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• W2055738507 abstract "The majority of cervix cancers are attributed to effects of HPV viral infection, which may cause cellular dysregulation via viral associated protein interaction with p53 and Rb resulting in p16 over-expression as a cellular compensatory mechanism. It is possible that alternate mechanisms of cervical carcinogenesis exist that are independent of the viral effects. These may include p53 mutation, or alteration of cell cycle regulators, such as over-expression of the p53 inhibitor MDM2. To determine the effect of tumor HPV status, and the tumor expression of MDM2, p53, p21 and p16 on outcome of patients following radiotherapy for carcinoma of the cervix. This is a retrospective cohort of patients who completed radical radiotherapy alone for cervix cancer between 1986 and 1996. One hundred and ninety two patients were identified. Patient and tumor data, treatment parameters and outcomes, were obtained from patient records. One hundred and thirty two patients had pre-treatment paraffin-embedded tumor specimens available for analysis. Tissue microarrays were constructed on these specimens. Immunostaining was performed to detect protein levels of MDM2, p53, p16, and p21. Staining intensity was scored using a 4-point system: 0, no staining; 1, weak staining; 2, moderated staining; and 3, strong staining. HPV DNA was detected using a commercially available in-situ hybridization kit, and a 3-point scoring scale was used. Two independent observers, blinded to clinical outcome, scored the stains. Mean follow-up was 6 years. Mean patient age was 54 years. The majority of patients (63%) had FIGO stage IIB or III disease, and 86% of tumors were squamous cell carcinomas. Mean radiation dose to point A was 8165 cGy, typically using a combination of external beam radiotherapy and low dose rate brachytherapy. Seventy-seven percent of patients had pre-treatment hemoglobin greater than 115 g/L. Twenty-three percent of tumors were HPV negative; 5% of tumors had intense (3+) p53 immunostaining; 6% of tumors had intense MDM2 immunostaining. The majority of tumors stained intensely for p16 (89%) and p21 (69%) proteins. The 5-year risk of death increased with the level of MDM2 expression: 71% for staining score 3, versus 33% for MDM2 negative tumors (p = 0.025). In addition, increasing MDM2 expression predicted incomplete response to radiotherapy, with 38% of tumors with MDM2 score 3 failing to achieve complete local response, versus 5% with score 0 (p = 0.005). Negative or weakly positive HPV expression status predicted adverse overall survival, 5-year risk of death 49% and 47% versus 29% for HPV strongly positive tumors (p = 0.056). In addition, negative p16 staining predicted adverse overall survival, 5-year risk of death 72% versus 38% for intensely immunostaining tumors (p = 0.03). There was a trend to worse overall survival in tumors with intense p53 staining (p = 0.067). There was no association with p21 staining and overall survival (p = 0.77). Patients with cervical cancer treated with radiotherapy with tumors exhibiting intense MDM2 positivity, p16 negativity, and HPV negativity have significantly worse overall survival. Increasing MDM2 staining predicted for failure to respond to radiotherapy. This is of clinical interest as novel antagonists of MDM2 are under investigation." @default.
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• W2055738507 date "2007-11-01" @default.
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• W2055738507 title "Expression of MDM2, p16, and HPV Status is Associated with Survival after Radiotherapy in Patients with Carcinoma of the Cervix" @default.
• W2055738507 doi "https://doi.org/10.1016/j.ijrobp.2007.07.217" @default.
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