Technologies to Determine the Effectiveness of Experimental Drugs: Are Circulating Tumor Cells One Possible Solution?

Triple negative (TN) breast cancer, typically defined as estrogen- and progesterone- receptor negative and Her2 normal or not amplified, represents 10-15% of all breast cancers. This would mean that ~20,000-30,000 women will be diagnosed with TN breast cancer in the United States annually. Although TN cancers represent only a small proportion of all breast cancers it is responsible for a disproportionate number of breast cancer-related deaths. This subtype of breast cancer is unique in several ways: it typically affects younger women and is more prevalent in African-American women, particularly premenopausal AA women and in women who are carriers of BRCA-1 gene mutation. A common theme to these triple negative tumors is their impaired ability to repair DNA damage and their sensitivity to DNA damaging agents such as platinum chemotherapy. Elegant preclinical work has shown the effectiveness of further inhibiting DNA repair using PARP inhibitors in BRCA deficient tumors inducing a state of “synthetic lethality”.

Several clinical trials of PARP inhibitors are currently ongoing in breast cancer, and  we are using novel imaging and laboratory correlatives to answer a critical question of whether there is a dose- and schedule-dependent response in the tumor, using one of these experimental PARP inhibitors. Specifically, we are using novel imaging study, 3’-[F-18]Fluoro-3’-deoxythymidine Positron Emission Tomography (FLT-PET) scan to directly, yet non-invasively asses DNA damage in the tumor and obtaining circulating tumor cells, CTC, to determine the induction of the histone variant gH2AX as marker for increasing DNA damage.  We are also using  biomarkers in the tumor such as FANCD2 formation, BRCA1/2 and miR155, which could predict response to PARP inhibitors.

In this presentation, we wish to discuss the use of CTC and whether they can be used to predict the effectiveness of both the commonly used DNA damaging drugs, carboplatin alone or paclitaxel and carboplatin with an experimental, PARP inhibiting drug, ABT888.