Characterization of molecular scores and gene expression signatures in primary breast cancer, local recurrences and brain metastases

Abstract

Background Breast cancer is a leading cause of cancer-related death in women worldwide. Despite extensive studies in all areas of basic, clinical and applied research, accurate prognosis remains elusive, thus leading to overtreatment of many patients. Diagnosis could be improved by introducing multigene molecular scores in standard clinical practice. Several tests that work with formalin-fixed tissue have become routine. Molecular scores usually include several genes representing processes, response to oestrogens, progestogens and human epidermal growth factor receptor 2 (Her2), respectively, which are combined additively in single values. These multi-gene scores have the advantage of being more robust and reproducible than single-gene scores. Their utility may be further enhanced by combining them with classical diagnostic parameters. Here, we present an exploratory study comparing the RISK and research versions of Oncotype DX recurrence score (RS), Prosigna Risk of Recurrence (ROR) and EndoPredict (EP) with respect to their prognostic potential for ipsilateral recurrence and/or distant relapse in brain, and we compared the scores to the intrinsic subtypes based on PAM50. Methods RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue cores of primary tumours, local recurrences and brain metastases. Gene expression was measured on a NanoString nCounter Analysis System. Intrinsic subtypes and molecular scores were computed according to published literature and RISK, RS, ROR and EP were compared against each other and to the intrinsic subtypes Luminal A (lumA), Luminal B (lumB), Her2-enriched (Her2↑), Basal-like (basal), and Normal-like (normal) of PAM50. Local recurrences and brain metastases were compared to their corresponding primary tumours. Results All four molecular scores were highly correlated. Highest correlations were observed among genes related to proliferation while lower correlations were found among oestrogen-related genes. The scores were significantly higher in primary tumours progressing to brain metastases as compared to recurrence-free primary tumours and primary tumours that relapsed as local recurrences. Conclusions RISK and ROR-P are prognostic for primary tumours metastasizing to the brain. All four scores, RISK, RS, EP and ROR-P failed to discriminate between primary tumours that remained recurrence-free and primary tumours relapsing as local recurrences. Electronic supplementary material The online version of this article (10.1186/s12885-019-5752-8) contains supplementary material, which is available to authorized users.

Development and validation for research assessment of Oncotype DX® Breast Recurrence Score, EndoPredict® and Prosigna®

“…There is great interest in computing accurate RS, EP and ROR scores for academic clinical research. Attempts have been made to recapitulate these and other commercial prognostic scores using expression data derived by gene expression microarray 23 – 25 , RT-PCR 26 , 27 , RNA-sequencing 25 and NanoString 28 . However, the surrogate scores are rarely compared to their commercial counterparts derived from the same samples.…”

Diverse Distribution and Gene Expression on the 21-Gene Recurrence Assay in Breast Cancer Patients with Locoregional Recurrence Versus Distant Metastasis

“…The 21-gene RS is well known to be related to DM, 43 and association with LRR has been reported in several previous studies. 26 , 30 , 31 , 44 From a single institutional database, Turashvili et al observed 4-yearf LRR of 0.84%, 2.72%, and 2.80% in low-, intermediate-, and high-RS groups, respectively. 45 Moreover, in a recent analysis of Southwest Oncology Group (SWOG) Intergroup trial S8814, higher RS was associated with increased LRR rate in HR-positive breast cancer patients with regional lymph–node metastasis.…”

“…ER, HER2, proliferation, and invasion group scores were calculated accordingly. 29 Patients were divided into low-(RS <18), intermediate- (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and high-risk (≥31) groups as per our previous work. 37,38…”

“… 7 , 11 21–23 With multigene assays assessing the risk of disease recurrence, 24 , 25 most showed more prognostic value in DM than LRR. 26 Nowadays, the 21-gene recurrence score (RS) assay is most widely used to indicate systemic treatment, 27 and shows considerable prognostic value in hormone receptor (HR)–positive, HER2-negative breast cancer patients. 2 , 28 , 29 Recently, a few investigations have evaluated the prognostic value of RSs in LRR.…”

“… 2 , 28 , 29 Recently, a few investigations have evaluated the prognostic value of RSs in LRR. 26 , 30 , 31 Mamounas et al demonstrated that RS had prognostic value for LRR risk in ER-positive patients in both node-negative 30 and node-positive cohorts 31 based on large data from the National Surgical Adjuvant Breast and Bowel Project trials B14 and B20. Inconsistent results were revealed in subsequent smaller studies.…”