Breast cancer remains the most frequently diagnosed malignancy among women in Turkey and globally, accounting for a notable proportion of cancer-associated morbidity (1-3). Despite the rapid diversification and evolution of systemic therapies, including targeted agents and dose-dense regimens, chemotherapy-induced nausea and vomiting (CINV) continues to be among the most distressing and feared side effects reported by patients (4). Even with the advent of modern antiemetic guidelines, a marked number of patients experience breakthrough or delayed nausea, which notably impairs health-associated quality of life (QoL), leads to psychological distress and may result in dose reductions or treatment non-compliance (5,6).

The pathophysiology of CINV is a complex process involving both peripheral and central pathways (7). Primarily, highly emetogenic chemotherapy agents trigger the release of serotonin from enterochromaffin cells in the gastrointestinal tract, stimulating the vagus nerve. Concurrently, the activation of neurokinin-1 (NK1) receptors by substance P in the area postrema, the chemoreceptor trigger zone in the brain, serves a key role, especially in the delayed phase of emesis (7,8). However, previous evidence has suggested that neurotransmitter release alone does not fully account for the inter-individual variability in CINV severity, pointing toward the involvement of systemic inflammatory responses in modulating the emetic threshold (9).

Recent evidence has suggested that inflammatory pathways may contribute to the development of CINV in addition to the well-established serotonin- and substance P-mediated mechanisms (10,11). Chemotherapy-induced tissue injury can trigger the release of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. These cytokines may activate vagal afferents and sensitize central emetic circuits within the dorsal vagal complex, particularly the area postrema and nucleus tractus solitarius, thereby facilitating serotonin- and substance P-mediated emetic signaling (12). These observations have led to increasing interest in systemic inflammatory markers as potential predictors of CINV susceptibility (12,13). As a simple and widely available marker of systemic inflammation, the neutrophil-to-lymphocyte ratio (NLR) may reflect the inflammatory milieu that could modulate individual responses to emetogenic chemotherapy (10,11).

The NLR has emerged as a reliable and easily accessible systemic inflammatory marker, reflecting the balance between the innate immune response (neutrophils) and adaptive immunity (lymphocytes) (14). Systemic inflammation is characterized by the release of pro-inflammatory cytokines. These cytokines are known to interact with the central nervous system through the blood-brain barrier and the vagal afferents, potentially sensitizing the vomiting centers (15). High NLR levels, as a proxy for this inflammatory milieu, have been associated with increased symptom burden and worse tolerability of cytotoxic treatments in a number of oncological settings, including breast cancer (16,17). As a readily available marker of systemic inflammation, the NLR has been widely investigated in patients with solid tumors and has been associated with treatment outcomes and symptom burden across multiple cancer types, including breast, colorectal, lung and gastrointestinal cancers (18,19).

The present study aimed to investigate the association between systemic inflammatory status, represented by the pre-treatment NLR and the occurrence of CINV in Turkish female patients with breast cancer receiving highly emetogenic chemotherapy. Patients were stratified according to an NLR cut-off value of 3.0 to evaluate whether elevated baseline inflammatory status was associated with reduced antiemetic treatment efficacy. The primary objective was to assess the association between NLR levels and the rate of complete response (CR), defined as the absence of vomiting and no use of rescue antiemetic medication, during the acute (0-24 h), delayed (24-120 h) and overall (0-120 h) phases following chemotherapy.

In the present study, the association between pre-treatment NLR, as a marker of systemic inflammatory status, and the risk of CINV in patients with breast cancer receiving highly emetogenic chemotherapy was investigated. Specifically, the present study evaluated whether an elevated NLR (≥3) could predict the likelihood of achieving CR, defined as the absence of vomiting and no need for rescue antiemetic medication, during the acute, delayed and overall phases following chemotherapy. Based on the present findings, baseline NLR was not notably associated with CR outcomes in any of the evaluated phases. However, analyses revealed that certain clinical factors were associated with the likelihood of failure to achieve CR. In particular, a history of motion sickness and the type of antiemetic regimen appeared to influence treatment response, suggesting that patient-related susceptibility and pharmacologic prophylaxis may serve a more notable role in determining antiemetic efficacy compared with baseline inflammatory status in the patient population. Despite systemic inflammation theoretically being able to influence emetic sensitivity, the findings of the present study suggest that NLR has limited clinical utility in predicting CINV in patients receiving contemporary antiemetic prophylaxis.

The importance of identifying high-risk individuals in the breast cancer population is further underscored by a recent retrospective study by Jiang et al (22), which evaluated CINV risk factors specifically in patients undergoing chemotherapy. The findings of this study indicated that a history of nausea and vomiting, along with advanced age (>65 years) and a higher number of chemotherapy cycles, were notable predictors of emetic episodes. In partial agreement with these results, the present study further determined the importance of prior emetic sensitivity, as evidenced by the marked association between motion sickness and a higher likelihood of failure to achieve CR. However, a distinct contrast arises regarding the role of age; while the aforementioned study identified older age as a risk factor, the analysis in the present study did not find age to be a notable determinant, aligning more closely with classical literature that often suggests younger patients are at higher risk (23). Despite the focus on clinical risk factors in both studies, neither Jiang et al (22) nor the present study established NLR as a primary predictor for CINV in this specific oncological setting. This suggests that in patients with breast cancer receiving highly emetogenic regimens, the emetic response is more likely driven by individual neuro-susceptibility and treatment-associated cumulative toxicity rather than baseline systemic inflammatory status.

A key point of divergence in previous literature is a study by Naito et al (24), which suggested that a high baseline NLR could indeed serve as a predictor for CINV in patients with breast cancer receiving anthracycline-based regimens. The findings of this study indicated that patients with elevated systemic inflammation may be more susceptible to emetic episodes, contrasting with the results of the present study where no notable association was found between NLR and CR rates across any phase. This discrepancy may stem from differences in the defined NLR cut-off values or the specific antiemetic protocols employed; while both studies focused on highly emetogenic chemotherapy, variations in the administration of newer-generation NK1 receptor antagonists, such as the fosaprepitant used in the present cohort, might have mitigated the inflammatory-driven emetic response more effectively. When the authors examined the multivariate factors, the present analysis highlighted that pharmacological intervention and personal history, specifically motion sickness, exerted a more notable influence on outcomes compared with baseline hematological ratios. Consequently, while Naito et al (24) underscored the potential of the NLR as a biological marker, the findings of the present study suggest that its clinical utility may be diminished when patients are managed with optimized, contemporary antiemetic prophylaxis. The variability in findings across studies may be explained by a number of methodological and clinical factors. Differences in cancer types, chemotherapy regimens, antiemetic protocols, NLR cut-off values and outcome definitions may markedly influence the observed association between systemic inflammatory markers and CINV. Moreover, the limited number of studies specifically evaluating NLR in patients with breast cancer receiving highly emetogenic chemotherapy makes direct comparisons challenging and highlights the need for further prospective research in this area.

The absence of a notable association between NLR and CINV outcomes may reflect the multifactorial nature of CINV. Although systemic inflammation has been implicated in emetic pathways through cytokine-mediated signaling, established patient-associated risk factors and the effectiveness of antiemetic prophylaxis may exert a greater influence on clinical outcomes (7,9). Furthermore, the widespread use of contemporary NK1 receptor antagonist-based regimens in the present cohort may have reduced the potential impact of baseline inflammatory status on CINV susceptibility.

The multifactorial nature of CINV is further illustrated by the prediction model developed by Hu et al (25) which emphasizes the importance of patient-associated risk factors such as age and history of morning sickness in determining emetic susceptibility. In the present study, the identification of motion sickness as a notable independent predictor of failing to achieve CR in both the overall and delayed phases aligns with the emphasis on clinical phenotyping. However, while Hu et al (25) identified younger age as a primary risk determinant, the present analysis showed no such association, likely due to the demographic homogeneity of the breast cancer population receiving standardized highly emetogenic chemotherapy. Ultimately, the fact that established clinical triggers such as motion sickness remained predictive while the NLR did not reach statistical significance suggests that, in the context of modern antiemetic prophylaxis, individual neurobiological sensitivity may supersede baseline systemic inflammatory status in modulating the emetic threshold.

The influence of systemic inflammation on emetic pathways is not limited to oncology, as shown by previous research in the surgical setting (21,15,26). This evidence has suggested that in specific populations such as lung squamous cell carcinoma, physiological parameters, particularly pulmonary function and cardiovascular comorbidities, markedly influence CINV severity (26). The findings of Wang (26) indicated that lower oxygen partial pressure and compromised respiratory function (low forced expiratory volume in 1 sec) were associated with heightened emetic risk, likely due to the exacerbated systemic stress and impaired metabolic clearance in these patients. By contrast, the present study focused on a breast cancer cohort receiving AC regimens, where respiratory parameters were not a primary variable. However, a parallel can be drawn regarding inflammatory markers; while Wang (26) observed that elevated IL-6 levels had a protective effect against severe CINV in patients with lung squamous cell carcinoma (LSCC), data from the present study on NLR showed no such predictive value. This discrepancy highlights that the association between systemic inflammation and the emetic reflex may be highly tumor-specific and dependent on the primary organ affected. While LSCC-related CINV is influenced by respiratory-driven physiological stress, CINV in the breast cancer population in the present study appears more closely associated with individualized neuro-susceptibility, represented by motion sickness and the pharmacological potency of the antiemetic regimen (such as fosaprepitant).

Research regarding the association between systemic inflammation and emetic outcomes has also been reported in surgical settings. For instance, elevated preoperative NLR has been associated with an increased risk of postoperative nausea and vomiting in patients undergoing procedures such as rhinoplasty and breast reduction surgery (21,27). These findings support the hypothesis that baseline inflammatory status may influence the susceptibility of an individual to emetic stimuli. However, the present results in patients with breast cancer receiving highly emetogenic chemotherapy did not demonstrate a similar predictive value for NLR. This discrepancy may reflect fundamental differences in the mechanisms underlying postoperative nausea and vomiting and chemotherapy-induced nausea and vomiting. While surgical emesis is largely driven by perioperative inflammatory responses and anesthetic exposure, CINV involves complex neurochemical pathways activated by highly emetogenic cytotoxic agents, such as anthracyclines (e.g., doxorubicin or epirubicin) and cyclophosphamide. In addition, the routine use of modern antiemetic prophylaxis, particularly NK1 receptor antagonists such as fosaprepitant, may attenuate the potential contribution of baseline inflammatory markers in the oncology setting. Beyond baseline hematological ratios, the present findings suggest that emetic risk stratification in the era of modern antiemetic prophylaxis may depend more upon patient-associated susceptibility factors than on baseline inflammatory status. While NLR did not reach statistical significance in any phase of the present study, a history of motion sickness was consistently associated with lower odds of failure to achieve CR. In addition, fosaprepitant use was associated with improved CINV control, particularly during the delayed phase. We hypothesize that effective NK1 receptor antagonist-based prophylaxis may reduce the clinical impact of subtle neuro-inflammatory mechanisms involved in CINV. However, due to the retrospective and non-randomized nature of the present study, this finding should be interpreted as an association rather than evidence of a causal benefit, as antiemetic regimen selection may have been influenced by physician preference and other unmeasured clinical factors.

The clinical relevance of effective emetic control has been demonstrated by Pirri et al (28) who emphasized that despite advances in antiemetic therapy, ~50% of patients with cancer still suffer from nausea, which severely impairs their QoL and psychological adjustment. This research highlighted that persistent nausea, often more pervasive compared with vomiting, notably disrupts physical, social and role functioning. Although the present study did not find a significant predictive association between the NLR and CINV outcomes, the present findings may contribute a valuable perspective to the current, yet insufficient, body of knowledge regarding emetic risk stratification. While systemic inflammatory markers such as NLR may not serve as primary predictors in the context of highly emetogenic chemotherapy, identifying alternative markers such as motion sickness remains key for preserving the QoL. Therefore, despite the negative results regarding NLR, the present study provides an important contribution to the literature by refining the boundaries of biological predictors and underscoring the necessity of a personalized, phenotype-based approach to antiemetic prophylaxis.

The primary strength of the present study lies in its methodological focus on a highly homogeneous cohort of patients with breast cancer receiving a standardized AC regimen, which notably minimized treatment-associated confounding variables and supported the internal validity of the present findings. By conducting a granular temporal analysis across the acute, delayed and overall phases and utilizing multivariate models to adjust for critical covariates, the present study provided a robust assessment of the NLR as a potential biomarker. Additionally, the inclusion of real-world comparative data between fosaprepitant and oral aprepitant adds a layer of practical clinical relevance to the current literature. However, specific limitations must be acknowledged. While the present retrospective design imposed inherent limits on subjective symptom tracking, the reliance on hard clinical endpoints, including rescue medication use, provided a concrete measure of antiemetic failure. In addition, being a single-center study, the generalizability of the present results may be limited by institutional practices. In addition, CINV assessment was limited to the first chemotherapy cycle, and cumulative effects across multiple cycles were not evaluated. The reliance on a single baseline NLR measurement, without longitudinal tracking of inflammatory cytokines or post-chemotherapy fluctuations, may not fully capture the dynamic neuro-inflammatory environment triggered by cytotoxicity. Only baseline NLR values were evaluated in the present study; therefore, the findings do not exclude the possibility that other inflammatory biomarkers or dynamic changes in inflammatory status during chemotherapy may contribute to CINV susceptibility. Finally, nausea severity was not systematically recorded and therefore could not be analyzed independently from vomiting outcomes. As nausea is often reported as one of the most severe CINV symptoms, this may have limited the comprehensive assessment of treatment-associated symptom burden. Despite this, the present findings contribute to the growing body of evidence regarding CINV risk stratification and highlight the importance of individualized patient-associated risk factors when planning antiemetic prophylaxis.

Overall, in the present retrospective cohort of patients with breast cancer receiving highly emetogenic chemotherapy, baseline NLR was not associated with the risk of CINV. By contrast, a history of motion sickness and antiemetic regimen were markedly associated with CINV outcomes. These findings suggest that baseline NLR has limited utility as a predictor of CINV in this clinical setting. However, the present results do not exclude a potential role for other inflammatory biomarkers or dynamic changes in inflammatory status during treatment. Prospective studies incorporating longitudinal assessments of inflammatory markers are warranted to further clarify the association between inflammation and CINV.