Detection Of High-grade Disease Research Articles

Abstract CT233: A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)

Abstract IntroductionCG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG (J Urol. 2012;188:2391-7; Urol Oncol. 2018;36(10):440-7). This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC.Methods110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x1012 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 months (m) may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response.ResultsThe primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response.ConclusionThe study an ongoing trial, currently enrolling in the United States, Japan, South Korea, Australia, and Taiwan.Refs. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, Aimi J, Lerner S, Yeung AW, Kazarian T, Maslyar DJ, McKiernan JM. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. Citation Format: Ed Uchio, Donald Lamm, Neil Shore, Trinity Bivalacqua, Ashish Kamat, Mark Tyson, Paul Anderson, Paola Grandi, James Burke. A phase 3, single-arm study of CG0070 in subjects with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT233.

A phase 3, single-arm study of CG0070 in subjects with nonmuscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG).

TPS598 Background: CG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG (J Urol. 2012;188:2391–7; Urol Oncol. 2018;36(10):440–7). This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC. Methods: 110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x1012 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 months (m) may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response. The primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. Study enrollment globally is ongoing including in North America, Taiwan, Japan, and South Korea. Refs. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, Aimi J, Lerner S, Yeung AW, Kazarian T, Maslyar DJ, McKiernan JM. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. Clinical trial information: NCT04452591.

MP23-12 MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING AND RECLASSIFICATION FROM ACTIVE SURVEILLANCE

You have accessJournal of UrologyProstate Cancer: Localized: Active Surveillance I (MP23)1 Apr 2020MP23-12 MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING AND RECLASSIFICATION FROM ACTIVE SURVEILLANCE Christopher J. Magnani*, Nicolas Bievre, Beril Erdogdu, Laurence C. Baker, James D. Brooks, and Tina Hernandez-Boussard Christopher J. Magnani*Christopher J. Magnani* More articles by this author , Nicolas BievreNicolas Bievre More articles by this author , Beril ErdogduBeril Erdogdu More articles by this author , Laurence C. BakerLaurence C. Baker More articles by this author , James D. BrooksJames D. Brooks More articles by this author , and Tina Hernandez-BoussardTina Hernandez-Boussard More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000856.012AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Active Surveillance (AS) has gained traction as a first line approach for men diagnosed with low-risk early-stage prostate cancer; however, identifying occult high grade or progressive disease remains challenging. While multiparametric MRI (mpMRI) has been explored in the initial diagnostic setting as an aid to identify clinically significant disease, its role in AS is less studied and lacks consistent guidelines. We retrospectively evaluated the relationship between mpMRI and AS reclassification at a designated academic Comprehensive Cancer Center. METHODS: We used Natural Language Processing (NLP) to identify patients in electronic health records (EHR) undergoing AS at our institution. We included men 35+ with stage ≤ 2 and Gleason score ≤ 7 who did not receive definitive treatment 9 months after diagnosis. We limited to men diagnosed 2012-2016 to ensure a 3-year study period and institutional mpMRI availability for all patients. To assess the association between mpMRI and reclassification, we used Kaplan-Meier (KM) estimates and Log-Rank test. RESULTS: We identified 511 men on AS, including 189 (37.0%) that received a mpMRI with a mean administration at 1.17 years (CI: 1.06, 1.27) after diagnosis. Compared to patients without imaging, those receiving an mpMRI had similar Charlson comorbidity, race, Gleason score, and proportion at stage 1; however, the imaged group was slightly younger (64.0 vs 66.3y, p 0.001) and had more (+12.8%) privately insured and fewer (-11.4%) on Medicare (p 0.001). KM estimates and Log-Rank test suggest more patients receiving mpMRI reclassified with a 15.2% difference (CI: 6.1% to 24.3%, p 0.004) from those not imaged (Figure). CONCLUSIONS: Our results demonstrate increased conversion to treatment from AS at 3 years for patients receiving mpMRI despite similar Charlson comorbidity, proportion at stage 1, and Gleason score, highlighting the potential role of mpMRI in the AS setting. Imaging likely enhances detection of high grade disease and accounts for higher treatment rates, potentially earlier in the course of surveillance. Future work will need to test whether increased treatment after MRI improves outcomes, particularly since the technology is expensive, necessitating further study of clinical impact to ensure high value care. Source of Funding: National Cancer Institute of the National Institutes of Health, Award Number R01CA183962 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e342-e343 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher J. Magnani* More articles by this author Nicolas Bievre More articles by this author Beril Erdogdu More articles by this author Laurence C. Baker More articles by this author James D. Brooks More articles by this author Tina Hernandez-Boussard More articles by this author Expand All Advertisement PDF downloadLoading ...

MP20-10 TEMPORAL TRENDS IN PROSTATE BIOPSY CRITERIA AND OUTCOMES FROM 2012-PRESENT

INTRODUCTION AND OBJECTIVE: In 2012, the United States Preventive Services Task Force (USPSTF) issued guidelines discouraging screening for prostate cancer using prostate specific antigen (PSA). We evaluated trends in our biopsy practices during this time period, with the hypothesis that criteria for biopsy became increasingly stringent, and there was a shift in diagnosis from low risk to higher risk disease. METHODS: We queried our institution’s electronic medical record for transrectal ultrasound-guided prostate biopsies (CPT code 55700) from 2012-2017. Patient and biopsy parameters (age, PSA, standard vs. MRI fusion biopsy, Grade Group [GG]), were recorded. Biopsies for PSA >50 ng/mL or those done for surveillance were excluded. Chi-square correlation assessed differences between % clinically significant prostate cancer (csPCa, defined as GG ≥ 2) and %GG1 diagnosis between 2012 and 2017. Multivariate logistic regression assessed predictors of csPCa as well as clinically insignificant prostate cancer (GG1). RESULTS: A total of 1,031 prostate biopsies were reviewed, and 927 were retained as initial diagnostic biopsies. Overall, PSA increased 0.35 ng/mL/year. The %csPCa increased from 20% in 2012 to 43% in 2017 (p < 0.001) while the %GG1 decreased from 23% to 11% (p = 0.004). On multivariable logistic regression, year was a significant independent predictor of csPCa (OR 1.13, p = 0.016). Year was also an independent predictor of GG1 disease with a 14% decreased odds of GG1 diagnosis with each additional year (OR 0.86, p=0.013). CONCLUSIONS: In the post-2012 era, there has been migration in prostate biopsy outcomes from low risk to higher risk disease. Rising PSA for biopsied patients during this time reflects more stringent criteria for biopsy. While less diagnosis of low grade disease (“overdiagnosis”) is a desirable outcome, increased detection of high grade disease is potentially worrisome. The effects of these shifts on prostate cancer mortality and advanced disease will become evident over time.Source of Funding: None.

Influence of high risk HPV genotype on colposcopic performance: A large prospective study demonstrates improved detection of disease with ZedScan I, particularly in non-HPV 16 patients

ObjectiveTo assess the influence of high-risk Human Papilloma Virus (hrHPV) genotyping on the detection of high-grade disease (CIN2+) using colposcopic impression both with and without electrical impedance spectroscopy (ZedScan I) as an adjunct. Study designA prospective cohort of women with a known hrHPV genotype referred to a single colposcopy service. Results839 women underwent colposcopy and ZedScan I examination. 613 women were referred with abnormal cytology; 411 (67%) with low-grade dyskaryosis (67%) and 202 (33%) with high-grade dyskaryosis. 187 were referred with persistent hrHPV but negative cytology. 35 were attended for follow up and 4 for a clinical indication. 159 (19%) women were positive for HPV16 only; 54 (6%) with HPV18 only, 443 (53%) women were positive for hrHPV other types (HPV O). 183 (22%) were positive for multiple hrHPV genotypes. CIN2+ was present in 170 (84.2%) of high-grade and 69 (16.7%) of low-grade cytology referrals. Colposcopy was better at detecting HPV16 associated CIN2+ than that associated with HPV18 or HPV O (86.9% vs 79.7%, p=0.0191). ZedScan I increased the detection of CIN2+ from 85.6% to 96% irrespective of hrHPV genotype status (p<0.0001). ConclusionThe use of an electrical impedance spectroscopic device (ZedScan I) increases detection of CIN2+ irrespective of hrHPV genotype.

Performance characteristics of PSA in patients undergoing radical prostatectomy.

199 Background: The Prostate Cancer Prevention Trial demonstrated that the performance characteristics of PSA are improved for diagnosis of high grade disease. We assessed the performance of PSA for determining total and high grade cancer volume in a radical prostatectomy series. Methods: We identified 1307 patients from the Stanford Radical Prostatectomy Database with clinical stage T1c (n=658) and T2 (n=549) disease who had surgery between 1988 and 2002 and detailed morphometric mapping by a single pathologist. Patients with T1c and T2 disease were analyzed separately as the indication for biopsy was different in these two populations (elevated PSA versus abnormal DRE). We generated receiver operating characteristic (ROC) curves for PSA based on total tumor volume and volume of Gleason 4 or 5 disease and compared the areas under the curve (AUC) for different cut points of total and high grade cancer volume. Results: For patients with clinical stage T1c disease, as total and high grade cancer volumes increased, so did the AUC for PSA performance. There was a significant difference in AUC for PSA for total cancer volumes greater than 0.5 cc (AUC=0.62) compared to greater than 2 cc (AUC=0.72, p=0.02), and also between volumes greater than 2 cc (AUC=0.72) and 5 cc (AUC=0.79, p=0.0003, Fig.1). The AUC for PSA performance for volume of high grade disease increased from 0.66, to 0.68, to 0.76 for Gleason 4 or 5 volumes of 0, 0.5, and 3 cc, respectively (Fig. 2). For patients with clinical stage T2 disease, the AUCs for total or high grade cancer volume were not different across cut points, but were overall higher compared to the T1c group. Conclusions: In T1c patients, PSA performance improved in a stepwise fashion with higher total and high grade cancer volumes as evidenced by improved receiver operating characteristics. In T2 patients, no similar trend was observed, although overall PSA performance was improved compared to T1c patients. Prior studies show that PSA performs better for the detection of high grade disease; here, we show that PSA performs better in predicting volume of high grade disease in radical prostatectomy specimens.

Role of Protein Biomarkers in the Detection of High-Grade Disease in Cervical Cancer Screening Programs

Since the Pap test was introduced in the 1940s, there has been an approximately 70% reduction in the incidence of squamous cell cervical cancers in many developed countries by the application of organized and opportunistic screening programs. The efficacy of the Pap test, however, is hampered by high interobserver variability and high false-negative and false-positive rates. The use of biomarkers has demonstrated the ability to overcome these issues, leading to improved positive predictive value of cervical screening results. In addition, the introduction of HPV primary screening programs will necessitate the use of a follow-up test with high specificity to triage the high number of HPV-positive tests. This paper will focus on protein biomarkers currently available for use in cervical cancer screening, which appear to improve the detection of women at greatest risk for developing cervical cancer, including Ki-67, p16INK4a, BD ProEx C, and Cytoactiv HPV L1.

The Influence of Prostate Volume on Prostate-Specific Antigen Performance: Implications for the Prostate Cancer Prevention Trial Outcomes

Although showing a 25% reduction in the biopsy prevalence of cancer compared with placebo in the Prostate Cancer Prevention Trial, finasteride was associated with a higher prevalence of high-grade disease. This observation was driven by "for-cause" biopsies. We sought to understand how volume-dependent changes in prostate-specific antigen test performance characteristics may have contributed. A retrospective review was done on 1,304 men referred for initial biopsy with a prostate-specific antigen between 4 and 10 ng/mL or an abnormal digital rectal examination. Receiver-operator curves and positive predictive values were ascertained for prostate-specific antigen stratified by diagnosis and prostate volume. The performance of prostate-specific antigen changed for any and high-grade (Gleason, > or =3 + 4) cancer in a volume-specific manner. For any cancer, the area under the curve (AUC) decreased from 0.758 to 0.629 to 0.520 as prostate volume increased (<30, 30-50, >50 cm(3), respectively). For high-grade cancer, a similar trend was shown (AUC, 0.712, 0.639, and 0.497, respectively). The positive predictive value of a prostate-specific antigen of > or =4 ng/mL was also affected by prostate volume. Trends for Gleason < or = 6 decreased as prostate volume increased (positive predictive value for <30 cm(3), 25.0%; positive predictive value for 30-50 cm(3), 23.8%; and positive predictive value for >50 cm(3), 17.3%). A more significant trend was seen for high-grade cancer (positive predictive value for <30 cm(3), 39.0%; positive predictive value for 30-50 cm(3), 22.3%; and positive predictive value for >50 cm(3), 10.7%). Decreases in prostate volume over time and the resultant change in prostate-specific antigen performance characteristics may have contributed a bias toward the detection of high-grade disease in the finasteride arm of the Prostate Cancer Prevention Trial.

Cervical cytologic screening: Optimal management of atypical squamous cells of undetermined significance in young women

1019 Background: HPV testing is a cost-effective strategy for the management of ASC-US cytology. However, young women have a high prevalence of transient HPV infections and low incidence high grade cervical lesions which may limit the utility of HPV testing in these women. We sought to determine the utility of HPV testing for young women with ASC-US. Methods: A review of all patients with ASC-US cytology between January, 2003 and December, 2004 was performed. Reflex HPV testing using the Hybrid Capture II system was performed on all samples. Age stratified rates of HPV positivity, rates of high grade dysplasia and sensitivity and specificity were estimated. Results: A total of 1290 women with ASC-US cytology were identified. The percentage of ASC-US samples that were HPV positive was highest in the young women and decreased with advancing age: &lt; 25 yo (55%), 26–40 (36%), 41–50 (13%), &gt; 50 yo (12%) (p&lt;0.0001). Among HPV positive women with ASC-US, the identification of high grade lesions (HSIL, CIN2, CIN3, cancer) was lowest in the young women and increased with age: &lt; 25 (12%), 26–40 (24%), 41–50 (19%), &gt; 50 yo (24%) (p=0.05). A negative HPV test more reliably excluded high disease in the young women. No high grade lesions were detected in the HPV negative women ≤ 25 compared to 3.8% of those &gt; 50 (p=0.04). The sensitivity for detection of high grade disease was higher in women &lt; 25 compared to those &gt; 50 (100% vs. 50%), while specificity was lower (14% vs. 44%). Conclusions: Given the high prevalence of HPV and low occurrence of high grade lesions in young women with ASC-US, an HPV based triage strategy will result in the referral of a large number of women for colposcopy and may limit its cost effectiveness. A program of repeat cytology may be more appropriate for the follow-up of young women with ASC-US. [Table: see text]

Self testing for human papillomaviruses

Is it feasible and what samples should be used? A great deal has been written about the potential value of human papillomavirus (HPV) testing, particularly in the context of cervical screening programmes. Much of the published literature has focused on the assessment of specific patient groups, particularly women with mildly abnormal cervical smears, in an attempt to identify those women at greatest risk of either possessing or developing a high grade intraepithelial lesion which, according to current guidelines, requires treatment. Much of the value of HPV testing is dependent upon its high sensitivity for the detection of high grade disease and also the high negative predictive value of testing women both with low grade cytological abnormalities and in the context of primary screening.1–4 However, the duration of protection of a negative result is not yet known. These points are among those covered by the systematic review of the role of HPV testing within a cervical screening programme, published in 1999,5 and form the basis of many of the conclusions of that report. One of the other recommendations put forward was that HPV testing could potentially be applied to self collected cervical samples. In particular, this could help to improve coverage of the screened population by encouraging those who do not attend for routine cervical smears to provide samples for testing themselves. This issue is addressed in the study by Nobbenhuis et al in this issue of JCP ,6 in which both a self collected cervicovaginal lavage specimen and a cervical smear were analysed cytologically and by HPV DNA testing. …