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

Abstract

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 χ(2) (LR-Δχ(2)) 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-Δχ(2)=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-Δχ(2)=13·68; p=0·0002) and IHC4 was similar (HR 1·69 [95% CI 1·51-2·56]; LR-Δχ(2)=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-Δχ(2)=15·42, p<0·0001; 21-gene recurrence score HR 1·80 [1·42-2·29], LR-Δχ(2)=18·48, p<0·0001; IHC4 HR 2·90 [2·01-4·18], LR-Δχ(2)=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-Δχ(2)=7·97, p=0·0048; 21-gene recurrence score HR 1·13 [0·82-1·56], LR-Δχ(2)=0·48, p=0·47; IHC4 HR 1·30 [0·88-1·94], LR-Δχ(2)=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).

Conflict of interest statement

Conflicts of Interest

DCS and MGE are named inventors on a patent to use the Breast Cancer Index (BCI), HOXB13/IL17BR (H/I) and Molecular Grade Index (MGI) assays to predict breast cancer outcome. MD and JC declared that they have received grant support and lecture fees from Astrazeneca. PEG disclosed that he has received lecture fees from Novartis and Glaxo-Smith-Kline. MGE, CAS, YZ and BS are employees of bioTheranostics Inc. AD, KS, EL and IS have declared that they has no relevant conflicts of interest.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Performance of pre-specified risk groups based on BCI-C and BCI-L for overall 10-year distant recurrences in all ER+N0 patients. A) BCI-C; B) BCI-L.

Figure 2

Performance of BCI pre-specified risk groups for early and late distant recurrences in ER+ N0 patients. A) early 0–5 year distant recurrence; B) late 5–10 year distant recurrence. Population P1 refers to the pre-specified low and intermediate risk groups while P2, refers to the high risk group for early recurrence. P3 refers to the pre-specified low risk group, while P4 refers to the intermediate and high risk groups for late recurrence.

Figure 3

Risk of early and late distant recurrence as a function of continuous BCI index in ER+ N0 patients. A) risk of early 0–5 year distant recurrence; B) risk of late 5–10 year distant recurrence. Vertical lines delineate the borders between the low, intermediate (Inter) and high pre-specified BCI risk groups.

Figure 4

Performance of the pre-specified risk groups of BCI and RS and the post-hoc determined categorical risk groups of IHC4 for overall 10-year distant recurrences in ER+ N0 patients, both arms combined and anastrozole (ANA) and tamoxifen (TAM) arm separately. A) BCI in both arms combined; B) RS in both arms combined; C) IHC4 in both arms combined; D) BCI in anastrozole arm alone; E) RS in anastrozole arm alone; F) IHC4 in anastrozole arm alone; G) BCI in tamoxifen arm alone; H) RS in tamoxifen arm alone; I) IHC4 in tamoxifen arm alone.