BRCA1-associated DNA Repair Dysfunction in Patients With Early Triple Negative Breast Cancer Treated With Neoadjuvant Platinum-based Chemotherapy

Identification of BRCA1-associated DNA Repair Dysfunction in Patients With Early Triple Negative Breast Cancer Treated With Neoadjuvant Platinum-based Chemotherapy

The purpose of this study is to assess efficacy of platinum-based neoadjuvant chemotherapy in correlation with BRCA1-associated DNA repair dysfunction in patients with early triple negative breast cancer.

Study Overview

• Status: Completed
• Conditions: Early Triple Negative Breast Cancer
• Intervention / Treatment: Drug: Doxorubicin, Paclitaxel, Cisplatin

Detailed Description

Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 ("triple-negative" phenotype). Therefore, patients with basal-like cancers do not benefit from currently available targeted systemic therapy.

There is a lot of evidence about a link between basal-like breast cancer and BRCA1 deficiency. Many clinical characteristics and molecular features are shared by basal-like breast cancers and tumors that arise in carriers of BRCA1 germline mutations.

Some studies have indicated that BRCA1 mRNA expression was lower in basal-like sporadic cancers than in controls matched for age and grade. BRCA1 is rarely mutated in sporadic breast cancers and, therefore, it is believed that this may be a result of epigenetic mechanisms such as acquired methylation of the BRCA1 gene promoter or a dysfunction in the pathways that regulate BRCA1 expression, such as overexpression of ID4. The profound similarities between hereditary BRCA1-related breast tumors and basal-like tumors strongly implicate a fundamental defect in the BRCA1 or associated DNA-repair pathways (p53, PTEN) in sporadic basal-like tumors.

There is increasing evidence that the BRCA1-related DNA-repair defects, especially defective homologous recombination, determines sensitivity to certain agents, such as platinum salts-based chemotherapy. The complexity in downregulation of BRCA1 expression suggests that these approaches may only be effective in the treatment of a subset of sporadic basal-like cancers. Identification of specific markers for these cancers will be essential to translate an understanding of defective DNA repair into targeted treatments for this poor prognosis subtype.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115478
    • Russian Cancer Research Center named after N.N.Blokhin RAMS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Female patients, age ≥18 years≤75;
2. Histologically confirmed invasive ER-, PR-, and HER2-negative (triple- negative) adenocarcinoma of the breast;
3. Clinical stage T1-2, N0-1, M0.

Exclusion Criteria:

1. Previous treatment for this breast cancer
2. History of malignancy treated with curative intent within the previous 5 years with the exception of skin cancer, cervical carcinoma in situ, or follicular thyroid cancer. Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease
3. Pregnancy or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant platinum-based chemotherapy; Doxorubicin, Paclitaxel, Cisplatin	Drug: Doxorubicin, Paclitaxel, Cisplatin; Doxorubicin 25 mg/m2, IV weekly. Number of Cycles: 8 Paclitaxel 100 mg/m2, IV weekly. Number of Cycles: 8. Cisplatin 30 mg/m2, IV weekly. Number of Cycles: 8.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The pathological complete response rate to neoadjuvant platinum-based chemotherapy	Pathologic treatment response will be assessed in correlation with BRCA1-associated DNA repair dysfunction signature.	after 8 weeks of neoadjuvant chemotherapy

Secondary Outcome Measures

Outcome Measure	Time Frame
Disease-free survival	3 years
Clinical responses to neadjuvant chemotherapy	after 8 weeks of neoadjuvant chemotherapy

Other Outcome Measures

Outcome Measure	Time Frame
Number of patients with 3/4 Grade CTC adverse events to assess toxicity and tolerability of the chemotherapy regimen	after 8 weeks of neadjuvant chemotherapy

Collaborators and Investigators

• Sponsor: Russian Academy of Medical Sciences

Publications and helpful links

Helpful Links

• Breast Cancer, Neoadjuvant Chemotherapy
• Doxorubicin, Paclitaxel, Cisplatin

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: August 16, 2012
• First Submitted That Met QC Criteria: August 22, 2012
• First Posted (Estimate): August 27, 2012

Study Record Updates

• Last Update Posted (Estimate): November 3, 2015
• Last Update Submitted That Met QC Criteria: November 1, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Paclitaxel; Cisplatin; Doxorubicin
• Other Study ID Numbers: TNNP 001 (Other Identifier: Russian Cancer Research Center named after N.N.Blokhin RAMS)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No