Factors influencing the efficacy of neoadjuvant chemotherapy for HER-2-low early-stage breast cancer and a predictive model for pathological complete response

Introduction

In 2024, the China Cancer Center released its latest report, which showed that in 2022, the incidence of female breast cancer (BC) in China was 358,700, with an incidence rate of 51.17 per 100,000; meanwhile, the number of deaths was 75,000, with a mortality rate of 10.86 per 100,000, and the 5-year survival rate was only 82.0%. BC remains a major threat to women’s health in China, with human epidermal growth factor receptor 2 (HER-2)-low BC accounting for more than 50% of clinical cases (1). Currently, the design of the initial clinical treatment plan for BC relies on the molecular subtypes determined from the pathological information obtained from surgical biopsy or perforated pathological biopsy of the tumor lesion by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The binary determination of HER-2 positivity or negativity is an important basis for the direct decision to administer targeted therapy. Unfortunately, HER-2-low BC is not considered responsive to anti–HER-2 therapy under the current definitions and is therefore grouped with HER-2-zero in terms of treatment options.

However, in recent years, studies (2,3) have reported that novel antibody-drug conjugates (ADC) can exert tumor cell-killing effects through a high-cytotoxicity payload, the targeting of HER-2 surface antigens, endocytosis, and degradation, drug release, or bystander effects. It has been further suggested that this effectiveness can be extended to HER-2-low BC. Moreover, due to the development of precise quantitative HER-2 detection technology, the HER-2-low BC population is expected to become a potential candidate for targeted therapy. It should also be emphasized that HER-2-low early-stage breast cancer (eBC) accounts for 40–80% of clinical cases, constituting the largest group of HER-2 negative BC. Furthermore, the current clinical diagnosis and treatment protocols for neoadjuvant chemotherapy (NAC) are not generally effective, and if precise treatments can become available for this portion of patients, the overall survival of BC can be improved to a large extent. Therefore, developing effective targeted diagnostic and therapeutic protocols through examination of tumor heterogeneity is a key direction in clinical research.

For patients whose first diagnosis of BC does not warrant surgery, preoperative NAC can lower the clinical stage and reduce the size of the tumor lesion, thus improving the chances of implementing a more beneficial surgical option. Moreover, after NAC, information on how different BC tumor features, clinical characteristics, and pathological statuses respond to chemotherapy can be obtained, providing critical guidance for the development of appropriate treatment plans and effective treatment regimens after surgery to improve long-term outcomes. Therefore, preoperative NAC is an important therapeutic measure for a large portion of BC cases. Pathological complete response (pCR) remains an important alternative marker of good response to treatment, lower likelihood of tumor recurrence and metastasis, and higher overall survival. However, not all patients with BC undergoing NAC are able to achieve pCR. Compared with that in patients with HER-2 overexpression and triple-negative BC, the pCR rate in patients with HER-2-zero and HER-2-low BC after NAC is relatively low. The studies related to HER-2-low BC (4,5) have primarily focused on examining the clinical characteristics of tumors, molecular pathological expression, responsiveness to neoadjuvant and NAC, and prognostic survival status. However, there is a lack of consensus regarding the characterization of the HER-2-low BC population and no guidance on treatment options. Moreover, the ability of HER-2-low BC to represent a unique biological or clinical entity that could alter treatment decisions to the point of improving prognostic status is an important consideration in the classification of therapies, with the tumor heterogeneity related to HER-2-zero BC also being relevant. Moreover, no studies have examined the clinical and pathological factors influencing pCR after NAC for HER-2-low BC in clinical practice, and there is a lack of effective guidance for the choice of initial treatment regimen in this population.

Therefore, we conducted a retrospective study to compare the effects and influencing factors of NAC on HER-2-low and HER-2-zero eBC and to clarify the tumor heterogeneity between these two types in order to provide basic references for the clinical classification, diagnosis, and treatment. Moreover, the clinical and pathological factors influencing pCR after NAC for patients HER-2-low eBC were analyzed to inform the selection and formulation of the initial clinical diagnostic and treatment plans for HER-2-low eBC. It is critical that feedback from the effects of treatment plans and chemotherapy regimens in NAC for HER-2-low eBC be used to construct predictive models. We present this article in accordance with the TRIPOD reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-7/rc).

Methods

General information

In this study, we retrospectively collected clinical and pathological data of patients with HER-2–negative BC who attended the Breast Surgery Department of The First Affiliated Hospital of Xinjiang Medical University for NAC and surgical treatment from April 2013 to March 2024. Based on the inclusion and exclusion criteria, 212 patients with HER-2-negative early-stage invasive ductal carcinoma of the breast were ultimately included in the study (Figure 1), with 151 patients with HER-2-low and 61 patients with HER-2-zero eBC. Of the 151 patients with HER-2-low eBC, 20 achieved pCR while 131 did not. All patients enrolled in this study signed an informed consent form to voluntarily use the remaining samples of blood, tissues and other health information for scientific research. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional board of The First Affiliated Hospital of Xinjiang Medical University (No. 230714-08).

Figure 1 Flowchart of patient inclusion. BC, breast cancer; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.

Inclusion and exclusion criteria

The inclusion criteria for patients were as follows: ductal invasive carcinoma of the breast diagnosed as triple-negative or luminal type by core needle biopsy (CNB), clear indications for chemotherapy, administration of NAC, standardized surgical treatment performed after NAC, and complete of clinical and pathological data. Meanwhile, the exclusion criteria were as follows: IHC2+/FISH+ or IHC3+, BC diagnosed by lumpectomy prior to chemotherapy, nonductal invasive carcinoma of the breast, a primary diagnosis of stage IV BC, male BC, bilateral concurrent BC or concomitant other primary tumors, and incomplete clinical and pathological data.

Clinical diagnosis and treatment process of the study patients

For patients with a preliminary diagnosis of BC via physical examination and imaging, fine needle aspiration (FNA) and CNB were performed under the guidance of breast ultrasound to determine the IHC status. If BC combined with abnormal enlargement of axillary lymph nodes, FNA was also performed, and metal titanium clips were placed in the breast tumor lesions and suspected positive axillary lymph nodes to mark them. FNA was applied to clarify the nature of the mass and CNB to clarify the molecular subtypes, after which complete systemic examination was performed to clarify the presence of distant organ metastasis. Patients with locally advanced stage BC, a tumor diameter >2 cm, lymph node metastasis, or triple-negative BC, willingness to preserve the breast, or combination with other high-risk factors were deemed eligible for NAC. The chemotherapy regimens were selected in strict accordance with the Chinese BC guidelines, and other regimens were selected with patient suitability, drug accessibility, and other circumstances being considered. During NAC, the effect of chemotherapy was dynamically evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Surgery was immediately performed in patients with poor response to chemotherapy, and if the effect of chemotherapy was significant, surgery was performed after 6 cycles of chemotherapy; IHC was performed on the postoperative pathological specimens to obtain data for subsequent analysis.

Observation indicators

General clinical indicators including patient’s age, BMI, menstrual status, chemotherapeutic regimen, chemotherapy cycle, maximum tumor diameter, status of axillary lymph nodes via puncture, surgical approach, and results of RECIST 1.1 evaluation were analyzed. Other variables examined included pathological grading; tumor invasion; ER, PR, Ki-67, AR, and GATA3 expression status; Miller-Payne grading; pCR status; and other pathological indicators.

Definition of observational indicators

The maximum diameter of the tumor was determined via breast ultrasound. ER- and PR-negative status was defined as ≤10% cell nuclear coloration in IHC, while ER- and PR-positive status was defined as >10% cell nuclear coloration in IHC. AR- and GATA3-positive status was defined as >1% cell nuclear coloration in IHC. During the study period, we evaluated HER-2 test results based on the 2009, 2014, and 2019 versions of the Chinese Breast Cancer HER-2 Testing Guidelines. HER-2-negative status was defined as IHC0, IHC1+, and IHC2+/FISH(−); HER-2 zero as IHC0; and HER-2 low as IHC1+ and IHC2+/FISH (−). The evaluation results of RECIST 1.1 were defined as follows: complete response (CR), the disappearance of all target lesions and pathological lymph node short diameters <10 mm; partial response (PR), a decrease of >30% in the diameter sum of the target lesions from the baseline level; progressive disease (PD), an increase of >20% in the diameter sum of the target lesions, with the minimum of the diameter sum of the target lesions serving as the reference; and stable disease (SD), a decrease in the target lesions that does not reach the level of PR and an increase of the diameter sum of the target lesions that does not reach the level of PD. The Miller-Payne assessment system examines the cellularabundance of residual invasive tumors in primary breast tumors after NAC, primarily by comparing pretreatment hollow-core needle punctures with posttreatment surgical specimens. The five grades (G1 to G5) of the Miller-Payne system are as follows: G1, invasive cancer cells without change or only individual cancer cells with nooverall reduction in the number of cancer cells; G2, invasive cancer cells with a reduction of <30%; G3, invasive cancer cells with a reduction of 30% to 90%; G4, invasive cancer cells with a reduction of >90% and only scattered small clusters of cancer cells or single cancer cells remaining; and G5, a protoneoplastic tumor bed with no invasive cancer cells (the G5 primary tumor bed has no infiltrating cancer cells but may have ductal carcinoma in situ). pCR was defined as Miller-Payne G5 and negative for regional lymph nodes.

Statistical analysis

Numerical variables with a normal distribution according to the chi-squared test are expressed as the mean ± standard deviation (SD), with comparisons of two groups being conducted via the independent samples t test. Variables with a normal distribution are expressed as median and interquartile range (25–75%) and were compared with the Wilcoxon test. Categorical variables are expressed as the number of cases and percentage, and the Pearson chi-squared test was used for between-group comparisons when all theoretical frequencies were >5 and the total sample size was ≥40. The continuous correction chi-squared test was used for between-group comparisons if the theoretical frequency was <5 and ≥1 and the total sample size was ≥40. After data cleaning, one-factor binary logistic regression via a general linear model was used to screen the variables, which was followed by the application of multifactor binary logistic regression and model correlation tests. For the variable screening strategy, the variables in the univariate analysis that met the P value threshold (0.10) were entered into multivariate analysis for predictive model construction. The statistical software used was SPSS 26.0 (IBM Corp., Armonk, NY, USA). The model was constructed and calibrated via the “rms” and “ResourceSelection” R packages (R v. 4.2.1; The R Foundation for Statistical Computing), and receiver operating curve (ROC) analysis was performed viathe “pROC” and “ggplot2” packages. The significance threshold for all analyses in this study was a two-sided P value <0.05.

Results

RECIST 1.1 assessment results after NAC for HER-2-zero and HER-2-low eBC

In this study, the response of primary tumor lesions to NAC was evaluated via imaging modalities, including breast ultrasound, magnetic resonance imaging (MRI), and chest computed tomography (CT), according to RECIST1.1. The results showed that a greater portion of patients with HER-2-low eBC (35.1%) had SD after NAC compared than those with HER-2-zero eBC, while only 34.5% and 17.2% of patients with HER-2-low eBC, respectively, achieved partial or complete response. On imaging, primary tumor lesions demonstrated a high degree of stability and weak responsiveness to chemotherapy regimens with anthracyclines, taxanes, and cyclophosphamide as the primary agents (P<0.05) (Table 1).

Pathologic Miller-Payne grading assessment outcomes after NAC for HER-2-zero and HER-2-low eBC

All patients underwent standardized surgical procedures after the administration of NAC and were evaluated in terms of pathological Miller-Payne grading of residual tumor lesions in surgical specimens for pathologic testing. The results showed that there was no significant difference in the probability of reaching G4 and G5 status between HER-2-zero and HER-2-low eBC patients, but the HER-2-low patients had an only 57.6% probability of the pathologic responsiveness to NAC reaching G1 and G2 status, with the probability of attaining G3 status being significantly lower than that of HER-2-zero patients. Thus, in terms of the extent to which the primary tumor lesion regressed pathologically, HER-2-low had a worse responsiveness to NAC (P<0.05) (Table 2).

pCR rates after NAC for HER-2-zero and HER-2-low eBC

Based on these results, we further compared patients with HER-2-zero and those with HER-2-low eBC who achieved pCR after NAC, and the results did not suggest a significant difference between the two patient groups. This suggests that although HER-2-low eBC is less responsive to NAC at the imaging and pathological level, this variability is not reflected at the pCR level for the HER-2-low population as a whole (P>0.05) (Table 3).

Factors influencing the effect of NAC on HER-2-zero and HER-2-low eBC

To clarify whether the weaker responsiveness to NAC exhibited by patients with HER-2-zero and HER-2-low eBC at the imaging and pathologic levels and the nondifference in pCR were caused by general clinical features and puncture pathology characteristics, the clinical and pathological characteristics of both groups were statistically analyzed. The results did not reveal any significant difference between the two groups in terms of general clinical characteristics such as age, BMI, menstrual status, maximum diameter of tumor, axillary lymph node status through puncture, chemotherapy regimen, chemotherapy cycle, and tumor invasion (P>0.05). As for pathological grading, as well as ER, PR, Ki-67, AR, and GATA3 expression status, it was found that the HER-2-low group had a higher ER and PR expression rate, and Ki-67 had a probability of close to 80% of having a <50% low expression status, with statistically significant differences between groups (P<0.05) (Table 4).

Univariate analysis of pCR in HER-2-low eBC

In order to clarify the factors affecting the attainment of pCR after NAC in patients with HER-2-low eBC, the general clinical characteristics and puncture pathology characteristics were first included in the univariate analysis in this study. The univariate analysis indicated that the unfavorable influencing factors for achieving pCR included a maximum tumor diameter of >3 cm; positive axillary lymph nodes through puncture; pathological grade I or II through puncture; fewer chemotherapeutic cycles; low Ki-6 7 expression; tumor invasion of the nerves, blood vessels, muscles, and skin; and positivity for ER, PR, and AR (P<0.05) (Table 5).

Multifactorial analysis of pCR in HER-2-low eBC

Factors that were significant in the univariate analysis and that could influence pCR were incorporated into the multivariate binary logistic regression analysis. The results indicated that a maximum tumor diameter >3 cm, positive axillary lymph nodes through puncture, and fewer chemotherapeutic cycles were independent unfavorable factors (Table 6).

Construction of a predictive model for pCR after NAC for HER-2-low eBC

In order to be able to predict the probability of pCR after NAC for patients with HER-2-low eBC, we constructed a nomogram prediction model (Figure 2A). The receiver operating characteristic curve analysis of the participants indicated that the area under the curve (AUC) of the nomogram prediction model for predicting pCR after NAC in HER-2-low eBC was 0.861 (95% CI: 0.785–0.936), with a sensitivity of 80.0% and a specificity of 77.1% (Figure 2B). The predicted values of the calibration curves were in general agreement with the measured values (Figure 2C).

Figure 2 Nomogram prediction model (A), ROC (B), and calibration curve (C). AUC, area under the curve; CI, confidence interval; FPR, false positive rate; ROC, receiver operating characteristic; TPR, true positive rate.

Discussion

Continuously exploring the tumor heterogeneity between HER-2-low and HER-2-zero BC is an important prerequisite and foundation for classifying treatments and developing targeted protocols in future clinical practice. Tumor heterogeneity is reflected in clinical characterization, molecular pathology expression, responsiveness to NAC, and prognostic status. The findings regarding the difference in responsiveness to NAC between HER-2-low and HER-2-zero BC are conflicting, with some studies reporting better or worse (6) NAC outcomes in HER-2-low eBC and others reporting no significant differences between them (7,8). However, predicting the responsiveness of HER-2-low eBC to NAC and the probability of achieving pCR based on clinical and pathologic features can guide the choice of initial treatment regimen. Based on more than 10 years of clinical diagnosis and treatment in our center, we analyzed these issues, and we hope our findings have a positive impact on subsequent related studies and can guide clinical diagnosis and treatment to a certain extent.

This study examined the responsiveness of HER-2-low and HER-2-zero eBC to NAC, and based on the results, a comparative analysis of the clinical characteristic and molecular pathology expression was performed. We found that patients with HER-2-low eBC had a weaker response after anthracycline- and paclitaxel-based NAC according to the pathological and imaging findings. Further analysis revealed that this result was significantly correlated with the positive expression of ER and PR and the low expression of Ki-67 in CNB specimens, suggesting that heterogeneity exists between HER-2-low and HER-2-zero tumors, which is reflected in different response states to NAC. However, this variability did not manifest at the pCR level, as there was no significant difference in pCR rates after NAC between the HER-2-low and HER-2-zero eBC group, which differs from some others studies (9,10). The reason for this result may be that the sample size of our study was relatively small such that statistically significant results were not obtained. Another possible explanation is that current ICH assays cannot distinguish between the lower limits of ICH0 and ICH1+, and the evaluation criteria used by different by different laboratories vary, resulting in the inability to accurately determine and categorize ICH0 and ICH1+. However, a meta-analysis of large samples concluded that the pCR rate is lower in HER-2-low BC than in HER-2-zero BC (11).

Accordingly, we sought to determine the reason for HER-2-low eBC’s potentially weaker responsiveness to NAC. The Ki-67 tumor proliferation index is considered to be a positive predictor of pCR (12-17), and the tumor entities with a high expression of Ki-67 have stronger tumor cell proliferative activity and better responsiveness to chemotherapeutic agents, which causes stronger chemotherapeutic effects; therefore, the low Ki-67 expression of HER-2-low eBC may account for the reduced responsiveness of tumor cells to chemotherapeutic drugs to a certain extent and may lead to a weaker chemotherapeutic effect (18,19). Moreover, there remains controversy regarding the relationship between ER and PR expression status with responsiveness to NAC in HER-2-low eBC. Although it has been suggested that HER-2-low eBC results in better NAC outcomes and is significantly associated with positive of ER and PR expression (20), completely opposite results have been obtained in our study and in others (21-23). Several large-sample studies reported that the ER-positive rate in HER-2-low eBC ranged from 58.1% to 77.3% (20,24-26), suggesting that the high expression of ER is more specific in HER-2-low eBC than in HER-2-zero BC and that there may be an important connection betweenHER-2 expression and ER messenger mRNA; in this process, there is a higher likelihood for ER proteins to be expressed at high levels and thus are able to upregulate HER-2 expression by altering the tumor microenvironment or stimulating the NF-kB pathway (12), which results in bidirectional crosstalk between ER and HER-2 and ultimately drug resistance. Therefore, it is believed that the positive expression of ER and PR is a resistance factor that decreases sensitivity to chemotherapy, and when they interact with the HER-2 pathway, the responsiveness to chemotherapy is reduced.

In addition, it is important to note that the classical chemotherapy regimen consisting of anthracyclines and paclitaxel as the mainstay was applied in more than 80% of the patients in this study, but it seemed to be less effective for patients treated with NAC for HER-2-low eBC, which is in line with other research (21,27). Therefore, in order to improve the effect of NAC and obtain long-term benefits, future investigations should focus on the interaction mechanism between HER-2 and ER and seek to eliminate the adverse effects of low Ki-67 expression and ER-positive expression as much as possible; adjusting the classical chemotherapy regimen or adding additional treatment may also be a productive avenue of research.

The proportion of HER-2-negative BC cases with HER-2-low ranges from 47.5% to as high as 84% (18,20,24,25,28,29), and thus it is the predominant tumor entity. Therefore, another key aim of our study was to clarify the influencing factors of pCR after NAC for HER-2-low eBC and to construct a model that could predict the probability of pCR after NAC and thus aid in the selection of the initial treatment regimen.

In total, 151 with patients with HER-2-low eBC were included in the study to analyze the factors influencing pCR after NAC. Univariate analysis revealed that the unfavorable influencing factors for pCR were a maximum tumor diameter >3 cm; positive axillary lymph nodes through puncture; anthracycline- and paclitaxel-based chemotherapy; pathological grading I or II through puncture; fewer chemotherapeutic cycles; low Ki-67 expression; tumor invasion of the nerves, blood vessels, muscles, and skin; and positivity for of ER, PR, and AR. The influence of ER and PR status on the efficacy of chemotherapy is discussed above, whereas the significance AR of expression of in HER-2-low eBC has been confirmed in other work (30). AR is unfavorable influencing factor likely because androgens decrease the proliferation rate of tumors, which leads to chemotherapy resistance (31). Moreover, AR participates in the immune evasion of tumor cells, leading to lower immune response, thus reducing the chances of achieving pCR (32,33). However, it seems logical that a larger tumor diameter, positive axillary lymph node status, extensive tumor invasion (nerves, vasculature, muscle, and skin), and fewer chemotherapeutic cycles are detrimental to the attainment of pCR, as collectively, they represent a more advanced tumor staging and lack of treatment. Therefore, it should be emphasized that there are clinical limitations to the efficacy of preoperative NAC administered to patients with late staging and localized invasion, with the probability of achieving pCR being low. In addition, pathological grades I or II according to puncture and low expression Ki-67 are unfavorable influencing factors likely because the relatively low biological activity of the tumor leads to a lower immune response (34) and low responsiveness to chemotherapeutic agents, thus hindering the efficacy of chemotherapy. One study found that patients with HER-2-low eBC had significantly higher homologous recombination-associated gene defect scores and significantly lower immune cell abundance, which might have reduced the immune response to some extent (35).

Based on the results of univariate analysis, multifactorial analysis was performed in this study, which suggested that a maximum diameter of tumor >3 cm, positive axillary lymph nodes through puncture, and fewer chemotherapeutic cycles were independent unfavorable factors. We created a nomogram prediction model for pCR after NAC for HER-2-low eBC based on these unfavorable factors. The validation results showed that the predictive value of the diagnostic calibration curve was basically consistent with the measured value, and the area under the ROC was 0.861 (95% CI: 0.785–0.936), with a sensitivity of 80.0% and a specificity of 77.1%. Therefore, the model is able to predict, to some extent, the probability of achieving pCR after NAC, which has high clinical predictive value.

At time of the initial puncture for diagnostic confirmation, if the maximum diameter of the tumor >3 cm, there are positive axillary lymph nodes through puncture, chemotherapy with anthracycline is combined with paclitaxel as the main agent, and there are fewer cycles of chemotherapy, although it is possible to obtain chemotherapeutic effects and improve surgical treatment to a certain extent, the probability of achieving pCR is relatively low. Therefore, the initial treatment plan needs to be carefully selected in clinical practice. Fortunately, studies (2,3,24) have reported significant efficacy of novel ADC in metastatic HER-2-low eBC, and the clinical application of this drug may be extended to HER-2-low eBC in the future, providing a novel treatment for such patients. Meanwhile, it is also expected that the clinical application of more accurate ICH detection methods and more standardized diagnostic criteria will provide reliable guidance for the determination of HER-2-low eBC. It is also hoped that further clinical research will overcome the limitations of current treatments and provide a targeted and pronounced therapeutic effect.

Certain limitations to this study should be addressed. First, as we employed a single-center, retrospective design, there was no validation of the pathological findings with other centers at this time. Second, due to the long time span of the study, the implementation of the treatment regimen was affected by the accessibility of the drug at different periods. Finally, the sample size was relatively small, which could have biased the results to a certain extent.

Conclusions

Clinically HER-2-low eBC exhibited low pCR rates after application of classical anthracycline- and paclitaxel-based chemotherapy regimens. Moreover, the weak responsiveness to NAC at the imaging and pathological level may be due to the heterogeneity of HER-2-zero tumors. Meanwhile, the ability to achieve pCR after NAC for HER-2-low eBC was influenced by multiple factors such as treatment regimen, treatment period, and clinical and pathological features. Initial treatment regimens of NAC based on anthracycline and paclitaxel may not be suitable for achieving pCR in patients with HER-2-low eBC. Therefore, future clinical strategies should be refined to address the limitations of existing treatments for HER-2-low eBC. In addition, the nomogram prediction model consisting of the influencing factors identified in this study demonstrated a degree of clinical predictive value and may inform the selection of the initial treatment regimen.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-7/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-7/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-7/prf

Funding: This study was supported by the Youth Sailing Special Fund of The First Affiliated Hospital of Xinjiang Medical University (No. 2024YFY-QKQN-10).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-7/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional board of The First Affiliated Hospital of Xinjiang Medical University (No. 230714-08). All patients enrolled in this study signed an informed consent form to voluntarily use the remaining samples of blood, tissues and other health information for scientific research.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Gray)