Identification of BRCA1-associated DNA Repair Dysfunction in Patients With Early Triple Negative Breast Cancer Treated With Neoadjuvant Platinum-based Chemotherapy
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
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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
Russia: Ethics Committee