CA-IX, p16, Proliferative Markers, and HPV in Diagnosing Cervical Lesions in Patients With Abnormal Cervical Cells

Comparative Analysis of CA-IX, p16, Proliferative Markers, and Human Papilloma Virus (HPV) in the Diagnosis of Significant Cervical Lesions in Patients With a Cytologic Diagnosis of Atypical Glandular Cells (AGC)

This research trial studies carbonic anhydrase 9 (CA-IX), p16, proliferative markers, and human papilloma virus (HPV) in diagnosing cervical lesions in patients with abnormal cervical cells. Studying biomarkers in abnormal cervical cells may improve the ability to find cervical lesions and plan effective treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Atypical Endometrial Hyperplasia; Human Papillomavirus Infection; Stage 0 Cervical Cancer AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Cytology Specimen Collection Procedure

Detailed Description

PRIMARY OBJECTIVES:

I. To examine CA-IX, p16, Ki-67, and mini-chromosome maintenance complex component 2 (MCM2) expression in liquid-based cytology (LBC) specimens to see which subset of markers can provide the optimal diagnosis of significant cervical lesions in women in North America with a cytologic diagnosis of atypical glandular cells (AGC) and a positive test for high risk human papillomavirus (HPV).

II. To examine high risk HPV, CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens to see which subset of markers can provide the optimal diagnosis of significant cervical lesions in women in Japan and Korea (with each country's cohort analyzed separately) with a cytologic diagnosis of AGC.

SECONDARY OBJECTIVES:

I. To determine whether the accuracy of diagnosis based on high risk HPV and expression of CA-IX, p16, Ki-67, and/or MCM2 varies with patient age at enrollment and country of enrollment.

TERTIARY OBJECTIVES:

I. To assess biomarker expression, loss of heterozygosity, and chromosome gains/losses in formalin-fixed, paraffin-embedded tissue from the highest grade or most abnormal lesion in women from North America, Japan, or Korea presenting with a cytologic diagnosis of AGC or with a cytologic/histologic diagnosis of adenocarcinoma in situ (AIS).

II. To determine CA-IX, p16, Ki67, and MCM2 expression in LBC specimens to see which subset (or combination) of markers will provide higher sensitivity in the diagnosis of cervical adenocarcinoma in situ (AIS).

OUTLINE:

Patients undergo liquid-based cytology specimen sample collection for analysis of CA-IX, p16, Ki-67, and MCM2 expression via immunohistochemistry (IHC) and for the presence of high risk HPV deoxyribonucleic acid (DNA) and HPV genotyping.

• Study Type: Interventional
• Enrollment (Estimated): 877
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Japan
  • Hiroshima City, Japan, 734-8551
    • Hiroshima University Hospital
  • Matsuyama, Japan, 791-0280
    • Shikoku Cancer Center
  • Minami-ku, Japan, 811 1395
    • National Kyushu Cancer Center
  • Minato-ku, Tokyo, Japan, 105-8461
    • Jikei University School of Medicine
  • Osaka, Japan, 589 8511
    • Kindai University
  • Saitama, Japan, 350-1298
    • Saitama Medical University International Medical Center
  • Tokyo, Japan, 104 0045
    • National Cancer Center Hospital
  • Tottori, Japan, 680-8550
    • Tottori University
  • Aoba-ku
    • Sendai, Aoba-ku, Japan, 980-8574
      • Tohoku University School of Medicine
  • Hiroshima
    • Kure, Hiroshima, Japan, 737
      • Kure National Hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital
  • Hyogo
    • Akashi-city, Hyogo, Japan, 673-8558
      • Hyogo Cancer Center
  • Iwate
    • Shiwa-gun, Iwate, Japan, 028-3695
      • Iwate Medical University Hospital
  • Kagoshima
    • Kagoshima City, Kagoshima, Japan, 890-8760
      • Kagoshima City Hospital
  • Niigata
    • Niigata City, Niigata, Japan, 951-8520
      • Niigata University Medical And Dental Hospital
  • Okinawa
    • Nakagami-gun, Okinawa, Japan, 903-0215
      • University of the Ryukyus Hospital-Col Health Scnc
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan, 160-8582
      • Keio University
• Korea, Republic of
  • Incheon, Korea, Republic of, 405-760
    • Gachon University Gil Hospital
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 120-752
    • Yonsei University Health System-Severance Hospital
  • Seoul, Korea, Republic of, 134-727
    • Kyung Hee University Hospital at Gangdong
  • Seoul, Korea, Republic of, 06273
    • Gangnam Severance Hospital
  • Daegu
    • Dalseo-gu, Daegu, Korea, Republic of, 42601
      • Keimyung University-Dongsan Medical Center
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of, 410-769
      • National Cancer Center-Korea
  • Incheon
    • Jung-gu, Incheon, Korea, Republic of, 400-711
      • Inha University
  • Korea
    • Seoul, Korea, Korea, Republic of, 137-040
      • Catholic University of Korea-Seoul Saint Mary's Hospital
  • Kyeonggi-do
    • Seongnam City, Kyeonggi-do, Korea, Republic of, 463-707
      • Seoul National University Bundang Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
    • Tucson, Arizona, United States, 85719
      • University of Arizona Cancer Center-North Campus
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA / Jonsson Comprehensive Cancer Center
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • Orange, California, United States, 92868
      • UC Irvine Health/Chao Family Comprehensive Cancer Center
    • Orange, California, United States, 92868
      • Saint Joseph Hospital - Orange
    • Sylmar, California, United States, 91342
      • Olive View-University of California Los Angeles Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Britain, Connecticut, United States, 06050
      • The Hospital of Central Connecticut
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center-Boise
    • Caldwell, Idaho, United States, 83605
      • Saint Alphonsus Cancer Care Center-Caldwell
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Health - Coeur d'Alene
    • Emmett, Idaho, United States, 83617
      • Walter Knox Memorial Hospital
    • Meridian, Idaho, United States, 83642
      • Idaho Urologic Institute-Meridian
    • Nampa, Idaho, United States, 83686
      • Saint Alphonsus Medical Center-Nampa
    • Post Falls, Idaho, United States, 83854
      • Kootenai Clinic Cancer Services - Post Falls
    • Sandpoint, Idaho, United States, 83864
      • Kootenai Cancer Clinic
  • Illinois
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem-Evanston Hospital
    • Mount Vernon, Illinois, United States, 62864
      • Good Samaritan Regional Health Center
  • Indiana
    • Elkhart, Indiana, United States, 46515
      • Elkhart General Hospital
    • Elkhart, Indiana, United States, 46514
      • Michiana Hematology Oncology PC-Elkhart
    • Elkhart, Indiana, United States, 46514-2098
      • Elkhart Clinic
    • Kokomo, Indiana, United States, 46904
      • Community Howard Regional Health
    • La Porte, Indiana, United States, 46350
      • IU Health La Porte Hospital
    • Mishawaka, Indiana, United States, 46545
      • Michiana Hematology Oncology PC-Mishawaka
    • Mishawaka, Indiana, United States, 46545
      • Saint Joseph Regional Medical Center-Mishawaka
    • Plymouth, Indiana, United States, 46563
      • Michiana Hematology Oncology PC-Plymouth
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
    • South Bend, Indiana, United States, 46601
      • Michiana Hematology Oncology PC-South Bend
    • South Bend, Indiana, United States, 46617
      • South Bend Clinic
    • Westville, Indiana, United States, 46391
      • Michiana Hematology Oncology PC-Westville
  • Kansas
    • Kansas City, Kansas, United States, 66112
      • Providence Medical Center
    • Lenexa, Kansas, United States, 66219
      • Kansas Institute of Medicine Cancer and Blood Center
    • Lenexa, Kansas, United States, 66219
      • Minimally Invasive Surgery Hospital
    • Overland Park, Kansas, United States, 66209
      • Menorah Medical Center
    • Overland Park, Kansas, United States, 66213
      • Saint Luke's South Hospital
    • Shawnee Mission, Kansas, United States, 66204
      • Advent Health - Shawnee Mission Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70817
      • Woman's Hospital
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center-Bramhall Campus
    • Scarborough, Maine, United States, 04074
      • Maine Medical Center- Scarborough Campus
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Niles, Michigan, United States, 49120
      • Lakeland Hospital Niles
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital-Royal Oak
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Medical Center Saint Joseph
    • Saint Joseph, Michigan, United States, 49085
      • Marie Yeager Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
  • Missouri
    • Independence, Missouri, United States, 64057
      • Centerpoint Medical Center LLC
    • Kansas City, Missouri, United States, 64116
      • North Kansas City Hospital
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center
    • Kansas City, Missouri, United States, 64108
      • Truman Medical Centers
    • Kansas City, Missouri, United States, 64118
      • Heartland Hematology and Oncology Associates Incorporated
    • Kansas City, Missouri, United States, 64114
      • Saint Joseph Health Center
    • Lee's Summit, Missouri, United States, 64086
      • Saint Luke's East - Lee's Summit
    • Liberty, Missouri, United States, 64068
      • Liberty Radiation Oncology Center
    • Rolla, Missouri, United States, 65401
      • Delbert Day Cancer Institute at PCRMC
    • Rolla, Missouri, United States, 65401
      • Mercy Clinic-Rolla-Cancer and Hematology
    • Saint Joseph, Missouri, United States, 64506
      • Heartland Regional Medical Center
    • Saint Joseph, Missouri, United States, 64507
      • Saint Joseph Oncology Inc
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
    • Springfield, Missouri, United States, 65807
      • CoxHealth South Hospital
    • Springfield, Missouri, United States, 65804
      • Mercy Hospital Springfield
  • Montana
    • Anaconda, Montana, United States, 59711
      • Community Hospital of Anaconda
    • Billings, Montana, United States, 59101
      • Billings Clinic Cancer Center
    • Billings, Montana, United States, 59101
      • Saint Vincent Healthcare
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Hospital
    • Butte, Montana, United States, 59701
      • Saint James Community Hospital and Cancer Treatment Center
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
    • Great Falls, Montana, United States, 59405
      • Benefis Healthcare- Sletten Cancer Institute
    • Helena, Montana, United States, 59601
      • Saint Peter's Community Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Missoula, Montana, United States, 59804
      • Community Medical Hospital
    • Missoula, Montana, United States, 59802
      • Saint Patrick Hospital - Community Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Women's Cancer Center of Nevada
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
    • Nashua, New Hampshire, United States, 03063
      • Norris Cotton Cancer Center-Nashua
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • Newark, New Jersey, United States, 07101
      • Rutgers New Jersey Medical School
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Einstein Campus
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth of the Carolinas-Moore Regional Hospital
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Belpre, Ohio, United States, 45714
      • Strecker Cancer Center-Belpre
    • Chillicothe, Ohio, United States, 45601
      • Adena Regional Medical Center
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Cancer Center-UC Medical Center
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43219
      • The Mark H Zangmeister Center
    • Columbus, Ohio, United States, 43214
      • Columbus Oncology and Hematology Associates Inc
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital
    • Columbus, Ohio, United States, 43213
      • Mount Carmel East Hospital
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health Center West
    • Delaware, Ohio, United States, 43015
      • Delaware Health Center-Grady Cancer Center
    • Delaware, Ohio, United States, 43015
      • Delaware Radiation Oncology
    • Delaware, Ohio, United States, 43015
      • Grady Memorial Hospital
    • Dublin, Ohio, United States, 43016
      • Dublin Methodist Hospital
    • Gahanna, Ohio, United States, 43230
      • Central Ohio Breast and Endocrine Surgery
    • Lancaster, Ohio, United States, 43130
      • Fairfield Medical Center
    • Mansfield, Ohio, United States, 44903
      • OhioHealth Mansfield Hospital
    • Marietta, Ohio, United States, 45750
      • Marietta Memorial Hospital
    • Marion, Ohio, United States, 43302
      • OhioHealth Marion General Hospital
    • Mount Vernon, Ohio, United States, 43050
      • Knox Community Hospital
    • Newark, Ohio, United States, 43055
      • Licking Memorial Hospital
    • Newark, Ohio, United States, 43055
      • Newark Radiation Oncology
    • Portsmouth, Ohio, United States, 45662
      • Southern Ohio Medical Center
    • Westerville, Ohio, United States, 43081
      • Saint Ann's Hospital
    • Zanesville, Ohio, United States, 43701
      • Genesis Healthcare System Cancer Care Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists and Research Institute-Tulsa
  • Oregon
    • Baker City, Oregon, United States, 97814
      • Saint Alphonsus Medical Center-Baker City
    • Ontario, Oregon, United States, 97914
      • Saint Alphonsus Medical Center-Ontario
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hazleton, Pennsylvania, United States, 18201
      • Geisinger Medical Center-Cancer Center Hazleton
    • Lewisburg, Pennsylvania, United States, 17837
      • Geisinger Medical Oncology-Lewisburg
    • Lewistown, Pennsylvania, United States, 17044
      • Lewistown Hospital
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pottsville, Pennsylvania, United States, 17901
      • Geisinger Cancer Services-Pottsville
    • Scranton, Pennsylvania, United States, 18510
      • Community Medical Center
    • Selinsgrove, Pennsylvania, United States, 17870
      • Geisinger Medical Oncology-Selinsgrove
    • State College, Pennsylvania, United States, 16801
      • Geisinger Medical Group
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Geisinger Wyoming Valley/Henry Cancer Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health Cancer Center
    • Greenville, South Carolina, United States, 29601
      • Saint Francis Hospital
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Medical Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
  • Texas
    • Galveston, Texas, United States, 77555-0565
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Memorial Hermann Texas Medical Center
    • League City, Texas, United States, 77573
      • UTMB Cancer Center at Victory Lakes
  • Wyoming
    • Cody, Wyoming, United States, 82414
      • Big Horn Basin Cancer Center
    • Cody, Wyoming, United States, 82414
      • Billings Clinic-Cody
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with a cytologic diagnosis of AGC (AGC, atypical endocervical cells [AEC], atypical endometrial cells [AEmC]) or a cytologic/histologic diagnosis of AIS documented within the last 6 months who can wait at least one week after the AGC or AIS diagnosis to have an LBC specimen (i.e., ThinPrep) collected and then receive any other intervention; acceptable time frame range is 4 days prior to registration to 7 days after registration
• Patients with positive HPV results who are willing to undergo a complete histologic examination of the uterus and cervix, including the cervical transformation zone, within 6 months of the AGC or AIS diagnosis (histologic examination includes a loop electrosurgical excision procedure [LEEP], loop excision of the transformation zone [LETZ], excisional cone biopsy, or hysterectomy)
• Patients must have signed an approved informed consent and authorization permitting release of personal health information

Exclusion Criteria:

• Patients who have had a hysterectomy
• History of endometrial hyperplasia or cancer of the endometrium, vagina, or cervix
• Patients who have previously been treated, or are currently being treated with radiation therapy or chemotherapy for vaginal or cervical cancer
• Patients who are known to be human immunodeficiency virus (HIV)-positive
• Patients who are pregnant and thought to be at risk for excessive bleeding or preterm labor if a cone biopsy is performed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Ancillary-Correlative (biomarkers in cervical cancer); Patients undergo liquid-based cytology specimen sample collection for analysis of CA-IX, p16, Ki-67, and MCM2 expression via IHC and for the presence of high risk HPV DNA and HPV genotyping.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Cytology Specimen Collection Procedure; Correlative studies; Other Names: Cytologic Sampling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker expression in patients from North America	CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens is measured via IHC. A logistic regression and receiver operating characteristic (ROC)-type analysis will be performed.	Baseline
Biomarker expression in patients from Japan	CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens is measured via IHC. A logistic regression and ROC-type analysis will be performed.	Baseline
Biomarker expression in patients from Korea	CA-IX, p16, Ki-67, and MCM2 expression in LBC specimens is measured via IHC. A logistic regression and ROC-type analysis will be performed.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of patient age on the accuracy of diagnosis based on CA-IX, HPV, p16, Ki-67, and/or MCM2 expression in the North American population	Logistic regression analyses will be performed to assess the effect of age and country on sensitivity, specificity, false positive rate (FPR), and complement negative predictive value (NPVC.). For each country and at each age, an upper 95% confidence limit will be calculated for the NPVC.	Baseline
Effect of patient age on the accuracy of diagnosis based on CA-IX, HPV, p16, Ki-67, and/or MCM2 expression in the Korean and Japanese populations	Logistic regression analyses will be performed to assess the effect of age and country on sensitivity, specificity, FPR, and NPVC. For each country and at each age, an upper 95% confidence limit will be calculated for the NPVC.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker expression, loss of heterozygosity (LOH), chromosome gains, and chromosome losses in tissue from the highest grade or most abnormal lesions in women with AGC	Exploratory analyses of genomic alterations, including LOH as well as chromosome gains and chromosome losses will be performed to identify genomic alterations associated with cervical dysplasia/neoplasia.	Baseline
CA-IX expression, combined p16 and Ki67 expression, and MCM2 expression in LBC specimens	Will be used to see which subset of markers will provide the higher and sensitivity in the diagnosis of cervical AIS.	Baseline

Collaborators and Investigators

• Sponsor: GOG Foundation
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Shu-Yuan liao, Gynecologic Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2009
• Primary Completion (Estimated): May 31, 2025
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: May 2, 2009
• First Submitted That Met QC Criteria: May 2, 2009
• First Posted (Estimated): May 5, 2009

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Uterine Diseases; Disease Attributes; DNA Virus Infections; Tumor Virus Infections; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Hyperplasia; Endometrial Hyperplasia; Papillomavirus Infections
• Other Study ID Numbers: GOG-0237 (Other Identifier: CTEP); N01CM62201 (U.S. NIH Grant/Contract); UG1CA189867 (U.S. NIH Grant/Contract); U10CA101165 (U.S. NIH Grant/Contract); NCI-2009-01103 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CDR0000632236