Abstract Microtubule stabilizing taxanes are a mainstay of the treatment of breast cancer in both the adjuvant and neoadjuvant settings, including as backbone chemotherapy in combination with targeted agents. Despite their ubiquitous use and well-understood mechanism of action, there are currently no biomarkers to inform which tumors are most likely to respond to taxane treatment. A class of cytoskeletal associated small GTPases critical for multiple oncogenic processes, the septins, can directly interact with microtubules in a taxane-dependent manner with distinct septin9 isoforms having opposing effects. The longest isoform, sept9ᵢ1, is associated with tumor progression, promoting oncogenic activity and taxane resistance through direct binding to microtubules. In contrast, the sept9ᵢ2 isoform lacking this microtubule binding domain reduces migration with lower levels in tumors as compared to normal tissue. We hypothesized that the relative expression of these mechanistically distinct septin9 isoforms that differentially interact with microtubules could serve as a clinical biomarker of taxane response. We conducted a retrospective analysis of the relationship between septin9 isoform expression in tumor biopsies and the overall survival of taxane-treated breast cancer patients post-metastatic diagnosis. Septin9 isoform expression did not differ between primary and metastatic biopsies or between tumors of ductal versus lobular origin. However, tumors from triple-negative breast cancer (TNBC) patients expressed significantly lower levels of septin9ᵢ1 and higher levels of septin9ᵢ2 than ER and HER2 positive breast tumors. Elevated expression of septin9ᵢ2 was correlated with a significant increase in overall survival specifically in TNBC patients with no correlation observed for septin9ᵢ1. To further interrogate the role of septin9 isoform expression in the response of breast tumors to taxane-containing neoadjuvant chemotherapy we conducted a prospective clinical study in previously untreated patients where isoform expression was evaluated in pre and post-treatment biopsies and correlated with pathological response. Consistent with the retrospective study, we found a trend toward elevated levels of septin9ᵢ2 expression in patients who had a pathologic complete response (PCR) to taxane-containing chemotherapy and a reduction in expression post-treatment in patients without a PCR. Comparative studies found a high correlation between septin9 isoform expression at the mRNA level using qRT-PCR and the protein level by immunohistochemistry using isoform-specific antibodies. To further interrogate the potential underlying mechanism of septin9 isoforms in the response of breast cancer cells to taxane treatment we generated isogenic breast cancer cell lines where specific isoforms were stably knocked down or overexpressed. Consistent with published results, we found that reduced septin9ᵢ1 slightly improves the efficacy of taxane treatment in vitro however the beneficial role of septin9ᵢ2 observed in the clinical studies was not evident in vitro. We further interrogated how alterations in septin9 isoform expression regulate the ability of taxanes to stabilize cellular microtubules and demonstrate that drugs that differentially alter microtubule structure and dynamics effectively shift the association of oncogenic septins between the microtubule and actin cytoskeleton. Together, these data support further interrogation of the role of septin9 isoforms in tumor models and clinical samples to determine whether septin9ᵢ2 has a causal role in the response of tumors to taxane-containing chemotherapy and, if so, identify whether clinically approved chemotherapeutics that work through distinct mechanisms of action would have benefit in tumors with reduced expression of this isoform. Citation Format: J. Bush, J. Essif, K. Lathrop, R. Kannaiyan, A. L. Risinger. Septin9 isoforms predict taxane efficacy in triple negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32 (4 Suppl): Abstract nr PS4-03-13.
Bush et al. (Tue,) studied this question.