Prognostic utility of the breast cancer index and comparison to Adjuvant! Online in a clinical case series of early breast cancer

Department of Medicine, Division of Hematology/Oncology, UPMC, University of Pittsburgh Cancer Institute, 300 Halket Street, Suite 4628, Pittsburgh, PA 15213, USA.
Breast cancer research: BCR (Impact Factor: 5.49). 10/2011; 13(5):R98. DOI: 10.1186/bcr3038
Source: PubMed


Breast Cancer Index (BCI) combines two independent biomarkers, HOXB13:IL17BR (H:I) and the 5-gene molecular grade index (MGI), that assess estrogen-mediated signalling and tumor grade, respectively. BCI stratifies early-stage estrogen-receptor positive (ER+), lymph-node negative (LN-) breast cancer patients into three risk groups and provides a continuous assessment of individual risk of distant recurrence. Objectives of the current study were to validate BCI in a clinical case series and to compare the prognostic utility of BCI and Adjuvant!Online (AO).
Tumor samples from 265 ER+LN- tamoxifen-treated patients were identified from a single academic institution's cancer research registry. The BCI assay was performed and scores were assigned based on a pre-determined risk model. Risk was assessed by BCI and AO and correlated to clinical outcomes in the patient cohort.
BCI was a significant predictor of outcome in a cohort of 265 ER+LN- patients (median age: 56-y; median follow-up: 10.3-y), treated with adjuvant tamoxifen alone or tamoxifen with chemotherapy (32%). BCI categorized 55%, 21%, and 24% of patients as low, intermediate and high-risk, respectively. The 10-year rates of distant recurrence were 6.6%, 12.1% and 31.9% and of breast cancer-specific mortality were 3.8%, 3.6% and 22.1% in low, intermediate, and high-risk groups, respectively. In a multivariate analysis including clinicopathological factors, BCI was a significant predictor of distant recurrence (HR for 5-unit increase = 5.32 [CI 2.18-13.01; P = 0.0002]) and breast cancer-specific mortality (HR for a 5-unit increase = 9.60 [CI 3.20-28.80; P < 0.0001]). AO was significantly associated with risk of recurrence. In a separate multivariate analysis, both BCI and AO were significantly predictive of outcome. In a time-dependent (10-y) ROC curve accuracy analysis of recurrence risk, the addition of BCI+AO increased predictive accuracy in all patients from 66% (AO only) to 76% (AO+BCI) and in tamoxifen-only treated patients from 65% to 81%.
This study validates the prognostic performance of BCI in ER+LN- patients. In this characteristically low-risk cohort, BCI classified high versus low-risk groups with ~5-fold difference in 10-year risk of distant recurrence and breast cancer-specific death. BCI and AO are independent predictors with BCI having additive utility beyond standard of care parameters that are encompassed in AO.

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Available from: Mamatha Chivukula, Oct 06, 2015
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    • "For tamoxifen-treated and untreated ER-positive patients classified as low risk by the BCI, absolute risks of breast cancer death at 10 years post-diagnosis were 1.1% and 5.1% in their study and 3.5% and 5.1% in ours. In the only other study to evaluate the BCI to date [17], corresponding estimates for low-risk patients receiving adjuvant tamoxifen with or without chemotherapy or adjuvant tamoxifen alone were 3.8% and 7.2%, respectively. "
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    ABSTRACT: Introduction Studies have shown that a two-gene ratio (HOXB13:IL17BR) and a five-gene (BUB1B, CENPA, NEK2, RACGAP1, RRM2) molecular grade index (MGI) are predictive of clinical outcomes among early-stage breast cancer patients. In an independent population of lymph node-negative breast cancer patients from a community hospital setting, we evaluated the performance of two risk classifiers that have been derived from these gene signatures combined, MGI+HOXB13:IL17BR and the Breast Cancer Index (BCI). Methods A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 who did not receive adjuvant chemotherapy. For 191 cases (breast cancer deaths) and 417 matched controls, archived tumor tissues were available and analyzed for expression levels of the seven genes of interest and four normalization genes by RT-PCR. Logistic regression methods were used to estimate the relative risk (RR) and 10-year absolute risk of breast cancer death associated with prespecified risk categories for MGI+HOXB13:IL17BR and BCI. Results Both MGI+HOXB13:IL17BR and BCI classified over half of all ER-positive patients as low risk. The 10-year absolute risks of breast cancer death for ER-positive, tamoxifen-treated patients classified in the low-, intermediate-, and high-risk groups were 3.7% (95% confidence interval (CI) 1.9% to 5.4%), 5.9% (95% CI 3.0% to 8.6%), and 12.9% (95% CI 7.9% to 17.6%) by MGI+HOXB13:IL17BR and 3.5% (95% CI 1.9% to 5.1%), 7.0% (95% CI 3.8% to 10.1%), and 12.9% (95% CI 7.1% to 18.3%) by BCI. Those for ER-positive, tamoxifen-untreated patients were 5.7% (95% CI 4.0% to 7.4%), 13.8% (95% CI 8.4% to 18.9%), and 15.2% (95% CI 9.4% to 20.5%) by MGI+HOXB13:IL17BR and 5.1% (95% CI 3.6% to 6.6%), 18.6% (95% CI 10.8% to 25.7%), and 17.5% (95% CI 11.1% to 23.5%) by BCI. After adjusting for tumor size and grade, the RRs of breast cancer death comparing high- versus low-risk categories of both classifiers remained elevated but were attenuated for tamoxifen-treated and tamoxifen-untreated patients. Conclusion Among ER-positive, lymph node-negative patients not treated with adjuvant chemotherapy, MGI+HOXB13:IL17BR and BCI were associated with risk of breast cancer death. Both risk classifiers appeared to provide risk information beyond standard prognostic factors.
    Breast cancer research: BCR 03/2013; 15(2):R24. DOI:10.1186/bcr3402 · 5.49 Impact Factor
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    ABSTRACT: Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy. Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25). A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.
    PLoS ONE 01/2013; 8(1):e54078. DOI:10.1371/journal.pone.0054078 · 3.23 Impact Factor
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    ABSTRACT: Background We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit.DesignIndependent evaluation of six genomic tests [Oncotype Dx™, MammaPrint(®), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria.Panel statementsThe majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype Dx™ and MammaPrint(®) to be convincing. None of the genomic tests demonstrated robust evidence of clinical utility: it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome.Conclusions The IMPAKT 2012 Working Group proposed the following recommendations: (i) a need to develop models that integrate clinicopathologic factors along with genomic tests; (ii) demonstration of clinical utility should be made in the context of a prospective randomized trial; and (iii) the creation of registries for patients who are subjected to genomic testing in the daily practice.
    Annals of Oncology 01/2013; 24(3). DOI:10.1093/annonc/mds645 · 7.04 Impact Factor
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