ArticlesPrediction 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
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.
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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
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