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Purpose: Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches. Experimental Design: Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap. Results: p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV–positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively. Conclusions: p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies. Clin Cancer Res; 18(15); 4154–62. ©2012 AACR.

PURPOSE: There is now substantial data that poly (ADP-ribose) polymerase-1 (PARP) inhibitors have activity in tumors with defects in homologous recombination, in particular BRCA-related cancers. One of the challenges, however, is identifying patients that may best respond to these class of drugs. 18F-FTT (fluorthanotrace) is a novel PET imaging tracer that can quantify PARP enzyme activity in vivo. We report results on an initial pilot study of 18F-FTT imaging in patients with ovarian carcinoma. METHODS: Eight patients with newly diagnosed or recurrent ovarian, primary peritoneal, or fallopian tube carcinoma and measurable disease underwent both 18F-FDG PET/CT and 18F-FTT PET/CT imaging within 30 days of each other. Patients who were undergoing surgery or had disease amenable to biopsy underwent dynamic imaging of the abdomen/pelvis and static skull base to mid-thigh imaging following injection of approximately 10mCi of 18F-FTT. Patients with no biopsy accessible disease underwent a series of whole body PET/CT scans over 4 hours following injection of 18F-FTT to evaluate the biodistribution and dosimetry of 18F-FTT. Standardized uptake value (SUV) was calculated for primary and/or metastatic implants on all patients with quantifiable tumor on both PET/CT scans. Quantitative assessment of the 18F-FTT PET/CT was performed first using the 18F-FDG PET/CT to identify and match lesions. Regions of interest were then drawn over the tumor implant using multiple planar view. Up to three lesions were quantified on each dataset (primary and metastases if present). Ex vivo autoradiography with [ 125I]-KX (a novel radio-iodinated PARP radiotracer that can quantitatively assess PARP-1 enzyme expression in vitro), immunohistochemical staining with γh2ax, CD45, and keratin was performed on tumor samples. RESULTS: Active regions of disease was noted for 7/8 patients on 18F-FDG PET/CT imaging and 18F-FTT PET/CT imaging. Maximum SUV of primary or metastases on 18F-FDG PET/CT ranged from 1.97-14.54 and on 18F-FTT PET/CT ranged from 3.04-12.13. We acquired tumor tissue on four patients for analysis. SUV on 18F-FTT PET/CT correlated with average counts/area on [ 125I]-KX autoradiography (R=0.70) and gammh2ax immunohistochemistry staining on tumor specimens. Low SUV FTT:FDG ratio was noted in 4/4 patients with platinum resistant disease and/or low PARP-1 expression on [ 125I]-KX autoradiography and high FTT:FDG ratio was noted in 2/3 patients with platinum sensitivity and/or high binding on [ 125I] KX auto-radiography. CONCLUSION: Our initial preliminary studies demonstrate that 18F-FTT localizes to known areas of tumor and may distinguish between tumors with low level expression of PARP and platinum resistance vs high levels of PARP and platinum sensitivity and may be a promising biomarker for PARP inhibitor and platinum sensitivity. Citation Format: Lilie Lin MD, Mehran Makvandi PharmD, Austin Pantel MD, Robert Doot PhD, Lauren Schwartz MD, Fiona Simpkins MD, David Mankoff MD PHD, Robert Mach PhD. A PILOT STUDY OF A POLY (ADP–RIBOSE) POLYMERASE–1 (PARP) TARGETED NOVEL PET TRACER (18F–FLUOURTHANOTRACE) IN PATIENTS WITH OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP20.