Highlights • At least 193 commercial HPV tests and 127 variants of the original tests are available. • There was a 54% increase in the number of HPV tests in comparison with 2012. • All but two ...commercial HPV tests target alpha-HPV types only. • Only 35% of tests have performance evaluations published in peer-reviewed literature. • Manufacturers should invest greater effort into evaluating their products.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This study compares the detection sensitivity of two separate liquid biopsy sources, cell-free (cf) DNA/RNA and extracellular vesicle (EV)-associated DNA/RNA (EV-DNA/RNA), to identify circulating ...Human Papilloma Virus (HPV) DNA/RNA in plasma obtained from patients with oropharyngeal squamous cell carcinoma (OPCSCC). We also report on the longitudinal changes observed in HPV-DNA levels in response to treatment.
A prospective study was conducted that included 22 patients with locally advanced disease and six patients with metastatic OPCSCC. Twenty-three patients had HPV-related OPCSCC defined by p16 immunohistochemistry. Levels of circulating HPV-DNA and HPV-RNA from plasma-derived cf-DNA/RNA and EV-DNA/RNA were quantified using digital droplet PCR.
Circulating HPV-DNA was detected with higher sensitivity in cf-DNA compared to EV-DNA at 91% vs. 42% (p = <0.001). Similarly, circulating tumoral HPV-RNA was detected at a higher sensitivity in cf-RNA compared to EV-RNA, at 83% vs. 50% (p = 0.0019). In the locally advanced cohort, 100% (n = 16) of HPV-OPCSCC patients demonstrated a reduction in circulating HPV-DNA levels in cf-DNA following curative treatment, with 81% of patients demonstrating complete clearance to undetectable levels. However, in metastatic HPV-OPCSCC patients (n = 4), HPV-DNA levels did not correlate with treatment response.
Our study demonstrates that although HPV-DNA/RNA can be detected in EV associated DNA/RNA, cf-DNA/RNA is the more sensitive liquid biopsy medium. As circulating HPV-DNA levels were found to only correlate with treatment response in the locally advanced but not metastatic setting in our small cohort of patients, the use of HPV-DNA as a dynamic biomarker to monitor treatment response requires further evaluation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Cervical cancer screening guidelines for women aged ≥30 years allow for co-testing or primary cytology testing. Our objective was to determine the test characteristics and costs associated ...with
Cytology
,
HPV
and
Co-testing
screening strategies.
Main Methods
Retrospective cohort study of women undergoing cervical cancer screening with both cytology and HPV (Hybrid Capture 2) testing from 2004 to 2010 in an integrated health system. The electronic health record was used to identify women aged ≥30 years who had co-testing. Unsatisfactory or unavailable test results and incorrectly ordered tests were excluded. The main outcome was biopsy-proven cervical intraepithelial neoplasia grade 3 or higher (CIN3+).
Key Results
The final cohort consisted of 99,549 women. Subjects were mostly white (78.4 %), married (70.7 %), never smokers (61.3 %) and with private insurance (86.1 %). Overall, 5121 (5.1 %) tested positive for HPV and 6115 (6.1 %) had cytology ≥ ASCUS; 1681 had both and underwent colposcopy and 310 (0.3 %) had CIN3+. Sensitivity for CIN3+ was 91.9 % for
Primary Cytology
, 99.4 % for
Co-testing, and
94.8 % for
Primary HPV
; specificity was 97.3 % for
Co-testing
and
Primary Cytology
and 97.9 % for
Primary HPV
. Over a 3-year screening interval,
Primary HPV
detected more cases of CIN3+ and was less expensive than
Primary Cytology. Co-testing
detected 14 more cases of CIN3+ than
Primary HPV
, but required an additional 100,277 cytology tests and 566 colposcopies at an added cost of $2.38 million, or $170,096 per additional case detected.
Conclusions
Primary HPV
was more effective and less expensive than
Primary Cytology. Primary HPV
screening appears to represent a cost-effective alternative to
Co-testing
.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose In squamous cell carcinomas of the head and neck (HNSCC), the increasing incidence of oropharyngeal squamous cell carcinomas (OPSCCs) is attributable to human papillomavirus (HPV) infection. ...Despite commonly presenting at late stage, HPV-driven OPSCCs are associated with improved prognosis compared with HPV-negative disease. HPV DNA is also detectable in nonoropharyngeal (non-OPSCC), but its pathogenic role and clinical significance are unclear. The objectives of this study were to determine whether HPV plays a causal role in non-OPSCC and to investigate whether HPV confers a survival benefit in these tumors. Methods Meta-analysis was used to build a cross-tissue gene-expression signature for HPV-driven cancer. Classifiers trained by machine-learning approaches were used to predict the HPV status of 520 HNSCCs profiled by The Cancer Genome Atlas project. DNA methylation data were similarly used to classify 464 HNSCCs and these analyses were integrated with genomic, histopathology, and survival data to permit a comprehensive comparison of HPV transcript-positive OPSCC and non-OPSCC. Results HPV-driven tumors accounted for 4.1% of non-OPSCCs. Regardless of anatomic site, HPV+ HNSCCs shared highly similar gene expression and DNA methylation profiles; nonkeratinizing, basaloid histopathological features; and lack of TP53 or CDKN2A alterations. Improved overall survival, however, was largely restricted to HPV-driven OPSCCs, which were associated with increased levels of tumor-infiltrating lymphocytes compared with HPV-driven non-OPSCCs. Conclusion Our analysis identified a causal role for HPV in transcript-positive non-OPSCCs throughout the head and neck. Notably, however, HPV-driven non-OPSCCs display a distinct immune microenvironment and clinical behavior compared with HPV-driven OPSCCs.
We assessed carrageenan's potential to inhibit human papillomavirus (HPV) DNA extraction and amplification in vaginal swab samples collected in a trial, assessing the efficacy of a carrageenan‐based ...gel against HPV infections. Experiment #1 consisted of adding gel (carrageenan‐containing or placebo) to swabs and comparing HPV DNA detection by polymerase chain reaction (PCR) to unmanipulated samples collected from the same participants. For Experiments #2 and #3, we tested vaginal samples for inhibition by addition of an internal control and amplification by real‐time PCR. Experiment #4 investigated carrageenan's interference with the extraction process by assessing HPV45 detectability in undiluted and diluted HPV45 positive samples (n = 3) with carrageenan versus no gel. In Experiment #1, there was a loss of HPV positivity with the addition of carrageenan (n = 9), but none with placebo gel (n = 5). In Experiments #2 and #3, the absence of the amplified product was observed in samples from the carrageenan arm: 3.3% (1/30) and 0.5% (1/199) of samples. In Experiment #4, HPV45 was not detected in undiluted carrageenan‐containing samples, but after 1/50 dilution, the same HPV45 copy number was detected. Carrageenan does not affect the DNA extraction process, and inhibition of HPV DNA amplification by carrageenan occurs infrequently.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Highlights • Evidence suggests that primary HPV testing can be more effective than cytology. • Additional triage tests are needed to decide who among the HPV-positive women requires further ...management or treatment. • Evaluation of triage test candidates is based on absolute risk estimates compared to established clinical action thresholds. • An optimal integrated screening and triage strategy should reassure the vast majority of women that they are at very low risk of cervical cancer while sending the women at highest risk to colposcopy and treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV ...markers in a large series of VIN and IVC lesions. Methods Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25 ) (version 1). IVC cases were tested for p16INK4a by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16INK4a overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI). Results Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16INK4a positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) ( N = 1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) ( N = 326) were more likely to be HPV and p16INK4a positive (AP = 69.5%, CI = 63.6–74.8) versus KSCC (AP = 11.5%, CI = 9.7–13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold). Conclusion Combined data from HPV-DNA and p16INK4a testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Major organizations recommend cytology screening (Pap test) every 3 years for women aged 21–65; women aged 30 to 65 have the option of adding the HPV test (co-test) every 5 years. ...We examined national percentages of cervical cancer screening, and we examined use of co-testing as an option for screening. Methods We used 2015 U.S. National Health Interview Survey (NHIS) data to examine recent cervical cancer screening (Pap test within 3 years among women aged 21–65 without a hysterectomy; N = 10,596) and co-testing (N = 9,125). We also conducted a multivariable analysis to determine odds of having had a Pap test or co-test by demographic variables. To evaluate changes in screening over time, we examined Pap testing during the years 2000, 2005, 2008, 2010, 2013 and 2015. Analysis completed in Atlanta, GA during 2016. Results Overall, 81.1% of eligible women reported having a Pap test within 3 years; percentages declined over time among all age groups. An estimated 14 million women aged 21–65 had not been screened within the past 3 years. Recent immigrants to the United States, women without insurance, and women without a usual source of healthcare had lower odds of being up to date with screening. About 1/3 of women up to date on Pap testing reported having a co-test with their most recent Pap test. Conclusions Declines in screening among women aged 21–65 are cause for concern. More research is needed on co-testing practices. Provider and patient education efforts may be needed to clarify recommended use of HPV tests.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background The human papillomavirus (HPV) test, administered alone without the Papanicolaou (Pap) test, was recently recognized as a cervical cancer screening option in the United States by ...the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and the Food and Drug Administration has approved an HPV test for primary screening. Methods Surveys of US internists, family practitioners, nurse practitioners, and obstetrician–gynecologists were conducted in 2009 and 2012 to investigate providers' perceptions of the effectiveness of the HPV test administered alone as a population-based screening modality (2009: N = 1040, 141–494 per provider group; 2012: N = 1039, 155–435 per provider group). Results The majority in each provider group agreed that the HPV test administered alone is an effective screening modality in 2009 (75.3%–86.1%) and 2012 (79.5%–91.8%), and agreement rose significantly during this time period among family practitioners ( χ2 = 15.26, df = 1, p < 0.001) and nurse practitioners ( χ2 = 4.53, df = 1, p = 0.033). Conclusions Agreement that the HPV test administered alone is an effective cervical cancer screening modality was widespread among providers in both 2009 and 2012, however implementation of guidelines for screening with the HPV test may be influenced by many other factors including reimbursement and patient preferences.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal ...carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone.
In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA.
Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared.
p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone.
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