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.
Early Triple Negative Breast Cancer
Drug: Doxorubicin, Paclitaxel, Cisplatin
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Identification of BRCA1-associated DNA Repair Dysfunction in Patients With Early Triple Negative Breast Cancer Treated With Neoadjuvant Platinum-based Chemotherapy|
- The pathological complete response rate to neoadjuvant platinum-based chemotherapy [ Time Frame: after 8 weeks of neoadjuvant chemotherapy ] [ Designated as safety issue: No ]Pathologic treatment response will be assessed in correlation with BRCA1-associated DNA repair dysfunction signature.
- Disease-free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- Clinical responses to neadjuvant chemotherapy [ Time Frame: after 8 weeks of neoadjuvant chemotherapy ] [ Designated as safety issue: No ]
- Number of patients with 3/4 Grade CTC adverse events to assess toxicity and tolerability of the chemotherapy regimen [ Time Frame: after 8 weeks of neadjuvant chemotherapy ] [ Designated as safety issue: Yes ]
|Study Start Date:||August 2011|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01672671
|Contact: Mona Frolova, PhDfirstname.lastname@example.org|
|Contact: Ekaterina Ignatovaemail@example.com|
|Russian Cancer Research Center named after N.N.Blokhin RAMS||Recruiting|
|Moscow, Russian Federation, 115478|
|Contact: Mona Frolova, PhD +74993241880 firstname.lastname@example.org|
|Contact: Ekaterina Ignatova +74993241900 email@example.com|
|Principal Investigator: Mona Frolova, PhD|