Stratification of Prognosis of Triple-Negative Breast Cancer Patients Using Combinatorial Biomarkers

Abstract

BackgroundTriple-negative breast cancer (TNBC) is highly diverse group of cancers, and generally considered an aggressive disease associated with poor survival. Stratification of TNBC is highly desired for both prognosis and treatment decisions to identify patients who may benefit from less aggressive therapy.MethodsThis study retrieved 192 consecutive non-metastasis TNBC patients who had undergone a resection of a primary tumor from 2008 to 2012. All samples were negative for ER, PR, and HER2/neu. Disease-free-survival (DFS) and overall-survival (OS) were evaluated for expression of immunohistochemical biomarkers (P53, Ki-67, CK5/6 and EGFR), as well as clinicopathological variables including age, tumor size, grade, lymph node status, pathologic tumor and nodal stages. The cutoff values of the basal biomarkers, EGFR and CK5/6, were estimated by time-dependent ROC curves. The prognostic values of combinatorial variables were identified by univariate and multivariate Cox analysis. Patients were stratified into different risk groups based on expression status of identified prognostic variables.ResultsMedian age was 57 years (range, 28–92 years). Patients’ tumor stage and nodal stage were significantly associated with OS and DFS. EGFR and CK5/6 were significant prognostic variables at cutoff points of 15% (p = 0.001, AUC = 0.723), and 50% (p = 0.006, AUC = 0.675), respectively. Multivariate Cox analysis identified five significant variables: EGFR (p = 0.016), CK5/6 (p = 0.018), Ki-67 (p = 0.048), tumor stage (p = 0.010), and nodal stage (p = 0.003). Patients were stratified into low basal (EGFR≤15% and CK5/6≤50%) and high basal (EGFR>15% and/or CK5/6>50%) expression groups. In the low basal expression group, patients with low expressions of Ki-67, low tumor and nodal stage had significantly better survival than those with high expressions/stages of three variables, log-rank p = 0.015 (100% vs 68% at 50 months). In the high basal expression group, patient with high basal expression of both biomarkers (EGFR >15% and CK5/6 >50%) had worse survival (mean DFS = 25 months, 41.7% event rate) than those patient with high expression of either one marker (mean DFS = 34 months, 25.5% event rate).ConclusionsImmunoexpression of basal biomarkers, EGFR and CK5/6, is useful in predicting survival of TNBC patients. Integrated with Ki-67, tumor and nodal stages, combinatorial biomarker analysis provides a feasible clinical solution to stratify patient risks and help clinical decision-making with respect to selecting the appropriate therapies for individual patients.

Time-dependent ROC curve analysis in medical research: current methods and applications

“…Yue et al [47], [48] have used pre-treatment 18 F-FDG-PET/CT imaging and combinatorial biomarkers respectively to stratify the risk of TNBC (Triple-negative breast cancer) patients. TNBC is considered as a high risk disease and normally associated with poor survival.…”

Biological rationale for a patient-specific approach in the treatment of breast cancer. Clinical value of novel biomarkers of breast cancer

“…На основе пороговых значений когорта была разделена на 2 группы: EGFR ≤15 %; CK5 / 6 ≤50 % и EGFR >15 %; CK5 / 6 >50 %. В группе пациенток с высокой экспрессией обоих маркеров наблюдалась более низкая выживаемость (средняя БРВ -25 мес, частота события -41,7 %) в сравнении с группой пациенток, где наблюдалась высокая экспрессия одного из маркеров (средняя БРВ -34 мес, частота события -25,5 %) [114].…”

“…Экспрессия факторов проводилась с помощью метода ИГХ. У пациенток с отсутствием экспрессии CK5 / 6 при однофакторном и многофакторном анализах отмечалось уменьшение БРВ (p = 0,2 и p = 0,002 соответственно) [114].…”

An Update on Breast Cancer Biomarkers

“…Phosphorylation of EGFR may act as biomarker of response to time-staggered inhibition in EGFR driven tumor types such as lung cancer and triple negative breast cancer [54,55]. A recent study revealed that immunoexpression of biomarkers like CK5/6 and EGFR predict the survival of triple negative breast cancer patients [56]. Likewise, recent study revealed that combined measurement of three non-intuitive proteins EGFR, ERBB3, and CDKN1B determines responsiveness to drugs targeting their constituents and cellular dependence on PI3K vs. MAPK signaling pathways [57].…”