Abstract 4619: SEPT9 isoform expression and response to neo-adjuvant taxane treatment in breast cancer patients

Abstract Drugs that disrupt the microtubule cytoskeleton, such as the microtubule stabilizing taxanes, are regularly used in the treatment of breast cancer in the neoadjuvant setting. However, there are currently no molecular biomarkers that are used to guide which patients will respond to taxane treatment. Septins, a class of small GTPases, interact with both microtubules and actin to functionally link these cytoskeletal components and regulate cell biological processes shown to be critical for the invasion and migration of cancer cells. Septin 9 (SEPT9) directly interacts directly with microtubules through an N-terminal domain on the longest isoform, SEPT9 isoform 1, which is sufficient to promote migration and invasion of breast cancer cells in vitro. Additionally, both SEPT9 isoform 1 and SEPT9 isoform 3 have been shown to play a role in taxane resistance in vitro, but the possible role in clinical taxane resistance had not been studied. We hypothesized that the relative expression of SEPT9 isoforms in breast tumors could play a role in their response to treatment taxanes in the neoadjuvant setting. We performed a prospective clinical trial to correlate the expression of SEPT9 isoforms in breast tumors with pathological response to taxanes in the neoadjuvant setting. Pretreatment levels of SEPT9 isoform mRNA, as well as mRNA from other genes associated with clinically relevant drug resistance mechanisms, were determined from FFPE biopsy samples by multiplexed PCR, while protein levels of SEPT9 isoforms were determined by IHC. Patients were treated in the neoadjuvant setting with either paclitaxel (dose dense or weekly), docetaxel or nab-paclitaxel. Expression was reevaluated in post-treatment surgical samples of patients who did not have a pathological complete response (pCR). We found that the expression of SEPT9 mRNA variants and drug resistance genes differed amongst the pre-treatment patient samples. Initial SEPT9v2 mRNA levels are higher in patients that have a pCR. Additionally, expression of SEPT9v4, MDR1 and ABCC11 mRNA levels are statistically significantly reduced post-taxane treatment in patients that did not have a pCR. We are currently determining the mRNA expression levels of a panel of 96 clinically relevant genes in the pre-treatment samples to identify a genetic profile of response to taxane treatment. We are performing in vitro studies to determine if elevated levels of SEPT9v2 correspond with response to other chemotherapeutic drugs. Overall, the data support the hypothesis that the relative expression of SEPT9v2 in breast tumors plays a role in their response to treatment with to taxanes in the neoadjuvant setting and supports the use of SEPT9v2 expression levels in determining whether to use taxane treatment or other drug treatment in the neoadjuvant setting, facilitating the use of microtubule targeted chemotherapy in a more personalized manner. Citation Format: Jacob Nathaniel Essif, Kate Lathrop, April Risinger. SEPT9 isoform expression and response to neo-adjuvant taxane treatment in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4619.