Abstract B78: Evaluation of letrozole for the prevention and inhibition of tumor growth in human cervical cancer xenograft mouse models

Abstract Purpose: To evaluate the efficacy of letrozole, a third generation aromatase inhibitor, for the prevention or delay of cervical cancer recurrence in either human papillomavirus (HPV) positive (HeLa) or HPV negative (C-33a) cervical cancer xenograft mouse models. Method: In this three arm study with two xenograft cervical cancer mouse models, HeLa (HPV 16 positive), and C-33a (HPV negative), the efficacy of letrozole was evaluated in prevention and tumor growth inhibition. Sixty mice were divided into six groups of ten mice each of treatment arm, vehicle control arm and no treatment arm for two cell lines. Mice in the treatment arm received letrozole 10 μg orally once daily every day beginning seven days before the inoculation with respective cancer cells and continued until day 90 of the study. Mice were injected subcutaneously on eighth day of the study with 0.5 million cells of respective cell line. Tumor growth was assessed three times a week. After 90 days of letrozole treatment, a 30 day period without drug was observed to evaluate tumor growth. At the end of the study, tumors were extracted and the expression of estrogen receptor alpha (ERα and estrogen receptor beta (ERβ was evaluated from the extracted protein by immunoblotting and RT-PCR was completed on DNA samples from extracted tumors to evaluate the HPV expression. Results: After 90 days of continuous treatment, letrozole inhibited microscopic cervical tumor growth in the HeLa mouse models demonstrated by 45% reduction in tumor volume in the HeLa letrozole treated mice compared to the no treatment control (p < 0.05). Off treatment, the HeLa letrozole treated mice also had slower rate of tumor progression by 38% compared to untreated group (p< 0.05). In addition, overall survival (OS) was improved by 75% in HeLa letrozole arm with (OS of 40% in the letrozole arm compared to 10% in the no treatment arm). While there was only an 18% reduction (p= 0.63) in tumor volume in the C-33a letrozole treated mice compared to the no treatment control, once treatment was stopped, the mice that had been receiveing letrozole had a slower rate of tumor progression by 37% (p < 0.07). There was no survival benefit observed in the C-33a tumor model. In both studies, no change in ERa, ERb, or HPV expression was observed in the letrozole treatment group compared to no treatment group. Conclusion: Although there was no change in ERα, ERβ, or HPV expression observed in this study, the response data in the HPV 16 positive HeLa tumor model compared to the HPV negative C-33a tumor model suggests HPV expression is associated with the potential activity of letrozole for the prevention of cervical cancer recurrence/progression. Additional studies are needed to elucidate the differences of letrozole activity in presence and absence of HPV expression. Overall, this preliminary data indicates a potential agent for the prevention and treatment of cervical cancer recurrence. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B78.