A New Molecular Predictor of Distant Recurrence in ER-Positive, HER2-Negative Breast Cancer Adds Independent Information to Conventional Clinical Risk Factors

Abstract

Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy.Experimental Design: RNA levels assessed by quantitative reverse transcriptase PCR in formalinfixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n ¼ 378, ABCSG-8: n ¼ 1,324].Results: In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P ¼ 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P ¼ 0.024 (ABCSG-6) and 0.726 vs. 0.701, P ¼ 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively.Conclusions: The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.

The PAM50 Risk-of-Recurrence Score Predicts Risk for Late Distant Recurrence after Endocrine Therapy in Postmenopausal Women with Endocrine-Responsive Early Breast Cancer

“…Beyond the issue of identifying a low-risk prognostic group that may not need chemotherapy, now established for several multigene classifiers (8)(9)(10)(11)15), identifying patients at persistent risk for late distant recurrence is an urgent unmet clinical need. Only a few studies so far have evaluated the risk of recurrence in women who completed 5 years of tamoxifen treatment and remain recurrence-free at 5 years (3-7).…”

“…Several RNA-based multigene expression assays including Oncotype DX, EndoPredict, and MammaPrint have been developed to estimate the individual risk of recurrence of patients with breast cancer (8,9,11). In contrast with several other multigene tests (e.g., Oncotype DX and MammaPrint), EndoPredict and NanoString PAM50 can be performed in any qualified pathology laboratory.…”

“…Multigene tests have recently been introduced for individual risk assessment, and several of them have demonstrated that they can add valuable prognostic information: Oncotype DX (8), MammaPrint (9), Breast Cancer Index (10), EndoPredict (11), and PAM50 (12-15) describe risk scores based on the analysis of gene signatures established and validated in clinical trials. Specific potential usefulness for the prediction of late distant recurrence has been reported in abstract form for PAM50 (16,17), EndoPredict (18), and Breast Cancer Index (17,19).…”

Molecular signatures in breast cancer

“…These gene expression panel assays are risk predictors and examples include: MapQuantDX™ (Genomic Grade Index, GGI) [36], ProSigna® [24] [37], Mammaprint® [38], OncotypeDX® [39] and EndoPredict® [40] (Table 1). Each predictor was derived in a different manner and using a unique algorithm, but collectively they classify the risk of recurrence of breast cancer, and hence provide insight into whether a patient might require adjuvant chemotherapy or not.…”

Clinical Utility of Multigene Profiling Assays in Early-Stage Breast Cancer

“…EndoPredict (Myriad Genetics, Salt Lake City, U.S.A.) is an rna-based assay that was developed to prognosticate for distant recurrence in patients with er-positive, her2-negative breast cancer who are receiving adjuvant endocrine therapy 5 . EndoPredict uses reverse-transcriptase polymerase chain reaction to measure the mrna expression levels of 11 genes 5 .…”