Publications by authors named "Megan A Clarke"

40 Publications

Liquid biopsy for cancer detection: Clinical and epidemiological considerations.

Clin Cancer Res 2021 Aug 30. Epub 2021 Aug 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute.

Detection of circulating nucleic acids, also referred to as liquid biopsy, has been evaluated for detection of cancer in a variety of settings. We describe important clinical and epidemiological considerations for liquid biopsy applications in cancer early detection and for monitoring of cancer recurrence.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2426DOI Listing
August 2021

It's not just size that matters: Challenges in studying obesity and female-specific cancers.

Authors:
Megan A Clarke

Lancet Reg Health West Pac 2021 Jun 13;11:100164. Epub 2021 May 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

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http://dx.doi.org/10.1016/j.lanwpc.2021.100164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315589PMC
June 2021

STRIDES - STudying Risk to Improve DisparitiES in Cervical Cancer in Mississippi - Design and baseline results of a Statewide Cohort Study.

Prev Med 2021 Jul 20;153:106740. Epub 2021 Jul 20.

National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, Rockville, MD, United States of America. Electronic address:

Cervical cancer rates in Mississippi are disproportionately high, particularly among Black individuals; yet, research in this population is lacking. We designed a statewide, racially diverse cohort of individuals undergoing cervical screening in Mississippi. Here, we report the baseline findings from this study. We included individuals aged 21 years and older undergoing cervical screening with cytology or cytology-human papillomavirus (HPV) co-testing at the Mississippi State Health Department (MSDH) and the University of Mississippi Medical Center (UMMC) (December 2017-May 2020). We collected discarded cytology specimens for future biomarker testing. Demographics and clinical results were abstracted from electronic medical records and evaluated using descriptive statistics and chi-square tests. A total of 24,796 individuals were included, with a median age of 34.8 years. The distribution of race in our cohort was 60.2% Black, 26.4% White, 7.5% other, and 5.9% missing. Approximately 15% had abnormal cytology and, among those who underwent co-testing at MSDH (n = 6,377), HPV positivity was 17.4% and did not vary significantly by race. Among HPV positives, Black individuals were significantly less likely to be HPV16/18 positive and more likely to be positive for other high-risk 12 HPV types compared to White individuals (20.5% vs. 27.9%, and 79.5% and 72.1%, respectively, p = 0.011). Our statewide cohort represents one of the largest racially diverse studies of cervical screening in the U.S. We show a high burden of abnormal cytology and HPV positivity, with significant racial differences in HPV genotype prevalence. Future studies will evaluate cervical precancer risk, HPV genotyping, and novel biomarkers in this population.
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http://dx.doi.org/10.1016/j.ypmed.2021.106740DOI Listing
July 2021

Impact of COVID-19 on cervical cancer screening: Challenges and opportunities to improving resilience and reduce disparities.

Prev Med 2021 10 30;151:106596. Epub 2021 Jun 30.

Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.

The COVID-19 pandemic has a major impact on a wide range of health outcomes. Disruptions of elective health services related to cervical screening, management of abnormal screening test results, and treatment of precancers, may lead to increases in cervical cancer incidence and exacerbate existing health disparities. Modeling studies suggest that a short delay of cervical screening in subjects with previously negative HPV results has minor effects on cancer outcomes, while delay of management and treatment can lead to larger increases in cervical cancer. Several approaches can mitigate the effects of disruption of cervical screening and management. HPV-based screening has higher accuracy compared to cytology, and a negative HPV result provides longer reassurance against cervical cancer; further, HPV testing can be conducted from self-collected specimens. Self-collection expands the reach of screening to underserved populations who currently do not participate in screening. Self-collection and can also provide alternative screening approaches during the pandemic because testing can be supported by telehealth and specimens collected in the home, substantially reducing patient-provider contact and risk of COVID-19 exposure, and also expanding the reach of catch-up services to address backlogs of screening tests that accumulated during the pandemic. Risk-based management allows prioritizing management of patients at highest risk of cervical cancer while extending screening intervals for those at lowest risk. The pandemic provides important lessons for how to make cervical screening more resilient to disruptions and how to reduce cervical cancer disparities that may be exacerbated due to disruptions of health services.
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http://dx.doi.org/10.1016/j.ypmed.2021.106596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241689PMC
October 2021

Cervical Cancer Screening-Past, Present, and Future.

Cancer Epidemiol Biomarkers Prev 2021 03;30(3):432-434

Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.

Cervical cancer screening has undergone a transformation in recent decades. Historically, programs were based on cervical cytology (i.e., "Pap smear"), which had to be repeated often because of its limited sensitivity and reproducibility. In more recent years, the discovery of human papillomavirus (HPV) as the necessary cause of virtually all cervical cancers has led to the introduction of HPV testing into clinical practice, first as a triage test for minor cytologic abnormalities, then in conjunction with cervical cytology (cotesting), and most recently, as a standalone screening test. Multiple randomized trials have shown that HPV-based screening has higher sensitivity compared with cytology, providing great reassurance against cervical precancer and cancer for women testing HPV-negative for many years. Analyses have also been conducted in support of the recent U.S. Preventive Services Task Force guidelines that show that primary HPV screening achieves the greatest balance of benefits and harms compared with other strategies. An added benefit of primary HPV testing is the ability to conduct it from self-collected samples, which is critical for extending coverage among hard-to-reach individuals and could provide a safe and effective alternative to in-person screening visits during the COVID-19 pandemic..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1628DOI Listing
March 2021

The relationship of human papillomavirus and cytology co-testing results with endometrial and ovarian cancer diagnoses.

Gynecol Oncol 2021 04 14;161(1):297-303. Epub 2021 Jan 14.

Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer.

Methods: In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated.

Results: Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%.

Conclusions: Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.005DOI Listing
April 2021

Systematic review and meta-analysis of studies assessing the relationship between statin use and risk of ovarian cancer.

Cancer Causes Control 2020 Oct 20;31(10):869-879. Epub 2020 Jul 20.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD, 20850, USA.

Purpose: The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are inconclusive.

Methods: We conducted a systematic review and meta-analysis of studies reporting associations between statin use and ovarian cancer risk in PubMed. Summary risk ratios (RRs) and confidence intervals (CIs) were calculated. Subgroup analyses by cancer histotype, statin class (lipo- or hydrophilic) and duration of statin use were conducted. Use of individual statins in populations was assessed to determine population-specific differences in statin types.

Results: Nine studies with 435,237 total women were included (1 randomized controlled trial (RCT); 4 prospective; 4 case-control). Statin use was associated with a reduced risk of ovarian cancer (RR 0.87, 95% CI 0.74-1.03) and risk was significantly reduced in populations with low pravastatin use (RR 0.83, 95% CI 0.70-0.99). Risk estimates varied by statin class (3 studies; lipophilic: RR 0.88, 95% CI 0.69-1.12; hydrophilic: RR 1.06, 95% CI 0.72-1.57) and cancer histotype (3 studies; serous: RR 0.95, 95% CI 0.69-1.30; clear cell: RR 1.17, 95% CI 0.74-1.86). Long-term use was associated with a reduced risk of ovarian cancer (RR 0.77, 95% CI 0.54-1.10) that further reduced when pravastatin use was low (RR 0.68, 95% CI 0.46-1.01). Between-study heterogeneity was high overall and in subgroups (I > 60%).

Conclusion: Statins may be associated with a reduced risk of ovarian cancer, but the effect likely differs by individual statin, duration of use and cancer histotype. Additional well-powered studies are needed to elucidate important subgroup effects.
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http://dx.doi.org/10.1007/s10552-020-01327-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484024PMC
October 2020

Trends in hysterectomy-corrected uterine cancer mortality rates during 2002 to 2015: mortality of nonendometrioid cancer on the rise?

Int J Cancer 2021 02 17;148(3):584-592. Epub 2020 Aug 17.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Corpus uteri cancer is the most common gynecological malignancy in most developed countries. The disease is typically diagnosed at an early stage, is of endometrioid histologic subtype, and has a fairly good prognosis. Here, we describe hysterectomy-corrected mortality rates of corpus uteri cancer, overall and stratified by age, stage and histologic subtype. Using data from nationwide Danish registries, we calculated uncorrected and hysterectomy-corrected age-standardized mortality rates of corpus uteri cancer among women ≥35 years during 2002 to 2015. Individual-level hysterectomy status was obtained from national registries; hysterectomy-corrected mortality rates were calculated by subtracting posthysterectomy person-years from the denominator, unless hysterectomy was performed due to corpus uteri cancer. Correction for hysterectomy resulted in a 25.5% higher mortality rate (12.3/100000 person-years vs 9.8/100000 person-years). Mortality rates were highest in women aged 70+, irrespective of year of death, histologic subtype and stage. A significant decline was observed in overall hysterectomy-corrected mortality rates from 2002 to 2015, particularly among women aged 70+. Mortality rates of endometrioid cancer declined significantly over time (annual percent change [APC]: -2.32, 95% CI -3.9, -0.7, P = .01), whereas rates of nonendometrioid cancer increased (APC: 5.90, 95% CI: 3.0, 8.9, P < .001). With respect to stage, mortality rates increased significantly over time for FIGOI-IIa (APC: 6.18 [95% CI: 1.9, 10.7] P = .01) but remained unchanged for FIGO IIb-IV. In conclusion, increasing mortality rates of nonendometrioid cancer paralleled the previously observed rise in incidence rates of this histologic subtype. Given the poor prognosis of nonendometrioid cancer, more studies are needed to clarify the underlying reason for these findings.
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http://dx.doi.org/10.1002/ijc.33219DOI Listing
February 2021

Accuracy and Efficiency of Deep-Learning-Based Automation of Dual Stain Cytology in Cervical Cancer Screening.

J Natl Cancer Inst 2021 01;113(1):72-79

Steinbeis Transfer Center for Medical Systems Biology, Heidelberg, Germany.

Background: With the advent of primary human papillomavirus testing followed by cytology for cervical cancer screening, visual interpretation of cytology slides remains the last subjective analysis step and suffers from low sensitivity and reproducibility.

Methods: We developed a cloud-based whole-slide imaging platform with a deep-learning classifier for p16/Ki-67 dual-stained (DS) slides trained on biopsy-based gold standards. We compared it with conventional Pap and manual DS in 3 epidemiological studies of cervical and anal precancers from Kaiser Permanente Northern California and the University of Oklahoma comprising 4253 patients. All statistical tests were 2-sided.

Results: In independent validation at Kaiser Permanente Northern California, artificial intelligence (AI)-based DS had lower positivity than cytology (P < .001) and manual DS (P < .001) with equal sensitivity and substantially higher specificity compared with both Pap (P < .001) and manual DS (P < .001), respectively. Compared with Pap, AI-based DS reduced referral to colposcopy by one-third (41.9% vs 60.1%, P < .001). At a higher cutoff, AI-based DS had similar performance to high-grade squamous intraepithelial lesions cytology, indicating a risk high enough to allow for immediate treatment. The classifier was robust, showing comparable performance in 2 cytology systems and in anal cytology.

Conclusions: Automated DS evaluation removes the remaining subjective component from cervical cancer screening and delivers consistent quality for providers and patients. Moving from Pap to automated DS substantially reduces the number of colposcopies and also achieves excellent performance in a simulated fully vaccinated population. Through cloud-based implementation, this approach is globally accessible. Our results demonstrate that AI not only provides automation and objectivity but also delivers a substantial benefit for women by reduction of unnecessary colposcopies.
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http://dx.doi.org/10.1093/jnci/djaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781458PMC
January 2021

Toward a risk-based approach to evaluate and manage abnormal uterine bleeding.

Am J Obstet Gynecol 2020 10 1;223(4):607. Epub 2020 Jun 1.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, MD.

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http://dx.doi.org/10.1016/j.ajog.2020.05.050DOI Listing
October 2020

Risk assessment of endometrial cancer and endometrial intraepithelial neoplasia in women with abnormal bleeding and implications for clinical management algorithms.

Am J Obstet Gynecol 2020 10 5;223(4):549.e1-549.e13. Epub 2020 Apr 5.

Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, MD.

Background: Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer.

Objective: We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic.

Study Design: A total of 1163 women aged ≥45 years were enrolled from February 2013 to May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs recurrent bleeding episode and endometrial thickness measured through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage of cases detected and missed, and the ratio of biopsies per case detected.

Results: Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia, and 47 (7.9%) had endometrial cancer, and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia, and 7 (1.2%) had endometrial cancer. Maximum risk was noted in women aged 60+ years (17.7%; 13.0%-22.3%), followed by those with recurrent bleeding (14.7%; 11.0%-18.3%). Among women with an initial bleeding episode for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases.

Conclusion: Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations.
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http://dx.doi.org/10.1016/j.ajog.2020.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529796PMC
October 2020

Racial differences in HPV type 16 prevalence in women with ASCUS of the uterine cervix.

Cancer Cytopathol 2020 08 3;128(8):528-534. Epub 2020 Apr 3.

National Cancer Institute, Rockville, Maryland.

Background: Understanding racial influences on human papillomavirus (HPV) distribution in women with atypical squamous cells of undetermined significance (ASCUS) cytology via partial genotyping in a statewide population can inform HPV-based prevention efforts.

Methods: Women aged 21 to 65 years with any cytology result and partial HPV genotyping for ASCUS triage between January 1, 2014, and December 31, 2017, were included. All women attended a Mississippi State Department of Health clinic. Age, race, cytopathologic, and HPV data were extracted from the electronic health record and analyzed. Cytologic specimens were processed with ThinPrep and HPV testing with the Cobas 4800 assay. HPV genotypes were evaluated in hierarchical categories. Chi-square tests and multinomial logistic regression models evaluated associations between race and type prevalence.

Results: There were 43,106 women who underwent cervical cancer screening with cytology and ASCUS triage. Of these, 34,363 (80.2%) had normal cytology, 4672 (10.9%) had ASCUS, 2683 (6.3%) had a low-grade squamous intraepithelial lesion, and 633 (1.5%) had a high-grade squamous intraepithelial lesion. Blacks represented 69.3% of the sample and had a higher proportion of HPV-positive ASCUS (6.5%) in comparison with whites (5.6%). Blacks had significantly decreased odds of HPV-16 (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.6-0.9; P = .002) and significantly increased odds for 12 other types (OR, 1.37; 95% CI, 1.2-1.5; P < .0001) in comparison with whites.

Conclusions: In a diverse population, significant differences in HPV genotypes are shown by race. Importantly, blacks with ASCUS are less likely to be positive for HPV-16 in comparison with whites. Ongoing work is evaluating the individual genotype prevalence and genotype-specific risk of precancer by race.
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http://dx.doi.org/10.1002/cncy.22267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728239PMC
August 2020

Challenges Associated With Cervical Cancer Screening and Management in Obese Women: A Provider Perspective.

J Low Genit Tract Dis 2020 Apr;24(2):184-191

Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

Objectives: Obese women are at increased risk of cervical cancer, partly due to missed detection of cervical precancers during routine cervical cancer screening. We administered a clinician survey to better understand specific challenges and identify potential solutions to performing cervical cancer screening and management in obese women.

Materials And Methods: We administered a web-based survey to 2,319 members of the American Society of Colposcopy and Cervical Pathology including questions related to challenges associated with cervical sampling and visualization in obese compared with normal weight women and potential strategies for improvement. We summarized providers' responses using descriptive statistics and used Fisher exact tests to evaluate associations between provider characteristics and challenges with cervical sampling, visualization, and biopsy.

Results: Of the 240 providers that completed the survey, 89% and 93% reported that cervical sampling and visualization are more challenging in obese women, respectively, whereas 80% reported that taking a biopsy was more challenging. Commonly reported barriers included vaginal prolapse, difficulty visualizing and accessing the cervix, and lack of long enough sampling devices and large enough speculums. Frequently used techniques to improve sampling and visualization included use of a condom or examination glove finger to sheath a speculum and using a tenaculum. Most providers identified training for cervical sampling and colposcopy in obese women as a learning gap, and only 8% reported receiving such training.

Conclusions: Cervical cancer screening and management are more challenging in obese compared with normal weight women. Major barriers to cervical sampling and visualization included lack of adequately sized equipment and lack of education and training.
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http://dx.doi.org/10.1097/LGT.0000000000000506DOI Listing
April 2020

Reporting and Assessing the Quality of Diagnostic Accuracy Studies for Cervical Cancer Screening and Management.

J Low Genit Tract Dis 2020 Apr;24(2):157-166

Division of Cancer Epidemiology & Genetics, National Cancer Institute/NIH, Bethesda, MD.

Objective: We adapted the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for studies of cervical cancer screening and management and used the adapted tool to evaluate the quality of studies included in a systematic review supporting the 2019 Risk-Based Management Consensus Guidelines.

Methods: We evaluated the quality of all studies included in our systematic review for postcolposcopy (n = 5) and posttreatment (n = 23) surveillance using QUADAS-2 criteria. Subsequently, we adapted signaling questions to indications of cervical cancer screening and management. An iterative process was carried out to evaluate interrater agreement between 2 study authors (M.A.C. and N.W.). Discrepant ratings were discussed, and criteria were adapted accordingly. We also evaluated the influence of study quality on risk estimates and between study variation using stratified subgroup meta-analyses.

Results: Twelve signaling questions for bias assessment that were adapted to or newly developed for cervical cancer screening and management are described here. Interrater agreement on bias assessment increased from 70% to 83% during the adaptation process. Detailed assessment of bias and applicability showed that all studies on postcolposcopy management and 90% of studies on posttreatment management had high risk of bias in at least 1 domain. Most commonly, high risk of bias was observed for the patient selection domain, indicating the heterogeneity of study designs and clinical practice in reported studies.

Conclusions: The adapted QUADAS-2 will have broad application for researchers, evidence evaluators, and journals who are interested in designing, conducting, evaluating, and publishing studies for cervical cancer screening and management.
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http://dx.doi.org/10.1097/LGT.0000000000000527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141754PMC
April 2020

A Systematic Review of Tests for Postcolposcopy and Posttreatment Surveillance.

J Low Genit Tract Dis 2020 Apr;24(2):148-156

Division of Cancer Epidemiology & Genetics, National Cancer Institute/NIH, Bethesda, MD.

Objective: For the 2019 ASCCP Risk-Based Management Consensus Guidelines, we conducted a systematic review of diagnostic assays for postcolposcopy and posttreatment management.

Materials And Methods: A literature search was conducted to identify articles reporting on tests/assays for cervical cancer screening, triage, postcolposcopy surveillance, and posttreatment surveillance published between 2012 and 2019 in PubMed and Embase. Titles and abstracts were evaluated by co-authors for inclusion. Included articles underwent full-text review, data abstraction, and quality assessment. Pooled absolute pretest and posttest risk estimates were calculated for studies evaluating management of patients after treatment.

Results: A total of 2,862 articles were identified through the search. Of 50 articles on postcolposcopy, 5 were included for data abstraction. Of 66 articles on posttreatment, 23 were included for data abstraction and were summarized in the meta-analysis. The pooled posttreatment risk of cervical intraepithelial neoplasia (CIN) 2+ in all studies was 4.8% (95% CI = 3.4%-6.8%), ranging from 0.4%-19.5% (τ = 0.57) in individual studies. Among individuals testing negative for human papillomavirus (HPV) posttreatment, the risk of CIN 2+ was 0.69% (95% CI = 0.3%-1.5%); among individuals testing positive for HPV posttreatment, the risk of CIN 2+ was 18.3% (95% CI = 12.1%-26.6%) in all studies. All risk estimates were substantially higher for liquid-based cytology. The HPV-cytology co-testing provided slightly better reassurance compared with HPV alone at the cost of much higher positivity.

Conclusions: Despite a large number of published studies on postcolposcopy and posttreatment surveillance, only few met criteria for abstraction and were included in the meta-analysis. More high-quality studies are needed to evaluate assays and approaches that can improve management of patients with abnormal screening.
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http://dx.doi.org/10.1097/LGT.0000000000000526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141755PMC
April 2020

Identification of HPV genotypes causing cervical precancer using tissue-based genotyping.

Int J Cancer 2020 05 22;146(10):2836-2844. Epub 2020 Feb 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

Identification of high-risk human papillomavirus genotypes causing cervical precancer is crucial for informing HPV vaccine development and efficacy studies, and for determining which types to include in next-generation genotyping assays. Co-occurrence of hrHPV infections is common and complicates carcinogenicity assessment; accurate attribution requires tissue-based genotyping of precancers. We included all women with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) from the Biopsy Study, an observational study of 690 women enrolled between 2009 and 2012 at the University of Oklahoma. Tissue-based genotyping, including whole tissue sections (WTS) and laser-capture microdissection (LCM), was performed on all precancers with multiple hrHPV infections detected in cytology, totaling over 1,800 HPV genotyping assays. Genotype attribution was compared to hierarchical and proportional hrHPV-type attribution models. Of 276 women with CIN2+, 122 (44.2%) had multiple hrHPV genotypes in cytology. Of 114 women with genotyping data, 94 had one or more hrHPV detected in tissue. Seventy-one women (75.5%) had a single causal hrHPV genotype, while 23 women had multiple hrHPV genotypes causing CIN2+. Ten women had multiple causal infections in a single biopsy, contrary to the previous notion that each lesion is caused by a single type only. While HPV16 was the predominant causal hrHPV genotype using all approaches, the hierarchical model overattributed HPV16, whereas other causal hrHPV genotypes, particularly HPV18 and HPV35, were underattributed. Understanding true causal genotypes is important for the evaluation of vaccine efficacy, to estimate the extent of unmasking, and for type-specific risk assessment in screening and management.
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http://dx.doi.org/10.1002/ijc.32919DOI Listing
May 2020

Ultrasound detection of endometrial cancer in women with postmenopausal bleeding: Systematic review and meta-analysis.

Gynecol Oncol 2020 06 31;157(3):624-633. Epub 2020 Jan 31.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America.

Objective: To assess the performance of endometrial thickness (ET) cut-offs for detecting endometrial cancer (EC) in women with postmenopausal bleeding (PMB) and evaluate the clinical utility of additional ultrasound measures such as endometrial volume (EV), vascular flow index (VFI), vascularization index (VI), and uterine artery flow index (FI).

Methods: Clinicaltrials.gov and MEDLINE database via PubMed were queried for studies published between 1/1990 and 3/2016 using specific MeSH terms. Original, peer-reviewed cohort studies reporting EC outcomes and specific ultrasound findings by PMB status were included.

Results: Study design, country, clinical setting inclusion/exclusion criteria, aggregate study-level demographic and clinical data were extracted from 44 studies including 17,339 women with PMB and 1341 cases of EC (7.7%). In women with PMB and EC (n = 417), pooled mean ET was 16.4 mm (95% CI, 14.8-18.1 mm). In women with PMB without EC, pooled mean ET was 4.1 mm. 31 studies reported outcomes using different ET cut-off values ranging from 3 to 20 mm. Compared to ≥3 or 4 mm, a cutoff of ≥5 mm had similar sensitivity (96.2, 95%CI 92.3, 98.1) with improved specificity for EC (51.5, 95%CI 42.3-60.7), allowing to reduce the rate of invasive workup for PMB by 17%. EV, VI, VFI, and FI were significantly correlated with EC, but performance of specific cut-offs was not analyzed due to limited data.

Conclusion: Among women with PMB mean ET is substantially higher in women with EC compared to those without EC. An ET cutoff of ≥5 mm shows an acceptable tradeoff between sensitivity and specificity for diagnosis of EC.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.032DOI Listing
June 2020

A prospective clinical cohort study of women at increased risk for endometrial cancer.

Gynecol Oncol 2020 01 9;156(1):169-177. Epub 2019 Nov 9.

Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.

Objective: To evaluate endometrial cancer (EC) risk assessment and early detection strategies in high-risk populations, we designed a large, prospective cohort study of women undergoing endometrial evaluation to assess risk factors and collect novel biospecimens for future testing of emerging EC biomarkers. Here we report on the baseline findings of this study.

Methods: Women aged ≥45 years were enrolled at the Mayo Clinic from February 2013-June 2018. Risk factors included age, body mass index (BMI), smoking, oral contraceptive and hormone therapy use, and parity. We collected vaginal tampons, endometrial biopsies, and Tao brush samples. We estimated mutually-adjusted odds ratios (OR) and 95% confidence intervals (CI) using multinomial logistic regression; outcomes included EC, atypical hyperplasia, hyperplasia without atypia, disordered proliferative endometrium, and polyps, versus normal endometrium.

Results: Subjects included 1205 women with a mean age of 55 years; 55% were postmenopausal, and 90% had abnormal uterine bleeding. The prevalence of EC was 4.1% (n = 49), predominantly diagnosed in postmenopausal women (85.7%). Tampons and Tao brushings were obtained from 99% and 68% of women, respectively. Age (OR 1.14, 95% CI 1.1-1.2) and BMI (OR 1.39, 95% CI 1.1-1.7) were positively associated with EC; atypical hyperplasia (OR 1.07, 95% CI 1.0-1.1; OR 2.00, 95% CI 1.5-2.6, respectively), and polyps (OR 1.06, 95% CI 1.0-1.1; OR 1.17, 95% CI 1.0-1.3, respectively); hormone therapy use and smoking were inversely associated with EC (OR 0.42, 95%, 0.2-0.9; OR 0.43, 95% CI, 0.2-0.9, respectively). Parity and past oral contraception use were not associated with EC.

Conclusions: Well-established EC risk factors may have less discriminatory accuracy in high-risk populations. Future analyses will integrate risk factor assessment with biomarker testing for EC detection.
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http://dx.doi.org/10.1016/j.ygyno.2019.09.014DOI Listing
January 2020

Reply to M. Schlumbrecht et al.

J Clin Oncol 2019 12 2;37(35):3466-3467. Epub 2019 Oct 2.

Megan A. Clarke, PhD, MHS; Susan S. Devesa, PhD, MHS; and Nicolas Wentzensen, MD, PhD; National Cancer Institute, Rockville, MD.

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http://dx.doi.org/10.1200/JCO.19.02109DOI Listing
December 2019

Hysterectomy-Corrected Uterine Corpus Cancer Incidence Trends and Differences in Relative Survival Reveal Racial Disparities and Rising Rates of Nonendometrioid Cancers.

J Clin Oncol 2019 08 22;37(22):1895-1908. Epub 2019 May 22.

1National Cancer Institute, Rockville, MD.

Purpose: Uterine corpus cancer incidence rates have been projected to increase, a prediction often attributed to the obesity epidemic. However, correct estimation of these rates requires accounting for hysterectomy prevalence, which varies by race, ethnicity, and region. Here, we evaluated recent trends in hysterectomy-corrected rates by race and ethnicity and histologic subtype and estimated differences in relative survival by race and ethnicity, subtype, and stage.

Methods: We estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System. Hysterectomy-corrected age-standardized uterine corpus cancer incidence rates from 2000 to 2015 were calculated from the SEER 18 registries. Incidence rates and trends were estimated separately by race and ethnicity, region, and histologic subtype. Five-year relative survival rates were estimated by race and ethnicity, histologic subtype, and stage.

Results: Hysterectomy-corrected incidence rates of uterine corpus cancer were similar among non-Hispanic whites and blacks and lower among Hispanics and Asians/Pacific Islanders. Endometrioid carcinoma rates were highest in non-Hispanic whites, whereas nonendometrioid carcinoma and sarcoma rates were highest in non-Hispanic blacks. Hysterectomy-corrected uterine corpus cancer incidence increased among non-Hispanic whites from 2003 to 2015 and among non-Hispanic blacks, Hispanics, and Asians/Pacific Islanders from 2000 to 2015. Overall incidence rates among non-Hispanic blacks surpassed those of non-Hispanic whites in 2007. Endometrioid carcinoma rates rose among non-Hispanic blacks, Hispanics, and Asians/Pacific Islanders but were stable among non-Hispanic whites; however, nonendometrioid carcinoma rates rose significantly among all women. Non-Hispanic blacks had the lowest survival rates, irrespective of stage at diagnosis or histologic subtype.

Conclusion: Among all women, rates of nonendometrioid subtypes have been rising rapidly. Our analysis shows profound racial differences and disparities indicated by higher rates of nonendometrioid subtypes and poorer survival among non-Hispanic black women.
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http://dx.doi.org/10.1200/JCO.19.00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675596PMC
August 2019

Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program.

JAMA Intern Med 2019 07;179(7):881-888

Kaiser Permanente The Permanente Medical Group Regional Laboratory, Berkeley, California.

Importance: As cervical cancer screening transitions from Papanicolaou cytologic screening to primary human papillomavirus (HPV) testing worldwide, effective triage tests are needed to decide who among the HPV-positive women should receive further diagnostic evaluation to avoid unnecessary colposcopies and biopsies.

Objective: To evaluate the performance of the p16/Ki-67 dual stain (DS) and HPV16/18 genotyping for the triage of HPV-positive women.

Design, Setting, And Participants: A prospective observational study was conducted within the cervical cancer screening program at Kaiser Permanente Northern California of 3225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid DS result from September 16 to October 31, 2015, with follow-up through December 31, 2018.

Exposures: Human papillomavirus screening with partial genotyping and cytologic triage compared with DS triage.

Main Outcomes And Measures: Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) and grade 2 or more severe (CIN2+), diagnosed within 3 years after sample collection.

Results: A total of 3225 women (mean [SD] age, 37.9 [11.3] years) participated in the study. For triage of HPV-positive women with partial genotyping, DS showed better risk stratification for CIN3+ than did Papanicolaou cytologic testing, with women with positive DS results having a higher risk than women with positive Papanicolaou test results for CIN3+ (218 of 1818 [12.0%; 95% CI, 10.5%-13.5%] vs 219 of 2128 [10.3%; 95% CI, 9.0%-11.6%]; P = .005). Similarly, DS showed better risk stratification for CIN3+ compared with Papanicolaou cytologic testing in HPV-positive women, irrespective of genotyping. The greatest reassurance against CIN3+ was observed in HPV16/18-negative women with negative DS results, with a risk low enough to extend retesting intervals. Dual stain triage strategies required substantially fewer colposcopies per detection of CIN3+ compared with Papanicolaou cytologic testing, with a 32.1% (859 of 2677) reduction of colposcopies compared with the currently recommended triage strategy of HPV screening with Papanicolaou cytologic testing. Results for CIN2+ were very similar.

Conclusions And Relevance: Triage of HPV-positive women with DS was superior to Papanicolaou cytologic testing in this study, demonstrating equal immediate detection of precancerous lesions and substantially reduced referral to colposcopy. These findings suggest that DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to 3 years.
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http://dx.doi.org/10.1001/jamainternmed.2019.0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515572PMC
July 2019

5-Year Prospective Evaluation of Cytology, Human Papillomavirus Testing, and Biomarkers for Detection of Anal Precancer in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men.

Clin Infect Dis 2019 08;69(4):631-638

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: Human papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal precancer detection in human immunodeficiency virus-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM.

Methods: We enrolled 363 HIV+ MSM between 2009-2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models.

Results: There were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by those testing dual stain-positive. Those testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+.

Conclusions: HPV-related biomarkers provide long-term risk stratification for anal precancers. HR-HPV- and dual stain-negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.
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http://dx.doi.org/10.1093/cid/ciy970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669293PMC
August 2019

Five-Year Risk of Cervical Precancer Following p16/Ki-67 Dual-Stain Triage of HPV-Positive Women.

JAMA Oncol 2019 02;5(2):181-186

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Importance: As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical precancers; however, longitudinal studies are needed to determine the long-term risk of precancer following a negative DS result.

Objective: To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds.

Design, Setting, And Participants: Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter "cytology") co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017.

Exposures: All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity.

Main Outcomes And Measures: Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval.

Results: Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%; P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%; P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years.

Conclusions And Relevance: Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical precancer in p16/Ki-67 DS-negative women permits safe extension of follow-up intervals for 3 years.
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http://dx.doi.org/10.1001/jamaoncol.2018.4270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439556PMC
February 2019

Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis.

JAMA Intern Med 2018 09;178(9):1210-1222

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Importance: As the worldwide burden of endometrial cancer continues to rise, interest is growing in the evaluation of early detection and prevention strategies among women at increased risk. Focusing efforts on women with postmenopausal bleeding (PMB), a common symptom of endometrial cancer, may be a useful strategy; however, PMB is not specific for endometrial cancer and is often caused by benign conditions.

Objective: To provide a reference of the prevalence of PMB in endometrial cancers and the risk of endometrial cancer in women with PMB.

Data Sources: For this systematic review and meta-analysis, PubMed and Embase were searched for English-language studies published January 1, 1977, through January 31, 2017.

Study Selection: Observational studies reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB in unselected populations were selected.

Data Extraction And Synthesis: Two independent reviewers evaluated study quality and risk of bias using items from the Newcastle-Ottawa Quality Assessment Scale and the Quality Assessment of Diagnostic Accuracy Studies tool. Studies that included highly selected populations, lacked detailed inclusion criteria, and/or included 25 or fewer women were excluded.

Main Outcomes And Measures: The pooled prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB.

Results: A total of 129 unique studies, including 34 432 unique patients with PMB and 6358 with endometrial cancer (40 790 women), were analyzed. The pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumor stage. The pooled risk of endometrial cancer among women with PMB was 9% (95% CI, 8%-11%), with estimates varying by use of hormone therapy (range, 7% [95% CI, 6%-9%] to 12% [95% CI, 9%-15%]; P < .001 for heterogeneity) and geographic region (range, 5% [95% CI, 3%-11%] in North America to 13% [95% CI, 9%-19%] in Western Europe; P = .09 for heterogeneity).

Conclusions And Relevance: Early detection strategies focused on women with PMB have the potential to capture as many as 90% of endometrial cancers; however, most women with PMB will not be diagnosed with endometrial cancer. These results can aid in the assessment of the potential clinical value of new early detection markers and clinical management strategies for endometrial cancer and will help to inform clinical and epidemiologic risk prediction models to support decision making.
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http://dx.doi.org/10.1001/jamainternmed.2018.2820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142981PMC
September 2018

Strategies for screening and early detection of anal cancers: A narrative and systematic review and meta-analysis of cytology, HPV testing, and other biomarkers.

Cancer Cytopathol 2018 07 24;126(7):447-460. Epub 2018 May 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Anal cancer incidence and mortality have been increasing over the past decade. Although the incidence in the general population remains low, it is much higher in certain subgroups, including those living with human immunodeficiency virus and men who have sex with men. Approximately 90% of anal squamous cell cancers are caused by infection with carcinogenic human papillomavirus (HPV). Given the common etiology between anal and cervical carcinogenesis, screening for anal cancer has been proposed in certain high-risk populations using strategies adapted from cervical cancer prevention. In this review, the authors discuss important differences in anal and cervical cancer regarding the populations at risk, disease natural history, and clinical procedures and outcomes that need to be considered when evaluating strategies for anal cancer screening. They also performed a systematic review and meta-analysis of the performance of anal cytology, anal HPV testing, and various biomarkers for the detection of anal precancers and cancers. The implications of these performance estimates are summarized in the context of risk-based screening and management of anal precancers, and important research gaps are highlighted that need to be addressed to fully understand the benefits and harms of anal cancer screening. Cancer Cytopathol 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.
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http://dx.doi.org/10.1002/cncy.22018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252169PMC
July 2018

The Intersection of HPV Epidemiology, Genomics and Mechanistic Studies of HPV-Mediated Carcinogenesis.

Viruses 2018 02 13;10(2). Epub 2018 Feb 13.

Departments of Pediatrics, Microbiology and Immunology, Epidemiology and Population Health, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Of the ~60 human papillomavirus (HPV) genotypes that infect the cervicovaginal epithelium, only 12-13 "high-risk" types are well-established as causing cervical cancer, with HPV16 accounting for over half of all cases worldwide. While HPV16 is the most important carcinogenic type, variants of HPV16 can differ in their carcinogenicity by 10-fold or more in epidemiologic studies. Strong genotype-phenotype associations embedded in the small 8-kb HPV16 genome motivate molecular studies to understand the underlying molecular mechanisms. Understanding the mechanisms of HPV genomic findings is complicated by the linkage of HPV genome variants. A panel of experts in various disciplines gathered on 21 November 2016 to discuss the interdisciplinary science of HPV oncogenesis. Here, we summarize the discussion of the complexity of the viral-host interaction and highlight important next steps for selected applied basic laboratory studies guided by epidemiological genomic findings.
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http://dx.doi.org/10.3390/v10020080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850387PMC
February 2018

Human Papillomavirus DNA Methylation as a Biomarker for Cervical Precancer: Consistency across 12 Genotypes and Potential Impact on Management of HPV-Positive Women.

Clin Cancer Res 2018 05 2;24(9):2194-2202. Epub 2018 Feb 2.

Departments of Epidemiology and Population Health, Microbiology and Immunology, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York.

Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. In this nested case-control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives. HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932258PMC
May 2018

Epidemiologic Evidence That Excess Body Weight Increases Risk of Cervical Cancer by Decreased Detection of Precancer.

J Clin Oncol 2018 04 22;36(12):1184-1191. Epub 2018 Jan 22.

Megan A. Clarke, Li C. Cheung, Nicolas Wentzensen, Julia C. Gage, Hormuzd A. Katki, Maria Demarco, and Mark Schiffman, National Cancer Institute, Bethesda; Brian Befano and John Schussler, Information Management Services, Calverton, MD; Barbara Fetterman, Walter K. Kinney, Thomas S. Lorey, and Nancy E. Poitras, Kaiser Permanente Medical Group, Berkeley, CA; Tina R. Raine-Bennett, Kaiser Permanente Northern California, Oakland, CA; and Philip E. Castle, Albert Einstein College of Medicine, Bronx, NY.

Purpose Obesity has been inconsistently linked to increased cervical cancer incidence and mortality; however, the effect of obesity on cervical screening has not been explored. We investigated the hypothesis that increased body mass might decrease detection of cervical precancer and increase risk of cervical cancer even in women undergoing state-of-the-art screening. Methods We conducted a retrospective cohort study of 944,227 women age 30 to 64 years who underwent cytology and human papillomavirus DNA testing (ie, cotesting) at Kaiser Permanente Northern California (January 2003 to December 2015). Body mass index was categorized as normal/underweight (< 25 kg/m), overweight (25 to < 30 kg/m), or obese (≥ 30 kg/m). We estimated 5-year cumulative risks of cervical precancer and cancer by category of body mass index using logistic Weibull survival models. Results We observed lower risk of cervical precancer (n = 4,489) and higher risk of cervical cancer (n = 490) with increasing body mass index. Specifically, obese women had the lowest 5-year risk of precancer (0.51%; 95% CI, 0.48% to 0.54% v 0.73%; 95% CI, 0.70% to 0.76% in normal/underweight women; P trend < .001). In contrast, obese women had the highest 5-year risk of cancer (0.083%; 95% CI, 0.072% to 0.096% v 0.056%; 95% CI, 0.048% to 0.066% in normal/underweight women; P trend < .001). Results were consistent in subgroups defined by age (30 to 49 v 50 to 64 years), human papillomavirus status (positive v negative), and histologic subtype (glandular v squamous). Approximately 20% of cervical cancers could be attributed to overweight or obesity in the women in our study who underwent routine cervical screening. Conclusion In this large, screened population, overweight and obese women had an increased risk of cervical cancer, likely because of underdiagnosis of cervical precancer. Improvements in equipment and/or technique to assure adequate sampling and visualization of women with elevated body mass might reduce cervical cancer incidence.
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http://dx.doi.org/10.1200/JCO.2017.75.3442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908221PMC
April 2018

From clinical epidemiology to practice recommendations: Knowledge gaps and uncertainty in the management of anal precancers.

Cancer 2017 12 26;123(23):4530-4534. Epub 2017 Sep 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1002/cncr.31033DOI Listing
December 2017

Somatic Host Cell Alterations in HPV Carcinogenesis.

Viruses 2017 08 3;9(8). Epub 2017 Aug 3.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.

High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements. HPV-associated cancers have recurrent somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha () and phosphatase and tensin homolog (), human leukocyte antigen A and B ( and ), and the transforming growth factor beta (TGFβ) pathway, and rarely have mutations in the tumor protein p53 () and RB transcriptional corepressor 1 () tumor suppressor genes. There are some variations by tumor site, such as mutations which are primarily found in head and neck cancers. Understanding the somatic events following HPV infection and persistence can aid the development of early detection biomarkers, particularly when mutations in precancers are characterized. Somatic mutations may also influence prognosis and treatment decisions.
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http://dx.doi.org/10.3390/v9080206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580463PMC
August 2017
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