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

Abstract

Hyperpolarized 13C-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 approximately 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 approximately 2,000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX was 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. SIGNIFICANCE: Hyperpolarized carbon-13 MRI allows response assessment in patients with breast cancer after 7-11 days of neoadjuvant chemotherapy and outperformed state-of-the-art and research quantitative proton MRI techniques.

Trial registration: ClinicalTrials.gov NCT03150576.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Graphical abstract

Figure 1.

Changes in LAC/PYR between baseline and very early response assessment in a responder and nonresponder. A, C, F, and H, Coronal T1-weighted 3D spoiled gradient echo (SPGR) images with LAC/PYR map overlaid on the breast tumor. B, D, G, and I, Coronal reformatted DCE images obtained 150 seconds after intravenous injection of a gadolinium-based contrast agent. A patient with HER2+ breast cancer was imaged at baseline (A and B) and for ultra-early response assessment (C and D) following standard-of-care treatment and showed a decrease in LAC/PYR of 41% (E), indicating nonresponse. At surgery, non-pCR with residual invasive cancer was identified. Another patient with TNBC was imaged at baseline (F and G) and for ultra-early response assessment (H and I) following treatment with chemotherapy and a PARP inhibitor and showed an increase in LAC/PYR of 157% (J), indicating response. At surgery, pCR without residual invasive breast cancer was found. HER2+, HER2/neu positive.

Figure 2.

Parameters obtained from hyperpolarized 13C-MRI and 1H-MRI at baseline and in early follow-up scans. Differences between baseline and follow-up were significant for tumor volume (A) and diffusivity (B) but not for the other parameters (C–G); neither change in volume or diffusivity could distinguish pCR from non-pCR. Correlation of SLC16A1 (MCT1) and LDHA mRNA expression with LAC/PYR was significant (H and I). Only images acquired with identical 13C-MRI acquisition parameters (spectral–spatial excitation) were included in these correlations.

Figure 3.

Changes in hyperpolarized 13C-, but not 1H-MRI–derived metrics, after approximately one week of treatment distinguish responders (pCR) from nonresponders (incomplete response; non-pCR). In the five patients undergoing standard-of-care neoadjuvant treatment, an increase of ≥20% in LAC/PYR was only observed in patients who responded (A), whereas a lower increase or even a decrease in LAC/PYR was observed in nonresponders (B).Both patients treated with a PARP inhibitor in addition showed an increase in LAC/PYR (A and B) and again the increase was highest in the responder (A). Although kPL increased in all patients receiving a PARP inhibitor, but not in the other patients (C and D), neither kPL nor any of the 1H-MRI–based metrics from dynamic contrast-enhanced (DCE) MRI (such as Ktrans) or from intravoxel incoherent motion (IVIM) as part of diffusion-weighted MRI (such as perfusion fraction f and tissue diffusivity D) could distinguish between responders and nonresponders (I–P). None of the parameters differed significantly between baseline and follow-up when evaluated for responders and nonresponders separately (P > 0.05). kPL was not available in one patient due to technical failure (C). Ktrans could not be assessed in one patient due to failed fat saturation (K).

Figure 4.

Changes in hyperpolarized 13C-MRI and 1H-MRI parameters in seven patients with complete and incomplete responses. Results are shown for standard-of-care treatment with and without PARP inhibitor treatment. A, A threshold of +20% change in LAC/PYR distinguished responders from nonresponders on standard-of-care therapy (shown with a dashed horizontal line). One nonresponder receiving PARP inhibitor treatment also showed an increase in LAC/PYR of ≥20%, which may be explained by NAD+ availability (see main text). B, A threshold set at a −15% change in kPL (dashed horizontal line) distinguished responders from nonresponders on standard-of-care therapy. A patient receiving PARP inhibitor treatment in addition, but demonstrating pCR, also showed a change in kPL above this threshold. kPL was not available for one patient due to a technical failure. C–H, There were no thresholds that could be used to distinguish pCR from non-pCR for any of the remaining 1H-MRI or 13C-MRI parameters. Change in Ktrans was not evaluable for one patient where fat saturation failed at baseline.

Figure 5.

Correlation matrix of LDHA, SLC16A1 (MCT1), CAIX, and HIF1A expression in METABRIC. There is a significant correlation between LDHA and SLC16A1 (MCT1) expression (z-scores) with the hypoxia markers CAIX and HIF1A. r, Pearson correlation coefficient.

Figure 6.

Correlation of LDHA, SLC16A1 (MCT1), CAIX, and HIF1A expression with survival in METABRIC. Kaplan–Meier curves for normal expression and overexpression (85th percentile) of LDHA (A and B), SLC16A1 (MCT) (C and D), HIF1A (E and F), and CAIX (G and H). The left column shows overall survival and the right column relapse-free survival. Number of events are shown in brackets.