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 Primary Completion Date:||January 2014 (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.
|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|