Early Triple Negative Breast Cancer Clinical Trial
Official title:
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.
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.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment