Identifying the potential mediators of pathological complete response to neoadjuvant chemotherapy among TACR1 gene...

Recent studies have shown that the truncated isoform of the neurokinin-1 receptor (NK-1R) and its ligand, substance P (SP), are overexpressed in tumor cells playing a crucial role in chemoresistance, leading to proliferation, angiogenesis, and metastasis. Hence, this study aims to assess if the polymorphisms of the NK-1R-encoding gene influence the truncated NK-1R level, chemoresistance, and pathological complete response (pCR) achievement in breast cancer patients.

The real-time PCR-HRMA was performed to genotype TACR1 eighteen tag SNPs in 153 neoadjuvant chemotherapy-receiving breast cancer patients. Univariate analysis was performed to assess the association of baseline and tumor characteristics with pCR achievement. The association of each variant and pCR achievement was assessed by executing logistic regression while adjusting for covariates and correcting for multiple tests using permutation.

The probability of pCR to neoadjuvant chemotherapy is higher for patients with tumor grade-III as well as stage-I. Assuming the additive, dominant, or recessive models, rs17010664, rs6715729, and rs3771869 were significantly associated with pCR achievement.

Positioned close to the truncation-occurring region, belonging to an exon-splicing enhancer motif, the rs17010664 C allele seems to play a crucial role in enhancing the TACR1 last exon splicing leading to increased truncated NK-1R production, chemoresistance, and decreased pCR achievement. Accordingly, The SP/truncated NK-1R axis blockade by NK-1R antagonists seems to be a therapeutic approach to overcoming chemoresistance and achieving pCR in the rs17010664 risk-allele-bearing patients. Hence, conducting further studies to determine the required dose of NK-1R antagonists, repurposed as an antitumor agent, is favored.