Abstract
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Introduction: Precision oncology approaches with systemic neoadjuvant therapy against the specific dysregulated oncogenic pathways in breast cancer (BC) is now widely adopted to downgrade the tumor stage, and reduce the risk of recurrence. In particular, given the preponderance of HER-PI3K-AKT axis activation in BC, inhibition of the nodes of this pathway are commonly used for neo-adjuvant therapy. However, HER3, a member of the epidermal growth factor (EGF) family of receptors has been implicated as the main driver of therapy resistance through forming heterodimers with other members of the EGF family (EGFR, HER2) and consequently reactivation of the downstream PI3K/AKT pathway nodes. HER3 imaging is an emerging and exciting avenue for the evaluation of dynamic HER3 expression, tailoring targeted therapy to this subgroup. To better understand the role HER3 PET imaging may play in guiding therapy in BC, we conducted a tissue-based clinical study in patients with tumor biopsies performed pre and post initiation of neoadjuvant therapy to determine the contribution of HER3 as a resistance mechanism.
Methods: The study was conducted between 25 May 2018 and 12 October 2019. Overall, 36 patients with different BC subtypes (ER+/-, PR+/-, HER2+/-) were enrolled in the study. Two tumor biopsies were taken from each patient pre and post initiation of neoadjuvant therapy to determine tumoral and intertumoral changes from baseline. Molecular characterization of the HER3 receptor and other EGF family receptors as well as downstream signalling nodes of the PI3K/AKT and MAPK pathways pre and post initiation of neoadjuvant therapy was performed. In patients for which a pre and post neoadjuvant therapy biopsy was available, qt-RT-PCR analysis of the EGF family members was performed. Immunohistofluorescence staining of HER3 was carried out in specimens pre and post neoadjuvant therapy to confirm findings.
Results: A total of 35/36 of enrolled patients underwent initial (pre-treatment) biopsy. Of the patients undergoing pre-treatment biopsy, 58% were ER+/PR+, 30% were HER2+ and 12% were ER-/PR-/HER2-. 4 out of 35 patients (11%) underwent a second biopsy after neoadjuvant therapy. From these patients 2 patient were ER+/PR+/HER2+, 1 patient was ER+/PR-/HER2- and 1 patient was ER+/PR+/HER2-. Variable HER3 expression at baseline was found in newly diagnosed BC across the different subtypes. We found increased phosphorylation of HER3 and subsequently signalling through the AKT pathway in response to neoadjuvant therapy in 50% of patients (P<0.05). This upregulation was observed in the ER+/PR+ and HER2+ BC subtypes. No ER-/PR-/HER2- patients were enrolled for neoadjuvant therapy.
Conclusions: Early evaluation of tumor response to neoadjuvant therapy can provide valuable information for therapeutic tailoring in BC patients. Specifically, HER3 receptor upregulation in response to neoadjuvant therapy may be a key indication of therapeutic resistance and may be an independently negative predictor of pathological complete response in BC patients. Thus, early assessment of HER3 upregulation, through non-invasive HER3 imaging may help stratify patients who would benefit from the additional therapeutic interventions. This ex vivo human work evaluating tumor signalling changes complements ongoing HER3 PET imaging translational efforts to allow non-invasive assessment to guide personalized treatment.