Background Whether the neurokinin-1 receptor (TACR1) antagonist aprepitant confers oncologic benefit beyond antiemesis remains uncertain. We evaluated the association between aprepitant exposure during adjuvant chemotherapy and long-term outcomes in breast cancer, and investigated the biological rationale through analysis of the SP-SLIT2–TACR1 signaling axis in a neoadjuvant cohort. Methods We retrospectively identified 887 women with operable breast cancer treated at Zhengzhou University People's Hospital (2018–2021). After exclusions, 777 patients comprised the initial adjuvant cohort (aprepitant, n = 275; other antiemetics, n = 502). After 1:2 propensity score matching, 654 patients were included in the matched analysis (aprepitant, n = 218; other antiemetics, n = 436). Primary endpoints were overall survival (OS) and disease-free interval (DFI). To explore the biological mechanism, an independent neoadjuvant cohort (n = 65) was collected to investigate whether the SP-TACR1 pathway is activated in chemoresistant tumors. Expression of neurotransmission-related markers (SP, SLIT2, and TACR1) was assessed by qPCR, Western blot, IHC, and SP immunofluorescence; receiver-operating-characteristic (ROC) analysis defined an SP cutoff for chemoresistance. Results In the matched cohort of 654 patients, fewer recurrence events were observed in the aprepitant group than in the other antiemetics group (45/218 vs 129/436). Kaplan–Meier analyses showed that aprepitant exposure was associated with significantly better OS and DFI across the TNBC, HR-positive, and HER2-positive subgroups (all log-rank P < 0.05). In patients receiving other antiemetics, the presence of perineural invasion (PNI) was associated with significantly worse OS (P = 0.038) and DFI (P = 0.011). However, among patients receiving aprepitant, PNI no longer conferred adverse prognostic impact (OS and DFI, P > 0.05), suggesting aprepitant may offset PNI-associated risk. Cox regression identified PNI as an independent risk factor for progression, while aprepitant intake was a protective factor. In the neoadjuvant cohort, expression of SP, SLIT2, and TACR1 was significantly higher in chemotherapy-resistant tumors than in chemotherapy-sensitive tumors (P < 0.001), confirming activation of this neural signaling axis in resistant disease and providing a biological rationale for TACR1 blockade as a chemosensitizing strategy. Conclusions Aprepitant exposure during adjuvant chemotherapy was associated with improved OS/DFI, and appeared to offset the adverse prognostic impact of PNI. Neoadjuvant cohort data supported activation of the SP-SLIT2–TACR1 neural signaling axis in chemoresistant breast cancer, providing a biological rationale for TACR1 blockade. Prospective trials are warranted to validate these findings and define optimal dosing and duration.

Aprepitant exposure and long-term prognosis in breast cancer: a propensity-score-matched cohort study

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2026年5月23日

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Limin Pan,
Zhiyuan Zhang,
Wanyue Li,
Feng Lv,
Yuanxiang Lu,
Yimin Liu

摘要

Background

Whether the neurokinin-1 receptor (TACR1) antagonist aprepitant confers oncologic benefit beyond antiemesis remains uncertain. We evaluated the association between aprepitant exposure during adjuvant chemotherapy and long-term outcomes in breast cancer, and investigated the biological rationale through analysis of the SP-SLIT2–TACR1 signaling axis in a neoadjuvant cohort.

Methods

We retrospectively identified 887 women with operable breast cancer treated at Zhengzhou University People's Hospital (2018–2021). After exclusions, 777 patients comprised the initial adjuvant cohort (aprepitant, n = 275; other antiemetics, n = 502). After 1:2 propensity score matching, 654 patients were included in the matched analysis (aprepitant, n = 218; other antiemetics, n = 436). Primary endpoints were overall survival (OS) and disease-free interval (DFI). To explore the biological mechanism, an independent neoadjuvant cohort (n = 65) was collected to investigate whether the SP-TACR1 pathway is activated in chemoresistant tumors. Expression of neurotransmission-related markers (SP, SLIT2, and TACR1) was assessed by qPCR, Western blot, IHC, and SP immunofluorescence; receiver-operating-characteristic (ROC) analysis defined an SP cutoff for chemoresistance.

Results

In the matched cohort of 654 patients, fewer recurrence events were observed in the aprepitant group than in the other antiemetics group (45/218 vs 129/436). Kaplan–Meier analyses showed that aprepitant exposure was associated with significantly better OS and DFI across the TNBC, HR-positive, and HER2-positive subgroups (all log-rank P < 0.05). In patients receiving other antiemetics, the presence of perineural invasion (PNI) was associated with significantly worse OS (P = 0.038) and DFI (P = 0.011). However, among patients receiving aprepitant, PNI no longer conferred adverse prognostic impact (OS and DFI, P > 0.05), suggesting aprepitant may offset PNI-associated risk. Cox regression identified PNI as an independent risk factor for progression, while aprepitant intake was a protective factor. In the neoadjuvant cohort, expression of SP, SLIT2, and TACR1 was significantly higher in chemotherapy-resistant tumors than in chemotherapy-sensitive tumors (P < 0.001), confirming activation of this neural signaling axis in resistant disease and providing a biological rationale for TACR1 blockade as a chemosensitizing strategy.

Conclusions

Aprepitant exposure during adjuvant chemotherapy was associated with improved OS/DFI, and appeared to offset the adverse prognostic impact of PNI. Neoadjuvant cohort data supported activation of the SP-SLIT2–TACR1 neural signaling axis in chemoresistant breast cancer, providing a biological rationale for TACR1 blockade. Prospective trials are warranted to validate these findings and define optimal dosing and duration.