Zoledronic Acid and the Mevalonate Pathway: An Opportunity to Overcome Resistance in Hormonal HER2 positive Breast Cancer| Biomed Grid

The HER2 positive breast cancer subtype exhibits a distinct behaviour from the others, usually accompanied with early relapse, including a higher percentage of brain metastasis [1]. Therefore, it remains a challenge in clinical practice [2]. On the other hand, anti-HER2 target therapy has dramatically changed the course of the disease [3]. In neoadjuvant, adjuvant and metastatic setting, the advent of trastuzumabe and pertuzumab, both monoclonal antibody which binds to HER2 receptor in different domains on tumoral cells inhibiting it progression synergistically with cytotoxic chemotherapy, has improved several endpoints such as pathological complete response rate, relapse-free, progressionfree and overall survival [4]. Beyond trastuzumab and pertuzumab combination, an antibody– drug conjugate (ADC) like trastuzumab emtansine (T-DM1) and an irreversible pan-HER tyrosine kinase inhibitor (TKI) such as neratinib meliorated the previous endpoints [5,6]. However, many patients still develop disease recurrence or progressive disease and die. The current effort from scientists and clinicians is improve the results of anti-HER therapy and mainly it's resistance [7]. There is a bidirectional crosstalk between HER2 and estrogen pathway [8]. Anti-HER2 targeting can up-regulate estrogen pathways and additionally estrogen pathway activation can reduce anti- HER2 activity [9]. Differences in responses are expected to occur depending on the positivity of hormonal receptors, justifying humbled performances of HR-positive subtype when compared to HR- negative in terms of pathological response rate in clinical trials as shown by Schedin 2018. Strategies to overcome resistance in HER2- positive breast cancer includes TKIs [10], and combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors [11], CDK4/6 inhibitors [12], and PI3K/AKT/mTOR inhibitors [13]. While the raise of cyclin inhibitors in pre-clinical models seems to be promising [14] and several studies are ongoing, other attempts has generally failed in demonstrating improvements such as standard therapy combination with hormonal agents in neoadjuvant setting [15]