Elsevier

The Lancet Oncology

Volume 14, Issue 11, October 2013, Pages 1067-1076
The Lancet Oncology

Articles
Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population

https://doi.org/10.1016/S1470-2045(13)70387-5Get rights and content

Summary

Background

Biomarkers to improve the risk–benefit of extended adjuvant endocrine therapy for late recurrence in patients with oestrogen-receptor-positive breast cancer would be clinically valuable. We compared the prognostic ability of the breast-cancer index (BCI) assay, 21-gene recurrence score (Oncotype DX), and an immunohistochemical prognostic model (IHC4) for both early and late recurrence in patients with oestrogen-receptor-positive, node-negative (N0) disease who took part in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial.

Methods

In this prospective comparison study, we obtained archival tumour blocks from the TransATAC tissue bank from all postmenopausal patients with oestrogen-receptor-positive breast cancer from whom the 21-gene recurrence score and IHC4 values had already been derived. We did BCI analysis in matched samples with sufficient residual RNA using two BCI models—cubic (BCI-C) and linear (BCI-L)—using previously validated cutoffs. We assessed prognostic ability of BCI for distant recurrence over 10 years (the primary endpoint) and compared it with that of the 21-gene recurrence score and IHC4. We also tested the ability of the assays to predict early (0–5 years) and late (5–10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathological variables, we calculated the change in the likelihood-ratio χ2 (LR-Δχ2) from Cox proportional hazards models.

Findings

Suitable tissue was available from 665 patients with oestrogen-receptor-positive, N0 breast cancer for BCI analysis. The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-C risk groups (p<0·0001) with 6·8% (95% CI 4·4–10·0) of patients in the low-risk group, 17·3% (12·0–24·7) in the intermediate group, and 22·2% (15·3–31·5) in the high-risk group having distant recurrence. The secondary analysis showed that BCI-L was a much stronger predictor for overall (0–10 year) distant recurrence compared with BCI-C (interquartile HR 2·30 [95% CI 1·62–3·27]; LR-Δχ2=22·69; p<0·0001). When compared with BCI-L, the 21-gene recurrence score was less predictive (HR 1·48 [95% CI 1·22–1·78]; LR-Δχ2=13·68; p=0·0002) and IHC4 was similar (HR 1·69 [95% CI 1·51–2·56]; LR-Δχ2=22·83; p<0·0001). All further analyses were done with the BCI-L model. In a multivariable analysis, all assays had significant prognostic ability for early distant recurrence (BCI-L HR 2·77 [95% CI 1·63–4·70], LR-Δχ2=15·42, p<0·0001; 21-gene recurrence score HR 1·80 [1·42–2·29], LR-Δχ2=18·48, p<0·0001; IHC4 HR 2·90 [2·01–4·18], LR-Δχ2=29·14, p<0·0001); however, only BCI-L was significant for late distant recurrence (BCI-L HR 1·95 [95% CI 1·22–3·14], LR-Δχ2=7·97, p=0·0048; 21-gene recurrence score HR 1·13 [0·82–1·56], LR-Δχ2=0·48, p=0·47; IHC4 HR 1·30 [0·88–1·94], LR-Δχ2=1·59, p=0·20).

Interpretation

BCI-L was the only significant prognostic test for risk of both early and late distant recurrence and identified two risk populations for each timeframe. It could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy.

Funding

Avon Foundation, National Institutes of Health, Breast Cancer Foundation, US Department of Defense Breast Cancer Research Program, Susan G Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, AstraZeneca, Cancer Research UK, and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden (London, UK).

Introduction

Oestrogen-receptor-positive breast cancer is a disease with a protracted risk of recurrence.1, 2 After 5 years of adjuvant tamoxifen, patients have a sustained risk of disease recurrence and death for at least 15 years after diagnosis.1 Long-term follow-up from pivotal upfront trials of adjuvant aromatase inhibitors, including the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial3, 4 and Breast International Group (BIG) 1-98 study,5 show a continuing rate of recurrence of about 2% per year after initial therapy, with greater than half of all recurrences occurring after 5 years of adjuvant endocrine therapy.3, 4, 5 These findings emphasise the need for extended adjuvant therapy and a biomarker that can guide the treatment decision-making process.

Multigene expression signatures studied in the past decade for assessment of recurrence risk in oestrogen-receptor-positive breast cancer rely mainly on the quantitative measurement of proliferation-related gene expression.6, 7, 8, 9, 10, 11, 12, 13, 14, 15 These multigene signatures, including the 21-gene recurrence score (Oncotype DX; Genomic Health, Redwood City, CA, USA), are strong predictors of distant recurrence, but their prognostic ability diminishes when assessing risk beyond 5 years from diagnosis.16, 17 By contrast, predictors of late recurrence are not well characterised, and different mechanisms might be associated with early and late recurrences.18, 19 An unmet clinical need exists for biomarkers that identify patients who are adequately treated with only 5 years of endocrine therapy, and conversely, those at increased risk of late recurrence who might warrant extended adjuvant endocrine or other therapy.

Members of our study team (specifically, those from Massachusetts General Hospital, Boston, MA, USA, and bioTheranostics, San Diego, CA, USA) previously developed and validated the breast-cancer index (BCI) assay that consists of two independently developed gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR.20, 21 MGI, a five-gene predictor that recapitulates tumour grade and proliferation, is highly prognostic in patients with oestrogen-receptor-positive breast cancer.22 HOXB13/IL17BR, which was developed independently of tumour grade or proliferation, is prognostic for early and late distant recurrences, and is predictive of extended adjuvant aromatase inhibitor benefit in patients with early-stage oestrogen-receptor-positive breast cancer.12, 23, 24 Both the BCI and 21-gene recurrence score assays measure gene expression by quantitative real-time PCR, although they differ in the genes that they detect.6, 22 IHC4, developed by members of our study team (MD and JC), is another prognostic model that measures protein expression of four of the most informative immunohistochemical biomarkers: oestrogen receptors, progesterone receptors, HER2, and Ki-67,25 none of which are encoded by genes in the BCI assay. BCI has not been assessed in patients with oestrogen-receptor-negative or triple-negative breast cancer.

In this study, our objective was to assess the prognostic value of BCI for early and late distant recurrence in postmenopausal women with localised lymph-node-negative (N0) breast cancer given either tamoxifen or anastrozole monotherapy in the ATAC trial, and to compare its prognostic ability in matched patients with that of the 21-gene recurrence score and IHC4.

Section snippets

Study design and patients

In this prospective comparison study, we obtained tissue samples from the TransATAC project, initiated in 2002 to establish a tissue bank of formalin-fixed paraffin-embedded (FFPE) primary tumour blocks from postmenopausal patients with oestrogen-receptor-positive breast cancer from the monotherapy groups of the ATAC trial to assist with translational research.3, 4 We requested archival tumour blocks from all patients for whom the 21-gene recurrence score and IHC4 had already been calculated,25

Results

Values for 21-gene recurrence score, IHC4, and BCI were calculated for 915 women, of whom 665 had oestrogen-receptor-positive, N0 breast cancer (appendix p 6). Clinical characteristics of these 665 patients are listed in table 1 and compared with the characteristics of 561 UK patients with oestrogen-receptor-positive, N0 breast cancer who participated in the ATAC trial but who were not part of TransATAC. We noted no significant differences between these two groups, except that the non-TransATAC

Discussion

We have shown that BCI (linear model) has a statistically significant prognostic ability over 10 years for the prediction of individual risk of distant recurrence in patients with oestrogen-receptor-positive, N0 breast cancer from the TransATAC cohort. Examining clinically relevant time periods of 0–5 years and 5–10 years separately showed that BCI might have the potential to affect two important decision points in the management of these patients. At baseline, BCI identified two apparently

References (34)

  • Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial

    Lancet Oncol

    (2008)
  • S Paik et al.

    A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer

    N Engl J Med

    (2004)
  • T Sorlie et al.

    Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

    Proc Natl Acad Sci USA

    (2001)
  • DS Oh et al.

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

    J Clin Oncol

    (2006)
  • S Loi et al.

    Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade

    J Clin Oncol

    (2007)
  • MJ van de Vijver et al.

    A gene-expression signature as a predictor of survival in breast cancer

    N Engl J Med

    (2002)
  • TO Nielsen et al.

    A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer

    Clin Cancer Res

    (2010)
  • Cited by (0)

    View full text