LobSig is a multigene predictor of outcome in invasive lobular carcinoma

Amy E Mccart Reed ,Gregory Miller,Lachlan Coin,Leesa Wockner,Lynne Reid ,Luyu Kuo,Sunil R Lakhani ,Colleen Niland,Kaltin Ferguson,Andrew J Dalley ,Georgia Chenevix-Trench,Samir Lal,Priyakshi Kalita-De Croft,Craig P Coorey ,Jodi M Saunus ,Julie K Johnson ,Xavier M De Luca ,Renique Males,Alan J Robertson ,Jamie R Kutasovic ,Peter T Simpson

doi:10.1038/s41523-019-0113-y

Abstract

Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify novel drivers and prognostic biomarkers, using in-house (n = 25), METABRIC (n = 125) and TCGA (n = 146) samples. Using in silico integrative analyses, a 194-gene set was derived that is highly prognostic in ILC (P = 1.20 × 10−5)—we named this metagene ‘LobSig’. Assessing a 10-year follow-up period, LobSig outperformed the Nottingham Prognostic Index, PAM50 risk-of-recurrence (Prosigna), OncotypeDx, and Genomic Grade Index (MapQuantDx) in a stepwise, multivariate Cox proportional hazards model, particularly in grade 2 ILC cases (χ2, P = 9.0 × 10−6), which are difficult to prognosticate clinically. Importantly, LobSig status predicted outcome with 94.6% accuracy amongst cases classified as ‘moderate-risk’ according to Nottingham Prognostic Index in the METABRIC cohort. Network analysis identified few candidate pathways, though genesets related to proliferation were identified, and a LobSig-high phenotype was associated with the TCGA proliferative subtype (χ2, P < 8.86 × 10−4). ILC with a poor outcome as predicted by LobSig were enriched with mutations in ERBB2, ERBB3, TP53, AKT1 and ROS1. LobSig has the potential to be a clinically relevant prognostic signature and warrants further development.

Highlights

Invasive lobular carcinoma (ILC) is the most common ‘special’ type of breast cancer, accounting for 5–15% of all cases
It is currently impossible to predict ILC clinical course at diagnosis, as a result of homogeneity in the standard diagnostic criteria for ILC. Molecular diagnostic tests, such as OncotypeDx, remain of limited value for ILC, since there is a paucity of data on their suitability and they were not developed npj Breast Cancer (2019) 18
MYC is recurrently altered across ILC and a common driver of tumor progression and recurrence in ER-positive breast cancers generally, this may not be the case in LobSig high tumors.[47,48]

Summary

INTRODUCTION

Invasive lobular carcinoma (ILC) is the most common ‘special’ type of breast cancer, accounting for 5–15% of all cases. GISTIC focal of various myoepithelial genes (including SOX10, KRT14, COL17A1)[15] and were more likely to be classified as normalalterations were associated with breast cancer-specific survival (BCSS) data to identify regions that are highly prognostic like using the intrinsic subtyping approach Whilst this analysis was focused more on biology than prognosis, it was unsurprising that the proliferative group had a worse outcome compared to the immune and reactive-like groups.[15] Independently, subtyping by a European team defined an immune-related group with high expression in lymphocyte signaling, together with a hormonerelated subgroup with elevated levels of PGR1, ESR1, and GATA3 protein expression.[16] these two ‘immune’ subtyping approaches do not identify the same cases when applied to the same dataset,[22] and detailed analyses confirm that ILC broadly have a low level of tumor infiltrating lymphocytes.[22].

RESULTS

DISCUSSION

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