Breast Cancer Index Assay Prognostic for Distant Recurrence in Estrogen Receptor–Positive, Node-Negative Breast Cancer

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In a study reported in The Lancet Oncology, Dennis C. Sgroi, MD, of Massachusetts General Hospital, and colleagues compared the ability of the breast-cancer index (BCI) assay, 21-gene recurrence score (Oncotype DX), and an immunohistochemical prognostic model (IHC4) to predict early and late distant recurrence in patients with estrogen receptor (ER)-positive, node-negative breast cancer. The study showed that a BCI-linear model was superior to a BCI-cubic model. Further, while all tests were significantly prognostic for overall risk of recurrence and early recurrence, only the BCI-linear assay, which is comprised of two independently developed gene expression biomarkers, was significantly prognostic for late recurrence.

Study Details

The study was performed in 665 patients with ER-positive, node-negative disease who received either tamoxifen or anastrozole monotherapy in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, using archived tumor blocks from patients for whom the 21-gene recurrence score and IHC4 values had already been ascertained. BCI analysis was performed in matched samples with sufficient residual RNA using BCI-linear and BCI-cubic models.

The prognostic ability of the BCI assay for distant recurrence over 10 years (the primary endpoint) was determined and compared with that of the 21-gene recurrence score and IHC4 for overall 10-year, early (0–5 years), and late (5–10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathologic variables, the change in the likelihood-ratio χ2 (LR-Δχ2) was calculated from Cox proportional hazards models.

BCI-Linear vs BCI-Cubic

The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-cubic risk groups (P < .0001), with 6.8% of patients in the low-risk group, 17.3% in the intermediate-risk group, and 22.2% in the high-risk group having distant recurrence.

Multivariate analysis showed that the BCI-linear test was a stronger predictor for overall distant recurrence compared with the BCI-cubic test (interquartile hazard ratio [HR] = 2.30 (95% confidence interval [CI] = 1.62–3.27), LR-Δχ2 = 22.69, P < .0001) and that both the 21-gene recurrence score (HR = 1.48, 95% CI = 1.22–1.78], LR-Δχ2 = 13.68, P = .0002) and IHC4 (HR = 1.69, 95% CI = 1.51–2.56], LR-Δχ2 = 22.83, P < .0001) were less predictive than the BCI-linear test. All further analyses were done using the BCI-linear model.

Prognostic for Overall, Early, and Late Recurrence

In multivariate analyses, the BCI-linear assay (HR = 2.77, 95% CI = 1.63–4.70, LR-Δχ2 = 15.42, P < .0001), 21-gene recurrence score (HR = 1.80, 95% CI = 1.42–2.29, LR-Δχ2 = 18.48, P < .0001), and IHC4 (HR = 2.90, 95% CI = 2.01–4.18, LR-Δχ2 = 29.14, P < .0001) all were significantly prognostic for early distant recurrence. Similarly, the BCI-linear (HR = 2.77, 95% CI = 1.63–4.70, LR-Δχ2 = 15.42, P < .0001), 21-gene recurrence score (HR = 1.80, 95% CI = 1.42–2.29, LR-Δχ2 = 18.48, P < .0001), and the IHC4 (HR = 2.90, 95% CI = 2.01–4.18, LR-Δχ2 = 29.14, P < .0001) were all prognostic for early distant recurrence. However, only BCI-linear was prognostic for late distant recurrence (HR = 1.95, 95% CI = 1.22–3.14, LR-Δχ2 = 7.97, P = .0048), with the 21-gene recurrence score (HR = 1.13, 95% CI = 0.82–1.56, LR-Δχ2 = 0.48, P = .47) and the IHC4 (HR = 1.30, 95% CI = 0.88–1.94, LR-Δχ2 = 1.59, P = .20) not achieving significance.

Results were similar in the subgroup of 597 HER2-negative patients, with all three tests being significantly prognostic for overall distant recurrence and early recurrence, but only BCI-linear being prognostic for late distant recurrence.

Two Distinct Risk Groups for Early and Late Recurrence

A post hoc analysis of BCI-linear in early recurrence showed that there was little difference in distant recurrence at 5 years between the BCI low-risk and intermediate-risk groups, which together included 556 (84%) of 665 patients with a combined 5-year rate of distant recurrence of 2.6%. The BCI high-risk group, which included 109 patients (16%), had a 5-year distant recurrence rate of 18·1%. After adjustment for clinical treatment score, the hazard ratio for the high-risk group vs this low-risk grouping was 4.61 (95% CI = 2.20–9.66).

An analysis of late recurrence showed that intermediate-risk and high-risk patients had highly similar rates of recurrence, with the combined groups including 230 (39%) of 596 patients with a distant recurrence rate of 13.4% for years 5 to 10. The low-risk group included 366 patients (61%) with a recurrence rate of 3.5% for years 5 to 10. After adjustment for clinical treatment score, the hazard ratio for this high-risk grouping vs the low-risk group was 2.94 (95% CI = 1.44–6.01).

The investigators noted that these modified risk groupings could allow baseline identification of a relatively small group of patients at higher risk of early recurrence who might be considered for therapy in addition to endocrine therapy and a larger group that might be regarded as adequately treated with endocrine therapy. Similarly, the finding of two distinct risk groupings for late recurrence in patients remaining disease-free on adjuvant tamoxifen or aromatase inhibitor treatment at 5 years suggests that there is a sizable group of patients at low risk who may require no further systemic therapy.

The investigators concluded, “[The BCI-linear assay] 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.” ■

Disclosure: The study was funded by the Avon Foundation, National Institutes of Health, Breast Cancer Foundation, U.S. 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).


1. Sgroi DC, Sestak I, Cuzick J, et al: 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. Lancet Oncology 14:1067-1076, 2013.