Clinicopathological and molecular predictors of [${}^{18}$F]FDG-PET disease detection in HER2-positive early breast cancer: RESPONSE, a substudy of the randomized PHERGain trial

The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [${}^{18}$Fluorine]fluorodeoxyglucose-positron emission tomography ([${}^{18}$F]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 [${}^{18}$F]FDG-PET disease detection were evaluated. 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 [${}^{18}$F]FDG-PET status. The association between baseline SUVmax and [${}^{18}$F]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${}^{TM}$ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [${}^{18}$F]FDG-PET eligibility criteria. 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). [${}^{18}$F]FDG-PET [-] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [${}^{18}$F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [${}^{18}$F]FDG-PET [-]/[+] criteria patients (p = 0.73), [${}^{18}$F]FDG-PET [-] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [${}^{18}$F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [${}^{18}$F]FDG-PET [-] and [${}^{18}$F]FDG-PET[+] criteria patients. 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 [${}^{18}$F]FDG-PET imaging as a tool to guide therapy.