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 ]
  

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.