[18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer

Abstract

Rationale: Pathological response to neo-adjuvant chemotherapy (NAC) represents a commonly used predictor of survival in triple negative breast cancer (TNBC) and the need to identify markers that predict response to NAC is constantly increasing. Aim of this study was to evaluate the potential usefulness of PET imaging with [18F]FDG and [18F]FLT for the discrimination of TNBC responders to Paclitaxel (PTX) therapy compared to the response assessed by an adapted Response Evaluation Criteria In Solid Tumors (RECIST) criteria based on tumor volume (Tumor Volume Response).

Methods: Nu/nu mice bearing TNBC lesions of different size were evaluated with [18F]FDG and [18F]FLT PET before and after PTX treatment. SUVmax, Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) and Proliferation (TLP) were assessed using a graph-based random walk algorithm.

Results: We found that in our TNBC model the variation of [18F]FDG and [18F]FLT SUVmax similarly defined tumor response to therapy and that SUVmax variation represented the most accurate parameter. Response evaluation using Tumor Volume Response (TVR) showed that the effectiveness of NAC with PTX was completely independent from lesions size at baseline.

Conclusions: Our study provided interesting results in terms of sensitivity and specificity of PET in TNBC, revealing the similar performances of [18F]FDG and [18F]FLT in the identification of responders to Paclitaxel.

Fig 1. Histological and Ki67 immunohistochemical staining of tumors treated with PTX or vehicle.

A) Representative images of histological morphology (H&E) and Ki67 staining of tumors receiving vehicle or PTX. B) Weights of tumors collected at the end of treatment significantly correlated with Ki67 P.I. values (r² = 0.707, p = 0.0006).

Fig 2. Effect of PTX on MDA-MB-468 tumors.

Tumor volume of xenograft mice treated with PTX (4 doses, twice a week, 18 mg/kg i.v.) or vehicle expressed as ratio between post-therapy and baseline. Student’s T test; *p<0,05.

Fig 3. PET imaging of TNBC mouse model.

Images of [¹⁸F]FDG and [¹⁸F]FLT scans of representative MDA-MB-468 xenografts mice performed pre and post PTX treatment. [¹⁸F]FDG and [¹⁸F]FLT uptake decreased in PR and SD, in contrast to the observed increase in PD and vehicle. Red arrows indicate cancer lesions. Color scale represents SUV value. PR = partial responder; SD = stable disease; PD = progressive disease.

Fig 4. [¹⁸F]FDG and [¹⁸F]FLT uptake variations after treatment with PTX.

[¹⁸F]FDG and [¹⁸F]FLT uptake expressed as percent variation (% change) in SUV_max (ΔSUV_max) between baseline and post-therapy in vehicle and treated mice categorized on the basis of TVR. One-way ANOVA multiple comparison, *p < 0.05, **p < 0.01 and ***p < 0.001.

Fig 5. ROC curve of ΔSUV_max to predict MDA-MB-468 response.

ROC analysis of [¹⁸F]FDG and [¹⁸F]FLT ΔSUV_max for prediction of different response to PTX therapy in the TNBC model. Optimal cut-off point was defined for [¹⁸F]FDG as -80.4% (89% sensitivity; 75% specificity) and for [¹⁸F]FLT as -70.7% (100% sensitivity; 50% specificity).