A metastasis biomarker (MetaSite Breast\u2122 Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer

Joseph A Sparano,Timothy D’Alfonso,Frank Gertler,Anthony Shuber,Joan Jones,Lori J Goldstein,Michael Peterson,Nancy E Davidson,John Condeelis,David Entenberg,Robert Gray,Douglas A Hamilton,Thomas Rohan,Michael Donovan,Xiaonan Xue,Maja H Oktay

doi:10.1038/s41523-017-0043-5

Abstract

Metastasis is the primary cause of death in early-stage breast cancer. We evaluated the association between a metastasis biomarker, which we call “Tumor Microenviroment of Metastasis” (TMEM), and risk of recurrence. TMEM are microanatomic structures where invasive tumor cells are in direct contact with endothelial cells and macrophages, and which serve as intravasation sites for tumor cells into the circulation. We evaluated primary tumors from 600 patients with Stage I–III breast cancer treated with adjuvant chemotherapy in trial E2197 (NCT00003519), plus endocrine therapy for hormone receptor (HR)+ disease. TMEM were identified and enumerated using an analytically validated, fully automated digital pathology/image analysis method (MetaSite Breast™), hereafter referred to as MetaSite Score (MS). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). MS was not associated with tumor size or nodal status, and correlated poorly with Oncotype DX Recurrence Score (r = 0.29) in 297 patients with HR+/HER2- disease. Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p = 0.001) and RFI (p = 0.00006) in HR+/HER2- disease in years 0–5, and by MS tertiles for DRFI (p = 0.04) and RFI (p = 0.01), but not after year 5 or in triple negative or HER2+ disease. Multivariate models in HR+/HER- disease including continuous MS, clinical covariates, and categorical Recurrence Score (<18, 18–30, > 30) showed MS is an independent predictor for 5-year RFI (p = 0.05). MetaSite Score provides prognostic information for early recurrence complementary to clinicopathologic features and Recurrence Score.

Highlights

Metastasis is the primary cause of death in breast cancer, the most frequently diagnosed cancer and the leading cause of cancer death among women, accounting for 25% of the total cancer cases (1.68 million) and 15% of the cancer deaths (520,000) worldwide.[1,2] breast cancer mortality rates have declined due to screening and more effective adjuvant systemic therapies,[3] more accurately identifying metastatic risk in order to minimize overtreatment or undertreatment, and developing new approaches to prevent metastasis remain major clinical chalenges.[4]
The MetaSite Score in all 600 between MetaSite Score and distant relapse free interval (DRFI) (p = 0.04) and relapse free interval (RFI) (p = 0.01) in the hormone receptor (HR)+/HER2- group when evaluated by empirical tertiles ( / = 18) for the entire cohort with follow-up truncated at 5 years (Fig. 1a–b)
The weighted mean MetaSite Score was significantly lower in the HR+/HER2- subtype than in the triple

Summary

Introduction

Metastasis is the primary cause of death in breast cancer, the most frequently diagnosed cancer and the leading cause of cancer death among women, accounting for 25% of the total cancer cases (1.68 million) and 15% of the cancer deaths (520,000) worldwide.[1,2] breast cancer mortality rates have declined due to screening and more effective adjuvant systemic therapies,[3] more accurately identifying metastatic risk in order to minimize overtreatment or undertreatment, and developing new approaches to prevent metastasis remain major clinical chalenges.[4]. Collection of streaming tumor cells using an in vivo invasion assay for gene expression profiling has led to the identification of the Invasion Signature and discovery of pathways that are upregulated in streaming tumor cells with transendothelial migration activity,[6,7,8,9,10,11,12,13,14,15] which includes differential expression of invasive Mena isoforms that regulate cancer cell streaming, transendothelial migration, and intravasation of breast tumor cells.[16,17,18,19,20,21] A subpopulation of Mena-expressing comes into direct contact with endothelial cells and macrophages, forming microanatomic structures that we have called “Tumor MicroEnvironment of Metastasis”, or “TMEM”, which serve as a doorway for other streaming tumor cells to intravasate.[22,23] TMEM are found in primary human breast cancers, as well as regional lymph node and distant metastases.[24]

Methods

Results

Conclusion