TRIPLE-negative breast cancer (TNBC): A persistent global challenge

Breast cancer remains the most frequently diagnosed malignancy in women worldwide. TNBC—defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)—comprises ~15–20% of cases and is disproportionately represented among younger women, women of African ancestry, and carriers of germline BRCA1 mutations. Biologically, TNBC is highly heterogeneous and clinically aggressive, with early visceral/CNS relapse and poor survival; contemporary series place median overall survival (OS) for metastatic disease at roughly 9–17 months, despite sequential chemotherapy. Immune checkpoint inhibitors (e.g., pembrolizumab, atezolizumab) have improved outcomes for programmed death-ligand 1 (PD-L1)–positive subgroups, and antibody–drug conjugates such as sacituzumab govitecan prolong OS in refractory settings; nevertheless, progression is common and durable control remains uncommon, underscoring the need for new modalities and robust translational biomarkers [1–6].

Current biomarkers and their limitations

The TNBC biomarker landscape has real but limited clinical utility. Ki-67 is widely assessed, yet cross-laboratory variability hampers its reproducibility and clinical precision, even after international harmonization efforts. Tumor protein p53 (TP53) mutations occur in ~70–80% of TNBC and signal genomic instability and poor prognosis, but they are not directly actionable in routine practice. PD-L1 expression guides first-line immunotherapy selection; however, its predictive value diminishes once resistance emerges, and it incompletely captures the multifactorial biology of response and escape. Collectively, these gaps motivate biomarkers that both prognosticate and mechanistically reflect treatment efficacy [7–12].

Rationale for a three-layered translational panel

To encompass complementary TNBC hallmarks—intrinsic cell survival, extracellular-matrix (ECM) remodeling, and systemic circadian-immune regulation—we focus on (Survivin) BIRC5, CST3, and the MTNR1A:

• Survivin (BIRC5): apoptosis suppression and treatment resistance. Normally scarce in differentiated tissues, Survivin is re-expressed in cancer and coordinates apoptotic blockade (e.g., caspase inhibition) with mitotic progression. In TNBC, high Survivin associates with chemotherapy resistance, Epithelial-to-Mesenchymal Transition (EMT) /angiogenesis, and worse outcomes; preclinical inhibition restores chemosensitivity and triggers apoptosis. Its accessibility in tissue (Immunohistochemistry [IHC]) and plasma (Enzyme-linked immunosorbent assay (ELISA)) supports dual “solid + liquid” biomarker utility [13–15].
• Cystatin C: counter-regulation of cathepsin-driven invasion. Cystatin C is an endogenous inhibitor of cysteine cathepsins (B/L/S), proteases that degrade ECM, promote angiogenesis, and facilitate metastasis in breast cancer. Experimental models show Cystatin C can antagonize TGF-β–driven EMT, restrain invasion, and in some contexts suppress tumor progression; nonetheless, clinical integration in TNBC remains limited and mechanistic complexity persists, warranting prospective translational evaluation [16–20].
• Melatonin receptor MT1: circadian control and immune-inflammatory tuning. Disruption of nocturnal melatonin signaling in cancer is linked to pro-proliferative and pro-inflammatory programs (e.g., NF-κB/STAT3). In breast cancer—including TNBC—loss or low expression of MT1 has been observed, whereas higher MT1 levels correlate with more favorable prognosis in select cohorts. Melatonin/MT1 signaling can down-modulate oncogenic pathways and may indirectly intersect with Survivin regulation and protease–inhibitor balance, nominating MT1 re-expression as a plausible mechanistic and theranostic biomarker [21–25].

AminoSine TriComplex: A natural remedy with multifaceted mechanisms

In this context, AminoSineTriComplas a novel therapeutic candidate designed to complement existing treatment modalities for metastatic colorectal cancer (mCRC). This remedy combines the principles of classical medicine and homeopathy with cutting-edge nanotechnology to enhance therapeutic efficacy and minimize adverse effects. AminoSineTriComplex integrates bioactive compounds derived from traditional medicinal plants, including Epimedium, Chamomile, Rheum rhabarbarum, Ginseng (Panax ginseng), and Lingzhi (Ganoderma lucidum).The formulation leverages multiple mechanisms of action to target cancer cells and modulate the tumor microenvironments include Icariin, Apigenin, Chamazulene, Emodin, Ginsenoside Rg3, and Melatonin, which have been extensively studied for their anti-inflammatory, antioxidant, and anti-cancer properties. These compounds inhibit pivotal signaling pathways such as NF-κB, STAT3, and Wnt/β-catenin, which are critical for tumor proliferation.

Nanotechnology-enhanced bioavailability

A significant innovation in AminoSineTriComplex lies in its utilization of advanced nanotechnology to enhance the efficacy of its components. Many natural compounds, while potent in vitro, face challenges in clinical application due to poor water solubility and limited cellular uptake. To address this, AminoSineTriComplex employs bioextraction, alcoholic fermentation, and nanocatalytic methodologies to activate and optimize biomolecules. Techniques such as photo- and electrochemical activation, plasma activation, and REDOX activation are employed to ensure maximum therapeutic activity.

Study design and oversight

This was a prospective, open-label, non-randomized, controlled, multicenter clinical study conducted at three oncology centers (January 2023–June 2025). The protocol was approved by local Institutional Review Boards and conducted in accordance with the Declaration of Helsinki (2013 update) and ICH-GCP E6 (R2) guidelines; all participants provided written informed consent prior to any study-specific procedure [1,2].

Patients

Eligible adults (≥18 years) had histologically confirmed stage IV TNBC defined as ER and PR <1% and HER2-negative per contemporaneous American Society of Clinical Oncology / College of American Pathologists (ASCO/CAP) testing guidelines [3,4]. All patients had radiographic progression following pembrolizumab and were refractory to ≥4 prior chemotherapy lines (including a platinum salt, gemcitabine, vinorelbine, a taxane, and sacituzumab govitecan). Additional key criteria included measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and adequate marrow/organ function; exclusion criteria encompassed active autoimmune disease requiring systemic therapy, uncontrolled infection, or clinically significant cardiac dysfunction [5].

Treatment and intervention

Participants were assigned to one of two prespecified groups for 12 weeks or until progression, unacceptable toxicity, or withdrawal:

• Intervention arm (n=147): AminoTriComplex (ATC)* 4 capsules PO three times daily + metronomic cyclophosphamide 50 mg PO daily + propranolol 40 mg PO twice daily.
• Control arm (n=119): Metronomic cyclophosphamide 50 mg PO daily + propranolol 40 mg PO twice daily.

Supportive care was provided per institutional standards (ATC is a nanotechnology-enhanced, standardized phytocomplex; manufacturing/QC details are reported elsewhere in the manuscript).

Endpoints

Primary endpoint: Objective response rate (ORR) at week 12 per RECIST v1.1.

Secondary endpoints: (i) Progression-free survival (PFS) by investigator assessment; (ii) prespecified biomarker dynamics (Serum Survivin; Serum Cystatin C; tissue MT1/MTNR1A expression); (iii) change in ECOG status; (iv) safety per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. [5,6]

Biomarker assessments

Blood-based markers: Peripheral blood was obtained at baseline and at 2-week intervals (weeks 2, 4, 6, 8, 10, 12).

• Serum Survivin was quantified by sandwich ELISA following manufacturer instructions and established immunoassay methodology [7].
• Serum Cystatin C was measured by particle-enhanced immunonephelometry using an IFCC-traceable procedure, with internal QC across runs [8,9].
• Exploratory circulating tumor DNA (ctDNA)/cell-free DNA (ccfDNA) and circulating tumor cells (CTCs) were collected; CTCs were enumerated with the CellSearch® system per validated protocols [10,11].

Tissue-based markers: Image-guided core biopsies were obtained at baseline and week 12 where feasible. Formalin-fixed paraffin-embedded sections were stained for Survivin (nuclear), Cystatin C (cytoplasmic), and MT1 (membranous/cytoplasmic) using validated, catalog-specified antibodies and standardized antigen retrieval. Two board-certified pathologists, blinded to treatment assignment and timepoint, performed semi-quantitative scoring (H-score, intensity × % positive cells); discrepant reads were adjudicated by consensus.

Imaging

Contrast-enhanced computed tomography (CT) (chest/abdomen), magnetic resonance imaging (MRI) (breast and/or liver as indicated), and whole-body positron emission tomography/computed tomography (PET-CT) were obtained at baseline and week 12. Response was assessed per RECIST v1.1; metabolic response on PET-CT followed PET Response Criteria in Solid Tumors (PERCIST) (SUL/SUV-based) conventions with centralized QA on regions of interest [5,12] (Figures 1–3).

Sample size and statistical analysis

The study was powered to detect a 25% absolute difference in ORR between arms with 80% power and two-sided α=0.05, requiring ≥240 patients; n=266 were enrolled to cover attrition. Categorical variables were compared by χ² or Fisher’s exact tests; continuous variables by paired/unpaired t-tests as appropriate. Spearman coefficients summarized correlations among ΔSurvivin, ΔCystatin C, and ΔMT1. Time-to-event endpoints (PFS) used Kaplan–Meier methods with log-rank comparisons and Cox regression for hazard ratios with 95% CIs; proportional hazards were checked by Schoenfeld residuals. For the prespecified biomarker triad (Survivin↓, Cystatin C↑, MT1↑), multiple testing was controlled using Benjamini–Hochberg false discovery rate (FDR) (q=0.10). Analyses were performed in IBM SPSS Statistics v27 (IBM Corp., Armonk, NY) [13–16] (Figure 4–8), (Supplementary Figure 1, Mechanistic model).

For assay reproducibility, we specify vendors, catalog numbers, and lot numbers for all key reagents used in IHC and ELISA workflows. Primary/secondary antibodies were from Thermo Fisher Scientific; buffers/consumables were from Sigma-Aldrich and Fluka as indicated (Table 1). Unless otherwise noted, slides underwent deparaffinization, heat-induced epitope retrieval (HIER) with either citrate (pH 6.0) or Tris-EDTA (pH 9.0), endogenous peroxidase quench, serum blocking, primary antibody incubation, horseradish peroxidase (HRP)-conjugated secondary, DAB (3,3'-diaminobenzidine) development, hematoxylin counterstain, and mounting. Working dilutions and retrieval conditions are reported below. QC acceptance criteria were met for every lot, and all runs included positive/negative tissue controls.

A total of 266 patients with metastatic TNBC were enrolled: 147 in the intervention arm (AminoTriComplex + metronomic cyclophosphamide + propranolol) and 119 in the control arm (metronomic cyclophosphamide + propranolol). All had progressed after pembrolizumab and ≥4 prior lines.

Intervention (n=147): CR 21/147 (14.3%, 95% CI 9.1–20.8%); PR 47/147 (32.0%, 95% CI 24.5–40.2%); ORR 68/147 (46.3%, 95% CI 37.9–54.8%). Control (n=119): CR 4/119 (3.4%, 95% CI 0.9–8.4%); PR 11/119 (9.2%, 95% CI 4.7–15.9%); ORR 15/119 (12.6%, 95% CI 7.2–19.9%).

Median PFS (Intervention): 8.9 months (95% CI 7.5–10.4); Median PFS (Control): 3.4 months (95% CI 2.6–4.2); HR (Cox, adjusted): 0.42 (95% CI 0.30–0.60), p<0.001.

Primary multiplicity control for the prespecified triad used BH-FDR (q=0.10); Bonferroni sensitivity yielded concordant inferences. Correlations are reported as Spearman’s ρ (95% BCa CI) with exact p-values.

Introduction to the main findings

In this controlled clinical study of 266 heavily pretreated patients with advanced TNBC—all progressed after checkpoint blockade and multiple chemotherapies—we observed three convergent findings. First, adding AminoTriComplex (ATC) to a metronomic backbone (cyclophosphamide + propranolol) produced markedly higher clinical efficacy than the backbone alone: ORR 46.3% (68/147) vs 12.6% (15/119) and median PFS 8.9 vs 3.4 months with an adjusted HR 0.42 (95% CI 0.30–0.60; p<0.001). Second, this benefit was strongly associated with an a priori biomarker triad—Survivin↓, Cystatin C↑, and MT1 re-expression—present in 80.9% of responders versus 11.4% of non-responders. Third, paired biopsies documented decreased proliferation (Ki-67 Δmedian −41%), increased immune infiltration (CD8+ Δmedian +34 cells/HPF), and re-establishment of circadian signaling (MT1↑) in the intervention arm. Together, these data indicate that ATC engages coordinated biological reprogramming—reactivating apoptosis, re-balancing protease/anti-protease dynamics to suppress invasion, and restoring circadian-immune control—thereby translating into meaningful clinical benefit.

Contextualizing efficacy in refractory TNBC

TNBC remains one of the most aggressive and heterogeneous breast-cancer subtypes, with poor survival once resistance to chemotherapy and immunotherapy emerges. Contemporary cohorts progressing after standard regimens report median OS often <12–18 months, driven by early visceral/CNS relapses and multi-drug resistance [1–4]. Although antibody–drug conjugates (ADCs) such as sacituzumab govitecan and first-line chemo-immunotherapy (pembrolizumab in PD-L1–positive disease) improved outcomes in selected settings, most patients with post-immune checkpoint inhibitor (ICI) refractory TNBC still experience rapid progression and short PFS [5–8]. Against this backdrop, the absolute ORR gain (≈+33.7%) and PFS prolongation (8.9 vs 3.4 months) in our study are clinically meaningful, especially given the inclusion of patients resistant to both pembrolizumab and sacituzumab.

Our regimen layered ATC, a multi-component phototherapeutic enhanced for bioavailability, onto metronomic cyclophosphamide and propranolol. Metronomic chemotherapy can exert anti-angiogenic and immunomodulatory effects, while β-adrenergic blockade mitigates stress-driven adrenergic signaling that fosters tumor growth, invasion, and immunosuppression [9–12]. However, prior experience suggests that metronomic dosing and propranolol alone rarely achieve durable responses in advanced TNBC [13]. The performance observed here therefore points to synergy contributed by ATC, raising the question of how its biomarker modulation maps onto known resistance circuits.

Survivin downregulation as a central mechanism

Survivin (BIRC5), an inhibitor-of-apoptosis protein, is consistently linked to poor prognosis and chemoresistance in breast cancer, including TNBC [14–17]. It suppresses caspase activation, stabilizes mitosis, and protects cells from cytotoxic stress. High Survivin correlates with resistance to taxanes, anthracyclines, and platinum, and meta-analyses identify it as an independent predictor of inferior PFS/OS [16,17]. In our study, the intervention arm showed near-complete IHC loss of Survivin in re-biopsies and a median 62% fall in circulating levels; responders (CR/PR) consistently demonstrated the largest declines, supporting predictive utility. Mechanistically, several ATC constituents (e.g., apigenin, resveratrol, ginsenosides, melatonin) suppress NF-κB/STAT3 programs that drive Survivin transcription—a plausible route for the observed downregulation [18–21].

Cystatin C upregulation: re-balancing protease biology

Whereas Survivin captures intrinsic apoptosis resistance, Cystatin C reflects tumor–stroma crosstalk. Cystatin C is an endogenous inhibitor of cysteine cathepsins (B/L/S); these proteases degrade ECM, facilitate invasion/angiogenesis, and are frequently upregulated in TNBC, associating with metastasis and poor survival [22–25]. We observed marked Cystatin C increases in serum and tissue with ATC, versus declines or stability in over half of controls. Larger Cystatin C rises tracked with objective response and disease control, suggesting restoration of the protease–anti-protease balance as a metastasis-suppressive mechanism. Prior translational work shows Cystatin C can limit ECM degradation, temper pro-angiogenic signaling, and shape immune contexture, aligning with our imaging evidence of reduced metastatic progression in the intervention arm [23,26].

MT1 re-expression: circadian and immune restoration

The MT1 (MTNR1A) is a systemic-circadian axis seldom integrated into clinical TNBC biomarker panels. Loss of MT1 expression disconnects tumors from nocturnal melatonin and promotes pro-proliferative, pro-inflammatory states via NF-κB/STAT3 activation and impaired immune surveillance [27–29]. Here, MT1 re-appeared in ~68% of intervention patients by week 12, with membranous/cytoplasmic intensity correlating with response. This is mechanistically coherent: MT1 signaling can down-modulate NF-κB/STAT3, potentially lowering Survivin; circadian regulation also intersects with protease activity, offering a bridge to Cystatin C dynamics [19,27,30]. Thus, MT1 restoration is unlikely to be an epiphenomenon; rather, it may be an active mediator of therapeutic efficacy and a theranostic target for circadian oncology.

Integration of the biomarker triad

The Survivin↓ / Cystatin C↑ / MT1↑ triad was present in 80.9% of responders vs 11.4% of non-responders—an integrated signature spanning apoptosis, ECM remodeling, and circadian-immune regulation. Conceptually, this matches systems-oncology expectations: coordinated network shifts, not single-node inhibition, are often necessary to overcome polygenic resistance in TNBC [31]. Clinically, the triad offers a monitoring framework: (i) tissue IHC (Survivin, MT1) paired with (ii) serum assays (Survivin, Cystatin C) for real-time response tracking and potential early stopping/continuation decisions.

Comparison with existing literature

Most clinical TNBC studies have focused on Survivin as a negative prognostic marker; investigations of Cystatin C in breast cancer are sparse and generally preclinical or exploratory, and MT1 work has emphasized ER-positive disease or in vitro models [15–17,23–29,31]. To our knowledge, this is the first clinical demonstration of coordinated modulation of all three markers in post-ICI, multi-line refractory TNBC, aligning clinical endpoints (ORR, PFS) with multi-axis biology. The inclusion of phytochemical constituents (melatonin, ginsenosides, apigenin, resveratrol) parallels preclinical reports of multi-targeted anti-cancer effects; our data extend these findings by showing concordant biomarker shifts in patients with entrenched resistance [18–21,32].

Strengths and Limitations

Strengths include the sample size for a translational TNBC study (n=266), paired serum + tissue biomarker assessments, and multimodal correlation (IHC, ELISA, PET-CT), all under standardized methods. Limitations include the open-label, non-randomized design (selection/assessment bias), a 12-week window that emphasizes early dynamics over long-term survival, and the inability to attribute effects to individual ATC components. While the triad correlates with clinical benefit, causality requires randomized and mechanistic testing (e.g., causal mediation, time-varying modeling).

Clinical implications and future directions

The Survivin↓ / Cystatin C↑ / MT1↑ triad provides a workable translational panel that could function as a surrogate endpoint in future TNBC trials, enabling early identification of responders and real-time therapy adaptation. The results also revive circadian biology as a therapeutic axis in oncology. Next steps include randomized phase III confirmation, mediation analyses to dissect causal chains, and expansion to other aggressive cancers. Operationally, routine implementation would combine liquid biopsy (Survivin, Cystatin C) with standardized MT1 IHC, integrated into response-adaptive protocols.

In summary, ATC plus metronomic therapy yields substantial clinical benefit in refractory TNBC and does so through a novel biomarker triad that unites apoptosis restoration, protease inhibition, and circadian-immune re-engagement—a systems-level signature of therapeutic efficacy.

Future work will orthogonally validate the triad using multi-omics (transcriptomic/proteomic) integration and public datasets (PMID: 37798249; 37986230), and incorporate pre-registered causal mediation in a randomized design.

TNBC remains one of the most formidable clinical challenges in modern oncology. Patients who progress after multiple lines of chemotherapy and immune checkpoint inhibitors have extremely limited options and face poor outcomes. In this context, the present study provides important new insights by demonstrating that the addition of AminoTriComplex (ATC) to a backbone of metronomic cyclophosphamide and propranolol not only improves clinical response rates and progression-free survival but also induces a coordinated shift in tumor biology. The most novel and impactful discovery is the emergence of a translational biomarker triad—Survivin downregulation, Cystatin C upregulation, and MT1 receptor re-expression—that appears to represent a signature of therapeutic efficacy in advanced TNBC.

This triad captures three essential and complementary domains of cancer control. The loss of Survivin expression reflects a restoration of apoptotic potential and the dismantling of one of the most powerful anti-apoptotic mechanisms driving therapeutic resistance in TNBC. The increase in Cystatin C expression represents suppression of protease-driven extracellular matrix degradation and a reduction in metastatic potential, thereby shifting the balance of the tumor microenvironment away from invasion and dissemination. The re-expression of the MT1 melatonin receptor highlights the restoration of circadian and systemic regulatory signals that may influence both tumor cell metabolism and immune surveillance. Taken together, this biomarker constellation integrates intrinsic tumor cell-death pathways, microenvironmental remodeling, and circadian-immune regulation into a unified framework of therapeutic reprogramming.

Clinically, the significance of these findings is considerable. The intervention arm achieved an ORR of 46% compared to only 12% in controls, and PFS was nearly tripled (8.9 vs 3.4 months). Importantly, these outcomes were not random but closely associated with the biomarker triad, which was present in over 80% of responders but only 12% of non-responders. Thus, the triad may serve as a powerful surrogate endpoint, enabling early identification of patients most likely to benefit. It also opens new opportunities for biomarker-driven trial design and for the personalization of treatment strategies in TNBC.

From a scientific perspective, this work underscores the value of systems-based approaches that move beyond single-target strategies. By integrating apoptosis, protease inhibition, and circadian biology, AminoTriComplex demonstrates that multi-component, phytochemical-based interventions can exert meaningful clinical and biological effects even in the most resistant cancers. These results encourage future investigations into the mechanistic interactions among Survivin, Cystatin C, and MT1, as well as exploration of whether this biomarker triad is relevant in other aggressive tumor types.

In conclusion, this trial establishes AminoTriComplex combined with metronomic therapy as a promising approach for advanced TNBC and introduces a novel translational biomarker triad as both a mechanistic explanation and a potential clinical tool. By bridging apoptosis restoration, metastasis suppression, and circadian regulation, the triad offers a new paradigm for understanding and monitoring therapeutic response. These findings lay the groundwork for larger randomized studies and for the development of biomarker-guided strategies that could finally shift the trajectory of treatment in advanced TNBC.

Written informed consent was obtained from all patients for publication.

ADC: Antibody:Drug Conjugate; AMPK: AMP-Activated Protein Kinase; ASCO/CAP: American Society of Clinical Oncology/College of American Pathologists; ATC: Amino Tricomplex; BC: Breast Cancer;
BICR: Blinded Independent Central Review; BIRC5: Baculoviral IAP Repeat Containing 5 (Survivin); BRCA1: Breast Cancer Gene 1; CI: Confidence Interval; CNS: Central Nervous System; CR: Complete Response; CT: Computed Tomography; CTCAE v5.0: Common Terminology Criteria for Adverse Events, version 5.0; CTC: Circulating Tumor Cell; ctDNA: Circulating Tumor DNA; cfDNA/ccfDNA: Cell-Free / Circulating Cell-Free DNA; CST3: Cystatin C (gene symbol); DCR: Disease Control Rate (CR+PR+SD); ECM: Extracellular Matrix; ECOG: Eastern Cooperative Oncology Group (Performance Status); EAIR: Exposure-Adjusted Incidence Rate; ELISA: Enzyme-Linked Immunosorbent Assay; EMT: Epithelial-Mesenchymal Transition; ER: Estrogen Receptor; FDR: False Discovery Rate; GCP / ICH-GCP: Good Clinical Practice / International Council for Harmonisation: GCP; GMP: Good Manufacturing Practice; HR: Hazard Ratio; HPF: High-Power Field (microscopy); H-score: Histologic Immunoreactivity Score (intensity × % positive cells); ICI: Immune Checkpoint Inhibitor; CH Q1A(R2): ICH Guideline Q1A(R2): Stability Testing of New Drug Substances and Products; IHC: Immunohistochemistry; IPTW: Inverse Probability of Treatment Weighting; K-M (KM): Kaplan-Meier; mTOR/PI3K/AKT: Mammalian Target of Rapamycin / Phosphoinositide-3-Kinase / Protein Kinase B pathway; MRI: Magnetic Resonance Imaging; MT1 (MTNR1A): Melatonin Receptor 1A; NF-κB: Nuclear Factor kappa-B; NK cell: Natural Killer cell; NO: Nitric Oxide; OR: Odds Ratio; ORR: Objective Response Rate; OS: Overall Survival; PD: Progressive Disease; PD-L1: Programmed Death-Ligand 1; PERCIST: PET Response Criteria in Solid Tumors; PET-CT: Positron Emission Tomography:Computed Tomography; PFS: Progression-Free Survival; PR (response): Partial Response; PR: Progesterone Receptor; QC: Quality Control; RECIST v1.1: Response Evaluation Criteria in Solid Tumors, version 1.1; RCT: Randomized Controlled Trial; SD: Stable Disease; SOP: Standard Operating Procedure; STAT3: Signal Transducer and Activator of Transcription 3; SUL/SUV/SUVmax: Standardized Uptake Values (lean body mass-adjusted / generic / maximum) on PET; TNBC: Triple-Negative Breast Cancer; TGF-β: Transforming Growth Factor-beta; G1:2 / ≥G3: Grade 1:2 (mild:moderate) / Grade ≥3 (severe) adverse events (CTCAE); Triad: The predefined biomarker signature: Survivin↓ / Cystatin C↑ / MT1↑

Ethics approval

Approved by IRB #CN-2021-11, #TX-UT-2021-08.

Competing interests

None declared.

Funding

Institute for Personalized Medicine, Tbilisi, Georgia and Foconsci Chemical Industry, Department of Biotechnology, China.

Authors’ contributions

All authors contributed equally to study design, patient management, and manuscript preparation.

Acknowledgments

We thank the patients, clinical teams, and laboratory staff for their dedication.