HER2 Phenotyping of CTCs By Peptide-Functionalized Nanoparticles As The Diagnostic Biomarkers of Anti-HER2 Treatment in Breast Cancer
Background: The efficacy of anti-human epidermal growth factor receptor 2 (HER2/neu) treatment is impacted by tissue-based evaluation bias due to tumor heterogeneity and dynamic changes of HER2 in breast cancer. Circulating tumor cell (CTC)-based HER2 phenotyping provides an integral and real-time assessment, benefiting accurate HER2 diagnosis for improved therapeutics.Methods: The study was exploratory. Fifty-four breast cancer patients, including 26 histopathologic HER2/neu-positive
... -positive (Histo-HER2/neu+) and 28 HER2/neu-negative (Histo-HER2/neu+), were enrolled for blood draws before a new line of treatment. We used peptide-functionalized magnetic nanoparticles to isolate CTCs from 2.0 mL whole blood and determined HER2 phenotypes of the enriched CTCs by immunocytochemistry (ICC). We investigated the correlation of the enumeration and HER2 phenotyping on baseline CTCs with the diagnosis, the prognosis, and the efficacy of the trastuzumab in combination with chemotherapeutic agents of breast cancer. We also explored the dynamic change of HER2 phenotypes on CTCs after the combination therapy in a cohort of Histo-HER2/neu+ individuals (n = 14).Results: We achieved high-efficient detection of the CTC-positive cases (≥ 3 CTCs) (38/54, 70.4%), from whom 71.1% (27/38) had a concordant HER2 status on CTCs and tumor tissues at baseline. Pretheraputic CTC enumeration showed a significant correlation with the histopathologic diagnosis (e.g. estrogen receptor/progesterone receptor (ER/PR) status or proliferation of cancer cells) and the progression-free survival/overall survival (PFS/OS) of breast cancer. However, it was not a practicable biomarker to predict the efficacy of the trastuzumab-based combination therapy. In contrast, we demonstrated a significantly higher possibility of good overall responses in the patients with < 3 CTCs (P = 0.006) or with HER2 overexpression in CTCs (CTC-HER2+) at baseline, as compared to the individuals without HER2 overexpression in CTCs (CTC-HER2–) (P = 0.028).Conclusions: We demonstrate the significance of the peptide-functionalized magnetic nanoparticle in noninvasive detection and HER2 phenotyping of CTCs, and highlight its diagnostic and prognostic values for the patients about to start the anti-HER2 treatment.