Hyperpolarized Carbon-13 MRI for Early Response Assessment of Neoadjuvant Chemotherapy in Breast Cancer Patients.

Ramona Woitek,Martin J Graves,Andrew B Gill,Suet-Feung Chin,Roslin Russell,Gabrielle Baxter,Carlos Caldas,Mary A Mclean,Kevin M Brindle,Beth Latimer-Bowman,Rolf F Schulte,Lucian Beer,Bruno Carmo,Rhys Slough,Ferdia A Gallagher,Andrew N Priest,Amy Schiller,Brian White,Ashley Grimmer,Elena Provenzano,Johanna Field-Rayner,Stephan Ursprung,Fiona J Gilbert,David Y Lewis,James Wason,Ilse Patterson,Titus Lanz,Oscar M Rueda,Vasiliki Papalouka,Amy Frary,Leonardo Rundo,Evis Sala,Joshua D Kaggie ,Jean Abraham ,Raquel Manzano García ,Arnold Julian Vinoj Benjamin ,Justine M Kane ,Andrew J Patterson ,Michael Locke

doi:10.1158/0008-5472.can-21-1499

Abstract

Hyperpolarized 13C-magnetic resonance imaging (MRI) is an emerging tool for probing tissue metabolism by measuring 13C-label exchange between intravenously injected hyperpolarized [1-13C]pyruvate and endogenous tissue lactate. Here we demonstrate that hyperpolarized 13C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric 1H-MRI and hyperpolarized 13C-MRI before and 7-11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of ~20% identified three patients who, following 5-6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter MCT1, and lactate dehydrogenase A (LDHA), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of ~2000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX were associated with reduced relapse-free and overall survival. Hyperpolarized 13C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential.

Highlights

Neoadjuvant chemotherapy (NACT) is the standard-of-care treatment for 17%–40% of patients with operable early-stage breast cancer, patients with HER2-positive (HER2þ) and triple-negative breast cancer (TNBC; ref. 1)
These included four patients with TNBC (ER and PR negativity defined as Allred score 0 to 3), three of which were invasive cancers of no specific type (IC NST) and one apocrine invasive cancer; and three HER2þ patients with breast cancer
We have previously demonstrated that LAC/PYR correlates with the expression of the membrane transporter for pyruvate in a cohort of treatment-na€ve breast cancers [11]

Summary

Introduction

Neoadjuvant chemotherapy (NACT) is the standard-of-care treatment for 17%–40% of patients with operable early-stage breast cancer, patients with HER2-positive (HER2þ) and triple-negative breast cancer (TNBC; ref. 1). Pathological complete response (pCR) at surgery indicates a favorable prognosis and rates of pCR have recently been shown to reach 68%–80% in Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom. Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom. 8Department of Oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England. 9Molecular Imaging Laboratory Cancer Research UK Beatson Institute, Glasgow, United Kingdom. 10Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. 11RAPID Biomedical, Rimpar, Germany. 12Population

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