977 and 1982, 1716 postmenopausal patients with tumours larger than 5 cm or positive axillary nodes were randomly assigned to no systemic therapy or tamoxifen 30 mg daily for one year. Archival tumour tissue from 1515 patients was analysed and the hormone receptor positive (estrogen receptor (ER) and/or progesterone receptor (PR)) cancers were defined as luminal A if Ki67 low and HER2-negative; as luminal B if Ki67 high or HER2-positive; and otherwise as non-luminal-HER2 positive or triple negative.

Findings

In the intent-to-treat (ITT) population one year of tamoxifen improved the disease-free-survival (DFS) (hazard ratio (HR) = 0.87; 95% confidence interval (CI) 0.77–0.98), the Breast Cancer Recurrence Rate (BCRR) (HR = 0.79; 0.69–0.90) and reduced the breast-cancer-specific-mortality (BCM) (HR = 0.83; 0.73–0.93). BCRR were improved significantly by tamoxifen in luminal A (HR = 0.66; 0.53–0.84) and luminal B/HER2– (HR = 0.54; 0.39–0.74) but not in the other subsets, and with similar results for BCM with 30 years follow-up.

Interpretation

One year of treatment with tamoxifen significantly improves BCRR and BCM in postmenopausal patients with ER positive breast cancers. The relative benefit from tamoxifen was not significantly different in luminal A and B subtypes.

Funding

The Danish Breast Cancer Cooperative Group (DBCG) prepared the original protocol (DBCG 77C) and was the sponsor of the study. Funding was not provided to the participating departments. The biomarker study was supported by grants from the Clinical Institute, Odense University.

Introduction

The recently updated meta-analysis regarding hormone receptors and long term effect of adjuvant tamoxifen, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) [1], found estrogen receptor (ER) status to be the only important predictor of reduced 15-year risks of breast cancer recurrence and death. Luminal cancers are biologically distinct from ER negative cancers as demonstrated by gene expression profiles more than a decade ago [2]. Specific biological characteristics or treatable targets have not enabled a further breakdown of the large group of luminal cancers and consequently the luminal group was divided according to proliferation genes [3], [4], [5], [6]. Gene expression profiling has only been carried out in a few of the adjuvant tamoxifen trials. Using the PAM50 classifier Chia et al., demonstrated a statistically significant benefit of adjuvant tamoxifen in the NCIC MA.12 trial among patients with luminal subtypes (hazard ratio (HR) = 0.52; confidence interval (CI) (95%), 0.32–0.86; p = .009) [6]. The classifier was superior to conventional local and central immunohistochemical (IHC) ER assessment for both prognosis and more importantly for prediction of benefit to adjuvant tamoxifen compared with placebo. Jerevall et al. [7] who used a molecular grade index (a gene expression assay comprised of five genes related to proliferation) on tumour blocks from the placebo controlled randomized Stockholm trial supported the predictive value of the proliferation index on breast cancer outcome, both in treated and untreated patients.

An IHC determined surrogate marker for proliferation, the Ki67-labeling index, has been investigated for its ability to predict prognosis and response to endocrine therapy. Cheang et al. [8] subtyped breast cancer specimens both by gene expression profiles (the PAM50 classifier) and by IHC including ER, progesterone receptor (PR), HER2 and Ki67-labeling index. They showed that the expression of ER, PR, HER2 and the Ki67 index appeared to distinguish luminal A from luminal B breast cancer subtypes and that the patients with luminal B tumours had an increased risk of breast cancer relapse and death in comparison with the more common luminal A subtype.

The predictive value of the Ki67 labeling index has been evaluated in three large adjuvant trials (BIG-98 [9], ABCSG [10] and ATAC [11]) comparing tamoxifen to an aromatase inhibitor or a sequence of the two drugs. The results were however inconclusive and a statistical significant heterogeneity between treatment and Ki67 status was not detected in any of the three trials.

At the 2011 St Gallen International Breast Cancer Conference the panel agreed that therapeutic decisions could be made based on ‘the approximated recognition of the intrinsic subtypes of breast cancer’ defined by the expression of ER, PR, Ki67 and HER2 [12]. The panel concluded, that the cut-point for Ki67 should be 14% based on previous comparison with the PAM50 methodology [13], [8]. At the 2013 St Gallen International Breast Cancer Conference the panel could not reach an agreement regarding a cut-point [14].

The DBCG 77C randomized high-risk, receptor unknown, postmenopausal breast-cancer patients to one year of tamoxifen or to observation. For the first time we report the overall results from the study and the predictive value of intrinsic subtypes compared with ER alone.

Section snippets

Materials and methods

The DBCG 77C tamoxifen trial was an open-labelled randomized trial [15]. The organization of DBCG and the design of the clinical database have previously been described in detail [16].

Results

Fig. 1 shows the assignment to the two treatment arms. A complete follow-up for survival until 1st June 2011 was achieved for all patients. Patients included in the per-protocol had at least one registration of treatment/follow-up after randomization and 75 patients were excluded in the per-protocol analysis. Treatment adherence in the ITT population was 81.2% (78.4–83.7) at 36 weeks and 74.4% (71.3–77.2) completed the pre-planned treatment.

End-point events in the DBCG 77C trial according to

Discussion

The DBCG 77C tamoxifen trial shows a life-lasting benefit from one year of tamoxifen as compared to no adjuvant systemic therapy and notably survival benefits achieved at 10 years persisted. With 30 years potential follow-up 1674 of the 1716 patients had died. In the 30-years breast-cancer-specific analysis the number of events has allowed us to detect a 17% decrease in BCM [24] despite the fact that 1/3 of the patients had ER-negative tumours (HR = 0.83; 95% CI, 0.73–0.93). In agreement with the

Contributors

All authors reviewed the data analyses, contributed to the writing of the report, made final decisions on all parts of the report, and approved the final version of the submitted report. BE participated in study design. BE, JA and DN enrolled patients. MJ undertook statistical analyses. AK and AL made the immunohistochemical assessments. AK, AL, MJ, JA, DN and BE contributed to data collation and generation of tables and figures. The academic authors vouch for the completeness and veracity of

Conflict of interest statement

None declared.

Acknowledgement

We thank Tine Rudbeck for excellent technical assistance with the HER2 FISH.

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Estrogen receptor, Progesterone receptor, HER2 status and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial

Abstract

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Materials and methods

Results

Discussion

Contributors

Conflict of interest statement

Acknowledgement

Lancet

Ann Oncol

Ann Oncol

Control Clin Trials

Lancet Oncol

Lancet Oncol

Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials

Lancet

Molecular portraits of human breast tumours

Nature

Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers

J Clin Oncol

The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade

J Pathol

A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen

Clin Cancer Res

Prognostic utility of HOXB13:IL17BR and molecular grade index in early-stage breast cancer patients from the Stockholm trial

Br J Cancer

Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer

J Natl Cancer Inst

Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole

J Clin Oncol

Adjuvant sequencing of tamoxifen and anastrozole is superior to tamoxifen alone in postmenopausal women with low proliferating breast cancer

Clin Cancer Res

Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer

J Clin Oncol