Study of CYP2C19 and ALDH3A1 Polymorphisms in Breast Cancer Patients

Breast Cancer Patients Clinical Trial

Official title:

Pharmacogenetic Risk Factors of Doxorubicin-Cyclophosphamide Chemotherapy Related Toxicities in Breast Cancer Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04581967
• Other study ID #: 201819010.4
• Status: Recruiting
• Start date: October 15, 2020
• Est. completion date: January 15, 2021

Study information

• Verified date: August 2020
• Source: Damanhour University
• Contact: Hoda Salem, Ass. Prof
• Phone: 00201000007613
• Email: hsalem[@]ut.edu.sa
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Genetic polymorphisms of metabolic enzymes may influence the metabolism of Doxorubicin-Cyclophosphamide regimen in breast cancer patients.

the investigators want to

1. evaluate the frequency or incidence of the genetic polymorphisms of CYP2C19 and ALDH3A1 in breast cancer patients, and

2. analyze the association between the genetic polymorphisms of CYP2C19 and ALDH3A1 and toxicities in breast cancer patients treated by Doxorubicin-Cyclophosphamide regimen therapy.

Description:

Breast cancer refers to the erratic growth and proliferation of cells that originate in the breast tissue, most commonly from the inner lining of milk ducts (ductal cancers) or the lobules that supply the ducts with milk (lobular cancers). Breast cancer is about 100 times more common in women than in men, although males tend to have poorer outcomes due to delays in diagnosis. Alteration in hormonal level and Family history of breast cancer are risk factors for breast cancer.

The classic symptom for breast cancer is a lump found in the breast or armpit. Doing monthly breast self-exam (BSE) is a great way to be familiar with the breasts' texture, cyclical changes, size, and skin condition. Breast cancer is usually diagnosed by biopsy of nodule detected by mammogram or by palpitation.

Today there are so many approaches, which can be made for the treatment of breast cancer such as surgery, radiation therapy, chemotherapy, hormonal therapy and recently nanotechnology and gene therapy. Chemotherapy is the use of anti-cancer drugs to treat cancerous cells. The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment.

Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. Four cycles of doxorubicin and cyclophosphamide (AC) chemotherapy regimen has become a standard regimen. No chemotherapy regimen administered for four cycles has proven to be superior to AC. The undeniable advantage of this therapy scheme is low cost of treatment, its proven efficacy and mostly acceptable toxicity. Hematological (neutropenia and anemia) and gastrointestinal (nausea, vomiting and mucositis) toxicities are common in patients treated with AC regimen.

Doxorubicin is metabolized by the CBR (carbonyl reductase) enzymes to its active component. Similarly cyclophosphamide, the cell cycle nonspecific prodrug, requires activation by a number of different cytochrome P450 enzymes, mainly of CYP2C family. The transport systems are also crucial for the treatment outcome, as both importers and exporters are responsible for the cellular drugs' concentration. It is expected that any variation that affects metabolic enzymes and transporter activity would be reflected in not only the response to treatment, but also in the development of drug-related toxicity. Each of these enzymes and transporter genes is known to exhibit a degree of genetic variation, characterized by single nucleotide polymorphisms (SNPs). In particular, there have been few investigations of the possible influence of variations in the genes encoding transporters and drug metabolizing enzymes relevant for the two drugs.

Pharmacogenomic analysis offers the promise that personalized regimens may be identified for individuals who might have more favorable outcomes with certain chemotherapies. Specifically, because genetic variation in metabolic enzymes is one determinant of drug concentration, pharmacogenomics has been proposed as an approach to tailor drug choice or dose to optimize efficacy and reduce toxicity of cancer treatments.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: January 15, 2021
• Est. primary completion date: December 15, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Confirmed diagnosis of breast cancer.

2. Age ranging from 18 to 75 years old female.

3. Patients will take Doxorubicin-Cyclophosphamide regimen as chemotherapy treatment.

Exclusion Criteria:

1. Any other malignancy.

2. Previous treatment for metastatic disease.

3. Pregnancy or breastfeeding female.

4. Inadequate bone marrow and cardiac function.

5. Serious or uncontrolled medical conditions.

Related Conditions & MeSH terms

• Breast Cancer Patients
• Breast Neoplasms

Intervention

Genetic:
• polymorphism analysis
DNA will be purified from whole blood samples by commercial DNA isolation kits. Genotyping and genetic polymorphism detection for some metabolic enzymes genes will be performed by real time PCR.

Drug:
• Doxorubicin-Cyclophosphamide regimen
Treatment with a combination of Doxorubicin and Cyclophosphamide, This regimen comprises 60 mg/m² Doxorubicin and 600 mg/m² Cyclophosphamide administered intravenously on day 1 of each 21-day cycle, and repeated for a total of four cycles.

Locations

Country	Name	City	State
Egypt	National Cancer Institute	Cairo

Sponsors (3)

Lead Sponsor	Collaborator
Damanhour University	Al-Azhar University, National Cancer Institute, Egypt

Country where clinical trial is conducted

Egypt, 

References & Publications (6)

Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AV. Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer. 2010 Mar 16;102(6):1003-9. doi: 10.1038/sj.bjc.6605587. Epub 2010 Feb 23. — View Citation

Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. — View Citation

Montoya JE, Luna HG, Morelos AB, Catedral MM, Lava AL, Amparo JR, Cristal-Luna GR. Association of creatinine clearance with neutropenia in breast cancer patients undergoing chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC). Med J Malaysia. 2013 Apr;68(2):153-6. — View Citation

Sharma GN, Dave R, Sanadya J, Sharma P, Sharma KK. Various types and management of breast cancer: an overview. J Adv Pharm Technol Res. 2010 Apr;1(2):109-26. — View Citation

Tecza K, Pamula-Pilat J, Lanuszewska J, Butkiewicz D, Grzybowska E. Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients. Oncotarget. 2018 Jan 10;9(10):9114-9136. doi: 10.18632/oncotarget.24148. eCollection 2018 Feb 6. — View Citation

Zhou X, Qiao G, Wang X, Song Q, Morse MA, Hobeika A, Gwin WR, Ren J, Lyerly HK. CYP1A1 genetic polymorphism is a promising predictor to improve chemotherapy effects in patients with metastatic breast cancer treated with docetaxel plus thiotepa vs. docetaxel plus capecitabine. Cancer Chemother Pharmacol. 2018 Feb;81(2):365-372. doi: 10.1007/s00280-017-3500-9. Epub 2017 Dec 14. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The frequency of the genetic polymorphisms of CYP2C19 in breast cancer patients	the blood samples will be DNA extracted using DNA extraction kit then single nucleotide polymorphisms of CYP2C19 gene will be detected by real time PCR	Up to 24 weeks
Primary	The frequency of the genetic polymorphisms of ALDH3A1 in breast cancer patients	the blood samples will be DNA extracted by DNA extraction kit then single nucleotide polymorphisms of ALDH3A1 gene will be detected by real time PCR	Up to 24 weeks
Secondary	Correlation between genetic polymorphisms of CYP2C19 and toxicities from Doxorubicin-Cyclophosphamide regimen therapy	the blood samples will be DNA extracted using DNA extraction kit then single nucleotide polymorphisms of CYP2C19 gene will be detected by real time PCR	up to 24 weeks
Secondary	Correlation between genetic polymorphisms of ALDH3A1 and toxicities from Doxorubicin-Cyclophosphamide regimen therapy	the blood samples will be DNA extracted by DNA extraction kit then single nucleotide polymorphisms of ALDH3A1 gene will be detected by real time PCR	up to 24 weeks