Clinicopathological and molecular predictors of [18F]FDG-PET disease detection in HER2-positive early breast cancer: RESPONSE, a substudy of the randomized PHERGain trial
Authors: Llombart-Cussac Antonio , Prat Aleix , Pérez-García José Manuel , Mateos José , Pascual Tomás , Escrivà-de-Romani Santiago , Stradella Agostina , Ruiz-Borrego Manuel , de las Heras Begoña Bermejo , Keyaerts Marleen , Galvan Patricia , Brasó-Maristany Fara , García-Mosquera Juan José , Guiot Thomas , Gion María , Sampayo-Cordero Miguel , Di Cosimo Serena , Pérez-Escuredo Jhudit , de Frutos Manuel Atienza , Cortés Javier , Gebhart Geraldine 
Published: April 2024

Abstract
Background
The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated.

Methods
A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria.

Results
Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients.

Conclusions
These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy.

Trial registration
Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.