Abstract P1-03-01: Generation of a Novel <i>In Vivo</i> Model of Patient-Derived Chemoresistant Breast Cancers
Authors: PF McAuliffe, AM Gonzalez-Angulo, C Sharma, G Singh, A Akcakanat, F. Meric-Bernstam
Journal: Cancer Research (2010)

Abstract Background: Breast cancer patients who have significant residual cancer after neoadjuvant chemotherapy (NCT) are at high risk of relapse. There is a pressing need to identify novel therapeutics that can be offered to these patients. In vivo models available to test new agents are limited. We hypothesized that tumors from patients with poor response to NCT can be transplanted into nude mice to establish xenografts, providing a novel in vivo model to study therapies for chemoresistant tumors. Materials and Methods: After informed consent, excess tumor was taken from the mastectomy specimens from six patients who had either disease progression during NCT or significant residual disease after NCT. On surgical pathologic evaluation, average tumor size was 8.6 ± 3.2 cm (range 4.5-12 cm), and average number of positive lymph nodes was 6.2 ± 6.8 (range 0-18). Patients had RECIST criteria of partial response (n=2), stable disease (n= 1) or progressive disease (n=3). For each patient, tumors were implanted subcutaneously into the flanks of five nude mice. Tumors were passaged to successive generations when they reached 1.5 cm in diameter. In vivo tumor growth and the ability to serially passage tumors were assessed. Patient and tumor characteristics, and patient outcomes were evaluated. Results: Three patients had ER+HER2- tumors and three had ER-HER2- tumors. Serially transplanted xenografts were established from all six patients (100%); see Figure 1. Within each group of five mice implanted with the human tumors, 60 ± 26% developed tumor. Time to tumor size of 1.5 cm diameter was 4.2 ± 2.6 months (range 1.5-7.8 months). Two mice also developed tumors at a location distant from the implantation site (Met). These tumors were separately engrafted, also with 100% take, reaching 1.5 cm diameter at 1.5 and 1.7 months. Of the six patients, one had metastatic disease at surgery and underwent palliative mastectomy. Of the other five patients, four (80%) developed metastatic disease 4-8.4 months after surgery. Mice developed passagable tumors at least 2 months before the donor patients developed distant recurrence. The one patient who remains distant disease-free had the longest time to tumor passage (8.4 months). Figure 1. Time to passage of tumor to next generation of mice. Flank tumors xenografts were derived from patients with chemoresistant breast cancers. When tumors reach 1.5 cm in diameter, they are passaged to the next generation of 5 mice. X-axis depicts time to reach 1.5 cm with each passage. Discussion: Patients with progression or significant residual disease after NCT are at very high risk of distant relapse. Their chemoresistant tumors can be used to create serially transplantable xenografts. This in vivo model of chemoresistant breast cancer may be utilized to allow individualization of additional adjuvant or metastatic breast cancer treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-03-01.