The Study of Quadruple Therapy Quercetin, Zinc, Metformin, and EGCG as Adjuvant Therapy for Early, Metastatic Breast Cancer and Triple-negative Breast Cancer, a Novel Mechanism

Study Overview
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Brief Summary
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breast cancer is the most common cancer in women. With more than 1 in 10 new cancer diagnoses each year, It is the second most frequent cancer-related death among women worldwide. Breast cancer develops slowly, and the majority of cases are found through routine screening. breast cancer-causing deaths among women all over the world and increased in the last few years even though the treatment is advanced like immunotherapy chemotherapy by yet no treatment for triple-negative breast cancer zinc and competition between znt1 and zip6,10 at breast cancer cells. Is zinc ionophore like quercetin and EGCG has a role, In a novel experimental study zinc is a trace metal that has many roles in cells, enzymatic activity, and gene regulations, and also for the integrity of DNA. Zinc transporters (zinc related -proteins such as ZIPs, and ZnTs are affected by triggers factors like cytokines and growth factors. There are two large families of zinc transporters like ZIPs ( 14 members) and ZnTs family (10 members), ZIPS family cause an influx of zinc from the extracellular to the cytoplasm and also from intracellular organelles like endoplasmic reticulum or Golgi or mitochondria in contrast to ZnTs which cause an influx of zinc from the cytoplasm to intracellular organelles. ( lower cytoplasmic zinc) (1) Breast cancer deaths occurred from metastasis; Catalytic enzymes called proteases like cathepsin L are frequently overexpressed in aggressive cancers. Breast tumor metastatic potential is correlated with macrophage presence. These macrophages associated with tumors frequently adopt an M2-like pro-tumorigenic phenotype, which results in the production of growth hormones and proteases, notably the lysosomal protease cathepsin L. Because cathepsin L is commonly released by breast cancer cells and aids in tumor invasion, metastasis, and angiogenesis. It is expected that cathepsin L secretion by both tumor-associated macrophages and neoplastic cells would promote the metastatic phenotype because cathepsin L is widely produced by breast cancer cells and helps with tumor invasion, metastasis, and angiogenesis. (2) this study target new mechanisms and achieves the best management as some types of cancer breast like triple-negative breast cancer (TNBC) no definite treatment so we target the following pathways and epigenetic processes by these adjuvant compounds which have a promising role in the immunity like EGCG, Quercetin, Zinc, Metformin so our team will discuss novel methods to achieve the best efficacy from chemotherapy

Detailed Description
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breast cancer is the most common cancer in women. With more than 1 in 10 new cancer diagnoses each year, It is the second most frequent cancer-related death among women worldwide. Breast cancer develops slowly, and the majority of cases are found through routine screening. breast cancer-causing deaths among women all over the world and increased in the last few years even though the treatment is advanced like immunotherapy chemotherapy by yet no treatment for triple-negative breast cancer zinc and competition between znt1 and zip6,10 at breast cancer cells. Is zinc ionophore like quercetin and EGCG has a role, In a novel experimental study zinc is a trace metal that has many roles in cells, enzymatic activity, and gene regulations, and also for the integrity of DNA. Zinc transporters (zinc related -proteins such as ZIPs, and ZnTs are affected by triggers factors like cytokines and growth factors. There are two large families of zinc transporters like ZIPs ( 14 members) and ZnTs family (10 members), ZIPS family cause an influx of zinc from the extracellular to the cytoplasm and also from intracellular organelles like endoplasmic reticulum or Golgi or mitochondria in contrast to ZnTs which cause an influx of zinc from the cytoplasm to intracellular organelles. ( lower cytoplasmic zinc) (1) Breast cancer deaths occurred from metastasis; Catalytic enzymes called proteases like cathepsin L are frequently overexpressed in aggressive cancers. Breast tumor metastatic potential is correlated with macrophage presence. These macrophages associated with tumors frequently adopt an M2-like pro-tumorigenic phenotype, which results in the production of growth hormones and proteases, notably the lysosomal protease cathepsin L. Because cathepsin L is commonly released by breast cancer cells and aids in tumor invasion, metastasis, and angiogenesis. It is expected that cathepsin L secretion by both tumor-associated macrophages and neoplastic cells would promote the metastatic phenotype because cathepsin L is widely produced by breast cancer cells and helps with tumor invasion, metastasis, and angiogenesis. (2) this study target new mechanisms and achieves the best management as some types of cancer breast like triple-negative breast cancer (TNBC) no definite treatment so we target the following pathways and epigenetic processes by these adjuvant compounds which have a promising role in the immunity like EGCG, Quercetin, Zinc, Metformin so our team will discuss novel methods to achieve the best efficacy from chemotherapy the study will include 100 cases with many types of breast cancer like hormonal sensitive, triple negative, and metastatic breast cancer, and another group of 100 patients not given this adjuvant therapy type of study is a randomized clinical control trial interventional with 4 compounds (EGCG,ZINC, QUERCETIN,METFORMIN)

Official Title
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The Study of Quadruple Therapy Quercetin, Zinc, Metformin, and EGCG as Adjuvant Therapy for Early, Metastatic Breast Cancer and Triple-negative Breast Cancer, a Novel Mechanism

Conditions
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Breast Cancer Female, Triple Negative Breast Cancer

Intervention / Treatment
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* Combination Product: quercetin, EGCG, metformin , zinc


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 Female patients with any type of breast cancer Ductal carcinoma in situ (DCIS) ... Invasive breast cancer (ILC or IDC) ... Triple-negative breast cancer. ... Inflammatory breast cancer. ... Paget disease of the breast. ... Angiosarcoma. ... Phyllodes tumor. HER2-positive by ASCO CAP 2018 guidelines, confirmed by central testing Participants must have normal organ and marrow function as defined below: ANC ≥ 1000/mm3 hemoglobin ≥8 g/dl platelets ≥ 75,000/mm3 AST and ALT both <5x institutional ULN Total bilirubin ≤ 1.5 mg/dL. For patients with Gilbert syndrome, the direct bilirubin should be <institutional ULN Serum creatinine ≤ 2.0 mg/dL OR calculated GFR ≥ 30mL/min 6- Locally advanced tumors at diagnosis, including tumors fixed to the chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge) Patients with a history of previous invasive breast cancer. - Exclusion Criteria: Neoadjuvant or adjuvant chemotherapy for this breast cancer prior to enrollment is prohibited. Any of the following due to teratogenic potential of the study drugs: Pregnant women Nursing women Women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragms, IUDS, surgical sterilization, abstinence, etc). Hormonal birth control methods are not permitted. Participants who are receiving any other investigational agents for treatment of breast cancer, unless specific approval is obtained from the Sponsor-Investigator. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: adjuvant quadruple thearpy of quercetin , zinc, EGCG, metformin for 100 breast cancer cases<br>experimental study of adjuvant quadruple therapy of quercetin, zinc, EGCG, and metformin for 100 cases of different types of breast cancer women daily dose as follows daily 500 mg orally quercetin OD daily 50 mg zinc sulfate orally OD daily 300 mg EGCG orally OD daily metformin 850 mg orally OD during chemotherapy courses and until last stage of treatment | Combination Product: quercetin, EGCG, metformin , zinc<br>* this intervention target many mechanisms at tumorigenesis, metastasis autophagy, apoptosis, interleukin 6, cathepsin L, and also epigenetic DNA methylation<br>|
| Experimental: no adjuvant thearpy for 100 cases of breast cancer breast for this group ( controlled group )<br>this arm ( 100 cases controlled group not taken adjuvant therapy only was taken the regular chemotherapy as prescription | Combination Product: quercetin, EGCG, metformin , zinc<br>* this intervention target many mechanisms at tumorigenesis, metastasis autophagy, apoptosis, interleukin 6, cathepsin L, and also epigenetic DNA methylation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| invasive Disease Free Survival at 3 Years from the time of randomization until the occurrence of the first of the following events: invasive local/regional recurrence, Contralateral invasive breast cancer, Distant recurrence, Death from any cause | Kaplan-Meier estimates of iDFS will be estimated and plotted with the corresponding 95% confidence intervals. from the time of randomization until the occurrence of the first of the following events: invasive local/regional recurrence, Contralateral invasive breast cancer, Distant recurrence, Death from any cause | Time Frame: 3 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease Free Survival at 10 Years | Kaplan-Meier estimates of iDFS will be estimated and plotted with the corresponding 95% confidence intervals. from the time of randomization until the occurrence of the first of the following events: invasive local/regional recurrence, Contralateral invasive breast cancer, Distant recurrence, Death from any cause | 10 years | 
| Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE v5.0 [ | NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting | 5 years | 
| Total patient chair time of drug administration | Mean difference will be estimated between HP FDC SC and IV admin of HP in sub-study | 18 months | 
| Breast cancer-specific survival (BCSS) at 10 Years | the time period between randomization and death due to breast cancer. | 10 years |