Homologous recombination defects in sporadic breast cancers

Abstract

22102 Background: Homologous Recombination (HR) is the only mechanism that can reliably repair double-strand DNA breaks. Alternative DNA repair mechanisms, such as non-homologous end joining exist, but these induce DNA mutations and chromosomal aberrations. Hence, tumors that have deregulating mutations in the key players of HR are extremely sensitive to DNA damaging agents, such as bifunctional alkylators and are targeted specifically by Poly(ADP-ribose) Polymerase (PARP) inhibiting drugs. Defects in homologous recombination arise through dysfunction of BRCA1 or BRCA2 or by abnormalities in the Fanconi Anemia pathway. In addition, the recently discovered oncogene EMSY is amplified in a subgroup of breast tumors and blocks HR by inactivating the Brca2 protein. HR defects have been reported to be present in up to 30% of sporadic breast cancers. This study was designed to develop a clinically useful test to identify patients with tumors deficient in homologous recombination. Methods: We have prospectively tested 38 HER2-negative breast cancers scheduled for preoperative chemotherapy. Evidence of a HR defect was sought by A) sequencing of the BRCA1 gene in triple-negative tumors; B) analysis of the expression levels of BRCA1, FANCC and FANCF by quantitative RT-PCR; and C) analysis of the amplification status of the EMSY gene by FISH and/or Multiplex Ligation-dependent Probe Amplification (MLPA). Results: Nine out of 38 tumors (24) had evidence of an HR defect, 5 were triple-negative and 4 ER+/HER2- (luminal). Conclusions: Some 20% of sporadic breast cancers may be defective in HR. Triple-negative tumors are predominantly associated with low BRCA1-expression, luminal tumors with low expression of one of the Fanconi anemia proteins. An update of this ongoing study will be presented. Detected abnormalities in the nine individual samples Subtype BRCA1 Sequence BRCA1 Expression FANC C Expression FANC F Expression EMSY Amplification triple-negative mutation low low low normal triple-negative normal low normal normal normal triple-negative normal low normal normal normal triple-negative normal low normal normal normal triple-negative normal normal normal low NA luminal not done normal normal normal amplified luminal not done low low normal normal luminal not done normal low normal normal luminal not done normal low normal normal No significant financial relationships to disclose.