CHARACTERIZING RESPONSE TO FOLFIRINOX IN PATIENT-DERIVED XENOGRAFT MODELS OF CLASSICAL AND BASAL-LIKE SUBTYPES OF PANCREATIC CANCER
Louisa Bolm*, Birte Purschke, Natalie Petruch, Miriam Abigail A. Ricanati, Susan Kuo, Andrew L. Warshaw, Carlos Fernandez-Del Castillo, Andrew S. Liss
Department of Surgery, Massachusetts General Hospital, Boston, MA
Introduction: FOLFIRINOX is a first-line treatment option in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of tumors from the COMPASS trial suggested a preferential downstaging of Classical versus Basal-like PDAC tumors after FOLFIRINOX treatment. However, a lack of appropriate experimental models has prevented the investigation of effects of FOLFIRINOX therapy on the divergent transcriptional subtypes of PDAC. Here we developed a modified FOLFIRINOX regimen for mice and examined its impact on the growth of patient-derived xenograft tumors.
Methods and Materials: The transcriptional subtypes of PDX tumors were determined based on the Classical and Basal-like signatures defined by Moffitt. Mice in the treatment group received single intraperitoneal injections of oxaliplatin, irinotecan and leucovorin followed by nine consecutive intraperitoneal injections of 5-fluorouracil every hour on the same day and again on the following day. Mice received chemotherapy cycles in four consecutive weeks. Drugs were administered at a 40% human equivalent dose of the modified FOLFIRINOX protocol for patients. Mice in the control group received the same injection schedule with sodium chloride vehicle over four weeks. Tumor growth was monitored by caliper measurement three times per week.
Results: Two PDX tumors models representative of Classical and Basal-like subtypes were implanted into mice (n=10/model). Mice were randomly allocated to the control (n=5) and treatment (n=5) groups once tumors reached 300 mm3. Minimal toxicity was observed in treatment group mice, with a mean weight loss of 7% (range 0-14%). FOLFIRINOX strongly inhibited the growth of Classical subtype tumors. The tumor volume increased by a mean of 354% (range 301-407%) in the control group while three mice in the treatment group showed tumor shrinkage of 10% (range 12%-7%) and two mice exhibited a minimal tumor growth of 5% (range 2%-7%) over the study period (p<0.001). The mean tumor volume at the end of study was 1226 mm3 (S.D. 33.1) for the control group and 354 mm3 (S.D. 26.3) for the treatment group (p=0.004). In contrast to Classical tumors, FOLFIRINOX did not inhibit the growth of basal-like subtype tumors. The tumor volume increased by a mean of 436% (range 355-477%) and 421% (range 371%-455%) of the original tumor volume in the control and treatment groups, respectively (p=0.871). Mean tumor volume at harvest was 1131 mm3 (S.D. 65.1) for the control group and 1259 mm3 (S.D. 80.0) for the treatment group (p=0.401).
Conclusion: Modified FOLFIRINOX can safely be administered at a 40% human dose-equivalent in mice. While FOLFIRINOX treatment results in arrested tumor growth in Classical subtype PDX tumors, there is no effect on tumor growth in Basal-like subtype PDX tumors.
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