Front. Oncol. Frontiers in Oncology Front. Oncol. 2234-943X Frontiers Media S.A. 10.3389/fonc.2023.1245650 Oncology Systematic Review Capecitabine-based chemotherapy in early-stage triple-negative breast cancer: a meta-analysis Bai Jie 1 Yao Xufeng 1 2 Pu Yinghong 1 Wang Xiaoyi 1 * Luo Xinrong 1 * 1 Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 2 Department of Head and Neck Surgery, The First Hospital of Jiaxing, Zhejiang, China

Edited by: Sharon R. Pine, University of Colorado Anschutz Medical Campus, United States

Reviewed by: Karl Reinhard Aigner, MEDIAS Burghausen Clinic, Germany; Md. Mustafizur Rahman, Khulna University, Bangladesh

*Correspondence: Xiaoyi Wang, wxytsf@sina.com; Xinrong Luo, xinrongluo@hospital.cqmu.edu.cn

25 10 2023 2023 13 1245650 23 06 2023 03 10 2023 Copyright © 2023 Bai, Yao, Pu, Wang and Luo 2023 Bai, Yao, Pu, Wang and Luo

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 Introduction

The efficacy and safety of adjuvant capecitabine in early-stage triple-negative breast cancer remains undefined. A meta-analysis was conducted to elucidate whether capecitabine-based regimens could improve survival in early-stage triple-negative breast cancer (TNBC).

 Methods

The current study searched Medline, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov proceedings up to 2023.9. Disease-free survival (DFS), overall survival (OS), and grade 3–4 adverse events (AEs) were assessed. Extracted or calculated hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled.

 Results

The capecitabine-based regimens showed significant advantages in DFS (HR = 0.81, 95% CI: 0.73–0.90; P <.001) and OS (HR = 0.75, 95% CI: 0.65–0.87; P <.001) from 12 randomized controlled trials (RCTs) with 5,390 unselected participants. Subgroup analysis of DFS showed analogous results derived from patients with lymph node negative (HR = 0.68, 95% CI: 0.50–0.92; P = .006) and capecitabine duration no less than six cycles (HR = 0.73; 95% CI: 0.62-0.86; P <.001). Improvement of DFS in the addition group (HR = 0.77, 95% CI: 0.68–0.87; P <.001) and adjuvant setting (HR = 0.79, 95% CI: 0.70–0.89; P <.001) was observed. As to safety profile, capecitabine was associated with more frequent stomatitis (OR = 5.05, 95% CI: 1.45–17.65, P = .011), diarrhea (OR = 6.11, 95% CI: 2.12–17.56; P =.001), and hand–foot syndrome (OR = 31.82, 95% CI: 3.23–313.65, P = .003).

 Conclusions

Adjuvant capecitabine-based chemotherapy provided superior DFS and OS to early-stage TNBC. The benefits to DFS in selected patients with lymph node negative and the addition and extended duration of capecitabine were demonstrated.

 capecitabine triple-negative breast cancer chemotherapy survival adverse events National Natural Science Foundation of China10.13039/501100001809 Natural Science Foundation of Chongqing10.13039/501100005230 section-in-acceptance Breast Cancer Introduction

Triple-negative breast cancer (TNBC) is characterized by aggressiveness, heterogeneity, and a higher relapse tendency. For histopathological diagnosis, it pertains to an estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) subtype. Anthracycline- and/or taxane-based standard chemotherapies have substantially improved survival outcomes (1, 2). However, the 10-year recurrence risk in early-stage TNBC remains approximately 20%–40% (3, 4). Accordingly, new drug-incorporated strategies should be explored for further clinical development.

Capecitabine is an oral fluoropyrimidine prodrug with high efficacy and favorable tolerability for advanced BC (5). It is not the standard chemotherapy for early BC. There were also some conflicting survival data (6–17). Recently, two meta-analyses were performed to explore the RCTs of capecitabine effect, but TNBCs were treated as a subgroup in these studies (18, 19). To further determine the influence of adjuvant capecitabine on early-stage TNBC, we incorporated prospective randomized controlled trials (RCTs) in full text, performed a meta-analysis to get robust conclusions.

 Methods Search strategy

This meta-analysis complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (20). Online databases Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched until September 17, 2023. Queries included the MeSH terms “breast cancer,” “breast neoplasm,” “triple-negative breast cancer,” “triple-negative breast neoplasms,” and the keywords “capecitabine” and “Xeloda.”.

 Selection criteria

Inclusion criteria were as follows: (a) phase III RCTs of early BC involving TNBC; (b) RCTs contained a comparison of capecitabine-based chemotherapy against capecitabine-free regimens; (c) available HRs with 95% CIs for DFS and/or OS. RCTs published other than English were excluded.

 Data extraction

Two reviewers (XL, JB) extracted data by search strategy independently. Discordance would be resolved by consensus. Information captured from RCTs included the following: trial name, authors, update year, study design, TNBC patients, baseline characteristics, chemotherapy schedules, median follow-up period, survival results (HRs and 95% Cis for DFS and/or OS), and grade 3–4 adverse events (AEs).

 Quality assessment

The quality of studies was independently assessed using the Cochrane Risk Of Bias Assessment Tool (CROBAT), which consists of “random sequence generation,” “allocation concealment,” “blinding of participants and personnel,” “blinding of outcome assessment,” “incomplete outcome data,” “selective reporting,” and “other bias” ( Figure S1 ). Publication bias was evaluated by Funnel plot and Egger’s regression asymmetry test (21) ( Figures S2–S4 ).

 Statistical analysis

By the generic inverse variance method, the HRs and 95% CIs for DFS and/or OS in TNBC were pooled (22).The odds ratios (ORs) of grade 3–4 AEs were weighted and estimated. In addition, current analysis followed the intention-to-treat principle. We conducted subgroup analyses in accordance with (a) nodal status, (b) capecitabine duration, (c) adding or replacing capecitabine in chemotherapy, (d) adjuvant or neoadjuvant chemotherapy, (e) dosage of capecitabine, (f) the TNBC proportion, (g) combined chemotherapy regimen, (h) sequential or concomitant capecitabine, (i) study region, (j) menopausal status, (k) tumor size, (l) histological grade, (m) basal or non-basal subtype, and (n) Ki-67 status. Heterogeneity among RCTs was evaluated by the Cochran Q statistics and I2 test (23). When P < 0.10 or I2 > 50%, we utilized the random-effect model. Otherwise, the fixed-effect model was used. Sensitivity analysis was conducted to assess the stability. Analyses were two-tailed with Stata 17.0 software.

 Results Characteristics of studies

There were 12 RCTs with 5,390 TNBC patients who met the predefined criteria ( Table 1 ; Figure 1 ) (6–17). The FinXX and CALGB 49907 trials, reported RFS rather than DFS; however, RFS was arguably the same definition as DFS (6, 11). Four studies reported early-stage TNBC only (7–10); nevertheless, the others incorporated all BC subtypes. The CBCSG010 trial conducted the modified intention-to-treat analysis, which might amplify the benefits, yet the dropouts were too small to yield a positive result (10).

Study characteristics.

Study Update year Treatment Age TNM stage TNBC, N(X/control) Region Median follow-up (years) TNBC proportion Design
Capecitabine arm Control arm
FinXX 2022 3TX–3CEX 3T–3CEF 18-65 T2-4N0M0/T1-4N1-3M0 93/109 Finland and Sweden 15 Subgroup Adjuvant
EA1131 2021 NAC-6X NAC-4Pla ≥18 T2-4N0M0/T1-4N1-3M0 160/148 USA 1.7 Whole cohort Neoadjuvant
SYSUCC-001 2021 Standard (neo) adjuvant chemotherapy-X (1 year, adjuvant) Standard chemotherapy-observation 18-70 T1c-3N0-2M0 221/213 China 5.1 Whole cohort Adjuvant
CIBOMA/2004-01 2020 Standard (neo) and/or adjuvant chemotherapy–8X standard (neo) and/or adjuvant chemotherapy-observation ≥18 T1-3N1-3M0/T1c-3N0M0 448/428 Spain and Latin America 7.3 Whole cohort Neo/adjuvant
CBCSG010† 2020 3TX–3CEX 3T–3CEF 18-70 T1-3N1-3M0/T1c-3N0M0 288/273 China 5.6 Whole cohort Adjuvant
CALGB 49907 2019 6X 6CMF/4AC ≥65 T1-3N1-3M0/T1c-3N0M0 76/78 USA 11.4 Subgroup Adjuvant
CREATE–X 2017 Standard neoadjuvant chemotherapy–6–8X (adjuvant) Standard neoadjuvant chemotherapy-observation 20-74 T1-4N1-2M0/T1c-4N0M0 139/147 Japan and Korea 5 Subgroup Adjuvant
GAIN 2017 ddEC–PwX (4EC–10T4X) iddEPC (3ETC) 18-65 T1-3N1-3M0 213/208 Germany 6.2 Subgroup Adjuvant
TACT2 2017 4E–4X 4E–4CMF ≥18 T0-3N0-2M0 419/448 UK 7.1 Subgroup Adjuvant
GEICAM/2003–10 2015 4ET–4X 4EC–4T 18-70 T1-3N1-3M0 95/71 Spain and Latin America 5 Subgroup Adjuvant
USO 01062 2015 4AC–4TX 4AC–4T 18-70 T1-3N1-2M0/T1c-3N0M0 396/384 USA 5 Subgroup Adjuvant
GeparTrio 2013 2TAC-4NX 2TAC-4/6TAC ≥18 T2-4N0M0/T1-4N1-3M0 362‡ Germany 5.2 Subgroup Neoadjuvant

†The trial used the modified intention-to-treat (mITT) population, which included randomized patients received at least one dose of study drug.

‡The trial did not mention population of TNBC in the capecitabine arm or control arm.

X, capecitabine; C, cyclophosphamide; M, methotrexate; F, 5-fluorouracil; A, doxorubicin; T, docetaxel; E, epirubicin; P, paclitaxel; N, number; TNBC, triple-negative breast cancer; NAC, neoadjuvant chemotherapy.

Flow diagram of the search process.

There was no significant publication bias from the Funnel plot or Egger’s test ( Figures S2–S4 ). Sensitivity analysis indicated that no certain trial affected the pooled results ( Figures S5, S6 ).

 Efficacy Pooled analysis

Due to the absence of heterogeneity (P = .187; I2 = 26.2%), we utilized the fixed-effect model to calculate the pooled DFS (HR = 0.81, 95% CI: 0.73–0.90; P <.001). It also corresponded to significant improvement in OS for the capecitabine group (HR = 0.75, 95% CI: 0.65–0.87; P <.001). The forest plots of DFS and OS are shown in Figure 2 .

Forest plot of pooled disease-free survival and overall survival for capecitabine-based regimens in early triple-negative breast cancer (A) Shows the results for pooled disease-free survival. (B) Shows the outcomes for pooled overall survival.

 Subgroup analysis

The nodal status subgroup analysis reached controversial outcomes ( Figure 3A ). DFS was statistically superior for women with lymph nodes negative (HR = 0.68, 95% CI: 0.50–0.92; P = .006) to positive (HR = 0.87, 95% CI: 0.72–1.05; P =.248). According to capecitabine duration, there were advantages of DFS (HR = 0.71, 95% CI: 0.60–0.84; P <.001) for patients who received capecitabine for at least 6 cycles (7, 9, 11, 12). For those with shorter duration (<6 cycles), no statistical significance was found (HR = 0.88, 95% CI: 0.73–1.01; P = .073) ( Figure 3B ) (6, 10, 13–17). The addition regimens improved DFS (HR = 0.77, 95% CI: 0.68–0.87; P<.001) ( Figure 3C ). In consideration of trials that TNBC acting as adjuvant chemotherapy, a greater DFS was determined (HR = 0.79, 95% CI: 0.70–0.89; P <.001) ( Figure 3D ) (6, 8–16).

Forest plot of disease-free survival for adjuvant capecitabine in subgroups with heterogeneous results. (A) Shows disease-free survival in the nodal positive or negative subgroup. CIBOMA/2004-01(1-3) denotes subgroup with one to three positive lymph nodes. CIBOMA/2004-01(≥4) is defined as subset with no less than four positive nodes. (B) Shows disease-free survival by capecitabine duration (≥6 cycles or <6 cycles). (C) Shows disease-free survival according to the addition or replacement of capecitabine. (D) Shows disease-free survival depending on capecitabine accounting for adjuvant or neoadjuvant chemotherapy.

As shown in Table 2 , DFS was superior in the anthracycline and taxane arm (HR = 0.83, 95% CI: 0.71–0.97; P =.020) and non-basal subtype group (HR = 0.47, 95% CI: 0.31–0.71; P <.001). We observed no statistical significance in either menopause status. However, subgroup analysis for DFS yielded positive effects by capecitabine dosage (<1,000 mg or ≥1,000 mg), TNBC proportion (as subgroup or whole cohort), capecitabine sequence (in sequential or concurrent), study region (America–Europe or Asia), tumor size (≤2 cm or >2 cm), histological grade (1–2 or 3), and Ki-67 status (<30% or ≥30%).

Subgroup analysis.

Subgroup Variable N† HR 95%CI P I2 § P for Q test §
Lymph node status
 Positive DFS 5 0.87 0.72-1.05 0.152 6.7% 0.161
 Negative 0.68 0.50-0.92 0.012 41.6% 0.355
Duration, cycle
 <6 DFS 12 0.88 0.73-1.01 0.073 30.0% 0.199
 ≥6 0.73 0.62-0.86 0.000 0.0% 0.486
 <6 OS 9 0.68 0.53-0.85 0.001 0.0% 0.742
 ≥6 0.80 0.66-0.97 0.026 3.7% 0.510
Addition or replacement of capecitabine
 Addition DFS 12 0.77 0.68-0.87 0.000 0.0% 0.435
 Replacement 0.95 0.77-1.17 0.641 49.6% 0.138
 Addition OS 9 0.74 0.63-0.87 0.000 0.00% 0.588
 Replacement 0.82 0.53-1.26 0.365 – –
Chemotherapy
 Adjuvant DFS 12 0.79 0.70-0.89 0.000 38.0% 0.105
 Neoadjuvant 0.92 0.71-1.19 0.519 0.0% 0.898
 Adjuvant OS 8 0.71 0.59-0.86 0.000 0.0% 0.830
 Neoadjuvant 0.69 0.41-1.16 0.159 51.6% 0.151
Dosage
<1,000 mg DFS 12 0.69 0.54-0.87 0.002 0.0% 0.399
≥1,000 mg 0.85 0.75-0.95 0.007 25.9% 0.214
<1,000 mg OS 9 0.65 0.50-0.85 0.001 0.0% 0.755
≥1,000 mg 0.80 0.67-0.96 0.014 0.0% 0.613
TNBC proportion
 Subgroup DFS 12 0.82 0.69-0.99 0.034 41.9% 0.099
 Whole cohort 0.76 0.63-0.91 0.003 0.0% 0.557
 Subgroup OS 9 0.68 0.56-0.84 0.000 0.0% 0.577
 Whole cohort 0.84 0.67-1.04 0.104 0.0% 0.775
Chemotherapy regimen
 Anthracycline without taxane DFS 8 0.92 0.76-1.12 0.409 18.4% 0.298
 Anthracycline and taxane 0.83 0.71-0.97 0.020 0.0% 0.470
 Anthracycline without taxane OS 3 0.62 0.41-0.94 0.024 – –
 Anthracycline and taxane 0.76 0.55-1.06 0.11 0.0% 0.604
Sequence
 Concurrent DFS 12 0.77 0.63-0.94 0.010 26.5% 0.253
 Sequential 0.83 0.73-0.94 0.004 33.2% 0.163
 Concurrent OS 9 0.68 0.54-0.85 0.001 0.0% 0.742
 Sequential 0.80 0.66-0.97 0.026 0.0% 0.510
 Menopause status
 Premenopausal DFS 2 0.72 0.49-1.05 0.087 0.0% 0.790
 Menopausal 0.72 0.36-1.18 0.190 54.8% 0.137
Region
 America–Europe DFS 12 0.87 0.77-0.98 0.025 7.5% 0.373
 Asia 0.63 0.50-0.79 0.000 0.0% 0.898
 America–Europe OS 9 0.78 0.66-0.92 0.005 0.0% 0.557
 Asia 0.651 0.48-0.88 0.006 0.0% 0.604
Tumor size, cm‡
 ≤2 DFS 2 0.52 0.31-0.88 0.014 0.0% 0.379
 >2 0.68 0.47-0.84 0.035 0.0% 0.035
Histological grade
 1–2 DFS 2 0.52 0.29-0.94 0.032 0.0% 0.705
 3 0.61 0.42-0.86 0.006 0.0% 0.437
Intrinsic subtype
Basal subtype DFS 3 0.93 0.76-1.12 0.434 0.0% 0.981
Non-basal subtype 0.47 0.31-0.71 0.000 45.5% 0.031
Ki-67
 <30% DFS 2 0.53 0.28-0.98 0.044 0.0% 0.448
 ≥30% 0.71 0.51-0.98 0.039 0.0% 0.738

†The number of studies in the subgroup.

‡Tumor size was based on pathological assessment.

§Only one trial included, so the value of I2 and P for Q test are not available.

HR, hazard ratio; CI, confidence interval; DFS, disease-free survival; OS, overall survival.

 Safety and tolerability

The safety profile included hematologic side effects, gastrointestinal events, general disorders, skin and subcutaneous disorders, nervous system disorders, investigations, musculoskeletal and connective disorders, vascular disorders, and other disorders (grades 3–4) ( Table 3 ). It was shown in four-RCT-specified TNBC (7–10). The pooled results indicated higher frequencies of stomatitis (OR = 5.05, 95% CI: 1.45–17.65; P =.011), diarrhea (OR = 6.11, 95% CI: 2.12–17.56; P =.001), and hand–foot syndrome (OR = 31.82, 95% CI: 3.23–313.65; P =.003) for capecitabine in early TNBC women.

Toxicity analysis.

Grade 3–4 AEs† X arm (N = 1,114) Control arm (N = 1,074) OR 95% CI p
Hematologic
 Leukopenia 1 1 0.98 0.06-15.63 0.986
 Neutropenia 144 118 3.09 0.25-38.15 0.379
 Thrombocytopenia 12 5 2.25 0.82-6.19 0.117
Gastrointestinal
 Nausea 10 5 1.85 0.66-5.23 0.421
 Vomiting 13 15 0.84 0.41-1.74 0.182
 stomatitis 15 3 5.05 1.45-17.65 0.011
 Diarrhea 24 3 6.11 2.12-17.56 0.001
 Abdominal pain 1 0 2.93 0.12-72.15 0.511
General disorders
 Fatigue 20 5 2.64 0.42-16.51 0.083
 Hand–foot syndrome 124 3 31.82 3.23-313.65 0.003
Skin and subcutaneous disorders
 Rash 1 2 0.48 0.04-5.36 0.553
 Alopecia 206 205 0.92 0.64-1.31 0.630
 Nail changes 2 0 4.90 0.23-102.29 0.306
 Nervous system disorders
 Sensory neuropathy 4 15 0.43 0.01-18.62 0.658
Investigations
 ALT and/or AST increase 8 10 1.33 0.19-9.32 0.123
 Hyperbilirubinemia 3 0 6.87 0.35-133.42 0.203
Musculoskeletal and connective disorders
 Musculoskeletal pain  (joint) 10 4 2.46 0.77-7.90 0.130
 Musculoskeletal pain  (muscle) 6 5 1.15 0.37-3.61 0.812
Vascular disorders
 Any cardiac event, general 2 1 1.95 0.18-21.63 0.585
Other
 Irregular menses 57 55 1.01 0.68-1.51 0.954

†Severity was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 or 4.0.

AEs, adverse events; OR, odds ratio; CI, confidence interval; ALT, alanine aminotransferase; AST, aspartate transaminase.

 Discussion

There were several RCTs with conflicting results about capecitabine in early TNBC. Recently, the EA1131 and SYSUCC-001 trials provided updated outcomes with details about patient characteristics and treatment strategies (7, 8). In addition, the FinXX trial updated overall survival on the basis of approximately 15-year follow-up of the patients (6). Therefore, it is reasonable to reevaluate the influence of capecitabine. As for metastatic TNBC, capecitabine had low response rates and limited activity in trials (23, 24). Selecting appropriate patients may enhance treatment effects, since the mechanisms remained unclear.

Focusing on the association of capecitabine and early TNBC, there were two meta-analyses recently (18, 19). However, meta-analysis from Xun et al. did not extract data from the TACT2 trial, which should be included as well (14, 18). In addition, the GAIN and GEICAM/2003-10 trials only consisted node-positive patients; in other words, they should be incorporated to the nodal status subgroup analysis as well (13, 15). Zhou et al. included trials more rigorously, so subgroup analysis performed with less information (19).

We conducted a comprehensive meta-analysis of 12 RCTs (full text) exploring the efficacy and safety of capecitabine-based chemotherapy. It significantly improved DFS and OS among 5,390 TNBC patients. Considering subgroup analysis, the survival benefits were observed in lymph node negative status, the addition, extended duration, and adjuvant setting of capecitabine.

Patients with nodal negative results had a superior DFS. Regarding the node-positive arm, the CBCSG010 trial reported an advantage for DFS (10), whereas four RCTs (SYSUCC-001, CIBOMA/2004-01, GAIN, GEICAM/2003-10) did not (8, 9, 13, 15). In addition, there were three arms of nodal status (0, 1–3, and ≥4) in the CIBOMA/2004-01 trial (9). However, no more details were available for lymph node positive status (1–3, 4–9, ≥10, without metastasis to internal mammary chain or infraclavicular/supraclavicular region). Therefore, we could not further determine the influence of different positive-node stages.

Metastasis of lymph node contributes to higher risk for TNBC. We speculated that capecitabine would confer further extended survival on node-positive patients. Nevertheless, the result was paradoxical. It might be strong distinction of capecitabine on micro-metastatic and overt lesions. Targeting the immune escape metastasis mechanism, dormant tumor cells with a lower proliferation index were more sensitive to an antimetabolite drug. Similar to capecitabine, it is a DNA synthesis inhibitor (25). Biomarkers determining which TNBC subtype favored most are also needed; for example, the PAM50 non-basal molecular subtype and the BRCA1-like DNA copy number (26, 27). Extrapolation from studies of the last decade with long-term follow-up should be cautiously applied. The RCTs of individual survival benefits of capecitabine for node-positive patients are still needed.

Adjuvant capecitabine added to the anthracycline and taxane regimens had survival advantages for early TNBC, in favor of the synergism of docetaxel and capecitabine in preclinical models (28). The results verified the rationale of combination chemotherapy (29). Patients derived greater DFS from extended capecitabine duration (≥6 cycles), which means capecitabine could modulate antitumor immune and anti-angiogenesis properties through metronomic therapy (30).

Our study has limitations. First, populations with various characteristics contributed to the heterogeneity. The definition of ER-negative in the CBCSG010 and CREAT-X studies (<10%) did not align with others (<1%) (10, 12). Second, the diverse chemotherapy regimens confounded the results and decreased robustness. Third, given no individual patient data available, the details (age and intrinsic subtype) were incomplete, so it was hard to assess and select the subpopulation.

 Conclusion

This meta-analysis showed that capecitabine-based regimens significantly improved both DFS and OS in early-stage TNBC. There was a substantial improvement for DFS in the groups with lymph node negative status, the adjuvant, addition, and longer duration (≥6 cycles) of capecitabine to standard chemotherapy.

 Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

 Author contributions

Design: JB and XL. Data collection: JB, XY, YP. Data analysis: JB, XL. Writing-original draft: JB. Writing-review and editing: XW, XL. All authors contributed to the article and approved the submitted version.

 Funding

This work was supported by the National Natural Science Foundation of China (no. 82003135) and the Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0147).

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1245650/full#supplementary-material

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