Abstract 2023: Whole exome and RNA sequencing reveals genetic alterations in DNA damage and homologous recombination pathways in triple negative breast cancer.
Authors: Wong Shukmei , O'Shaughnessy Joyce A. , LoRusso Patricia , Aldrich Jessica , Kurdoglu Ahmet , Christoforides Alexis , Dinh Jennifer , Izatt Tyler , Sinari Shripad , Baker Angela , Moses Tracy M. , Salhia Bodour , Mousses Spyro , Kiefer Jeffrey , Trent Jeffrey M. , Von Hoff Daniel , Shapiro Geoffrey , Liang Winnie , Craig David W. , Carpten John D. 
Published: August 2014

Triple negative breast cancer (TNBC), is characterized by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2). TNBC comprises about 15 of all breast cancer diagnoses, but ∼25% of deaths. TNBC has a more aggressive clinical course and long-term disease-free survival is poor. As is well known, tumors that develop in women who carry deleterious germline BRCA mutations typically have tumors characteristic of the basal-like TNBC phenotype associated with defects in double stand break repair and homologous recombination. These observations have led to the development of therapeutic strategies aimed at these mechanisms, such as PARP inhibitors, which are in mature stages of drug development for the treatment of a subset of patients diagnosed with mTNBC. Iniparib, although not believed to be a true PARP inhibitor, is believed to act through a similar mechanism of action.

We have completed a study of whole genome and transcriptome sequencing of 14 patients with metastatic triple negative breast cancer (mTNBC). One patient who was sequenced had a complete response to a combination including gemcitabine, carboplatin, and iniparib prior to sequencing. Sequencing analysis revealed a collection of somatic mutations and alterations in genes associated with DNA repair and homologous recombination, including DCLRE1C, MEI1, TP53, DDB1, RIF1, ZBTB40, BRIP1, and BRCA2. Furthermore, RNA-seq expression analysis demonstrated significant underexpression of BRCA1. Thus, these alterations may serve as markers that can be predictive of responders from non-responders of treatment regimens including iniparib or possibly PARP inhibitors.

To begin to identify a genomic profile indicative of PARP response, tumors and blood of four additional mTNBC patient samples were collected and subjected to whole exome and RNA sequencing. We have also obtained the mutational data of TNBC tumors sequenced by the Cancer Genome Atlas. The genetic profiles of these tumors will be compared to the previously sequence mTNBC sample that responded to iniparib to determine the frequency of these specific events in mTNBC. Through this work we hope to identify a genetic profile that can serve as a possible predictor of response to iniparib or true PARP inhibitors.

Citation Format: Shukmei Wong, Joyce A. O'Shaughnessy, Patricia LoRusso, Jessica Aldrich, Ahmet Kurdoglu, Alexis Christoforides, Jennifer Dinh, Tyler Izatt, Shripad Sinari, Angela Baker, Tracy M. Moses, Bodour Salhia, Spyro Mousses, Jeffrey Kiefer, Jeffrey M. Trent, Daniel Von Hoff, Geoffrey Shapiro, Winnie Liang, David W. Craig, John D. Carpten. Whole exome and RNA sequencing reveals genetic alterations in DNA damage and homologous recombination pathways in triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2023. doi:10.1158/1538-7445.AM2013-2023