HOXB13:IL17BR and molecular grade index and risk of breast cancer death among patients with lymph node-negative invasive disease

Abstract

IntroductionStudies 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).MethodsA 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.ResultsBoth 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.ConclusionAmong 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.

Nek2 and Plk4: prognostic markers, drivers of breast tumorigenesis and drug resistance

“…Nek2 was also included in a molecular grade index (MGI) predictive genetic profile that indicated significant difference in distant metastasis-free survival for tamoxifen-treated patients with intermediate and high risk. In this association, the risk classification and prognostic performance of MGI were independent of tumor size, grade, Her2 and PR expression (78, 79). Retrospective analyses of public dataset confirmed that overexpression of Nek2 conferred a poor survival outcome in breast tumors (19, 23).…”

Association of survivin splice variants with prognosis and treatment of breast cancer

“…Survivin (BIRC5) was included in the genes tested in the original validation study; however it was not selected for the final 70-gene panel [27,28] . Other commercial kits employ RT-PCR assays for selected genes from RNA extracted from formalin-fixed paraffin-embedded tissues: (1) an 8-gene panel from Aviara (now Biotheranostics Inc) combining the Breast Cancer Index HOXB13:IL17BR ratio with the Molecular Grade Index consisting of the average expression of five cell cycle-associated genes (BUB1B, CENPA, NEK2, RACGAP1 and RRM2) [29] ; (2) the PAM 50 assay (by ARUP Laboratories) that includes wild-type survivin among the 50 selected genes [30] ; and (3) the FDAapproved Oncotype DX Breast Cancer Assay (by Genomic Health). Oncotype DX testing may aid a patient by preventing redudant chemotherapy and its connected toxicity, while reduction of chemotherapy also leads to economical changes in health systems [31,32] .…”

A 16 Yin Yang gene expression ratio signature for ER+/node− breast cancer

“…However, the single two‐gene ratio may not reflect the complex tumor progression process for prognosis. Even though the accuracy of this test could be improved by including a 5‐gene molecular grade index, the relative risks (RR) of breast cancer death is not statistically significant after the tumor size and grade were added to the model …”