Abstract P1-11-15: Improving Patient Accrual to “Window of Opportunity” Trials
Authors: Kalinsky K , Crew KD , Feldman SM , Taback B , Joseph K-AP , Hibshoosh H , Refice S , Maurer M , Hershman DL. 
Published: April 2011

Background: A challenge in evaluating new targeted investigational agents is procuring tumor tissue to measure the direct biologic effect on tumor cells. Pre-surgical studies, i.e. “window of opportunity” trials, in women with newly diagnosed, operable breast cancer (BC) provide an opportunity to assess the biologic impact of new agents on human tissue. The study drug is taken between the time of diagnostic biopsy and definitive surgical resection (approx 2-4 weeks). Pre-and post-treatment blood and tumor tissue are collected to evaluate for biomarker modulation. While these trials are appealing, conducting them can be difficult. We present the evolution of a multidisciplinary pre-surgical program, focusing on “lessons learned” with regard to patient accrual, improving tissue acquisition, and maintaining quality control.

Material and Methods: We have completed 2 pre-surgical studies (anastrazole, polyphenon E), with 1ongoing (metformin).The Recruitment Core is a shared NCI cancer center resource that identifies and screens participants for active studies. Charts of women with newly diagnosed BC are screened for eligibility. If a patient is deemed appropriate by the surgeon, she is introduced to the recruiters, and the medical oncology research team evaluates the patient that day. Once consented, the patient undergoes blood collection and clinical evaluation prior to study drug usage (same day or next). The research staff contacts the patient by phone weekly to assess toxicities and ensure medication adherence. The patient presents the day of or prior to surgery for blood work and clinical examination. The post-treatment surgical resection tissue (paraffin embedded and frozen) is collected for biomarker analysis.

Results: We have enrolled 52 patients to 3 trials: 10 at a rate of 2.5/month, 25 at 1.5/month, and 17 at 2.5/month. Stress from the diagnosis and fear of toxicity are the main reasons for not enrolling. Another barrier to enrollment is strict eligibility criteria; for example,28/66 (43%) patients were ineligible due to a required BMI &gt; 25 without known diabetes. The majority of patients are not overwhelmed by the trial discussion and appreciate the oncology consultation prior to surgery. Weekly multidisciplinary meetings have resulted in improvements to study accrual and data quality. Over time, the requirements for tumor acquisition have been standardized to decrease variability in biomarker analysis. To ensure sufficient quantity of pre-study tumor tissue, patients undergo up to 4 core biopsies at diagnosis (tumor&gt;1cm). To limit the warm ischemia period and ensure biomarker reproducibility, core biopsies are fixed within 20 minutes. At resection, the surgical specimen is placed in ice-cold formalin within 30 minutes of devascularization. Excisions are fixed for 6-48 hours prior to processing.

Conclusion: Studying a new agent pre-surgically is an effective tool in assessing a drug's impact on tumor biology and predictive biomarkers. In order for pre-surgical studies to be successful, a close collaboration between radiology, surgery, medical oncology and pathology must be established and continually reassessed. We plan to utilize this multidisciplinary approach to successfully complete future pre-surgical studies, including a multicenter trial with a novel AKT inhibitor.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-15.