Prioritizing Phase I Treatment Options Through Preclinical Testing on Personalized Tumorgraft

Abstract

A 29-year-old woman with a history of advanced adenoid cystic carcinoma (ACC) that was resistant to standard of care treatments presented to our phase I clinic seeking treatment with experimental therapeutics. The patient was diagnosed with ACC 11 years before presentation and had been treated with surgery, radiation therapy, and several lines of conventional treatments including platinums, antracyclines, and imatinib mesylate. Eleven months before being seen in our clinic, the patient had developed a brain metastasis that had been surgically resected. A personalized tumorgraft was successfully established from this lesion by the implantation of fragments of tumor materials in immunecompromised mice as described by our group. 1At the time of presentation, the patient had pulmonary and liver metastasis and, compared with a computed tomography (CT) scan performed 6 months before, was progressing with the growth of a preexisting liver metastasis (Fig 1, before baseline CT scan, black arrow) and development of a new liver lesion, as depicted in Figure 1 (upper panel). Brain magnetic resonance imaging showed a stable 2-mm brain lesion (Fig 1, lower panel, black arrows). The patient was asymptomaticwithEasternCooperativeOncologyGroupperformancestatusof 0 and normal liver, bone marrow, and kidney functions.To determine which phase I clinical studies could be more appropriate for the patient, we characterized her tumor for KRAS mutations and HER2 amplification and found the tumor to be KRAS wild type and not HER2 amplified, respectively (Table 1). Because the patient had a personalized tumorgraft model developed from her brain metastases, we used the model to evaluate a battery of anticancer agents, both conventional and experimental. Briefly, a tumor specimen obtained at the time of removal of her brain tumor had been transplanted and propagated in nude mice. Once the tumor specimen was in an exponential growth phase, cohorts of mice with tumor sizes of 0.15 to 0.3 mL were randomized to several treatment groups. The results of these studies are listed in Figure 2A

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