Liauw, Stanley L.

Background/Objectives: Surveillance for anal squamous cell carcinoma (ASCC) recurrence relies on clinical examination and imaging. Post-treatment edema, fibrosis, and inflammation can result in clinically indeterminate findings (CIFs) that delay diagnosis and increase patient and system burden. Circulating tumor tissue-modified viral (TTMV)-HPV DNA offers a biologically specific, noninvasive biomarker that may clarify equivocal assessments. Methods: In this multi-center retrospective study, 233 patients with HPV-associated ASCC were evaluated, including 185 with ≥1 post-treatment TTMV-HPV DNA test. CIFs were defined as exams or imaging results not definitively positive or negative for disease, and were paired with subsequent TTMV-HPV DNA tests. Concordance was defined by prespecified follow-up windows comparing TTMV-HPV DNA results with subsequent clinical outcomes. Results: Ninety patients (39%) experienced 214 CIFs, arising from exams (46%, 98) or imaging (54%, 116). Indeterminate rates by assessment were 7% for exams, 17% for imaging, and 1.3% for TTMV-HPV DNA testing. Overall, 52 CIF/TTMV-HPV DNA pairs were eligible for analysis, and TTMV-HPV DNA resolved disease status accurately for 48/52 (92%, 95% CI: 81.5–97.9). Negative tests predicted cancer-free status for 37/41 CIFs (90%), while 100% of positive tests (11/11) were concordant with clinically confirmed recurrence. In 73% of positive cases (8/11), TTMV-HPV DNA was the first indication of recurrence (median lead-time 29 days; IQR 25–147). Conclusions: TTMV-HPV DNA testing reliably clarifies clinically indeterminate findings during ASCC surveillance, demonstrating high accuracy (92%) and earlier detection of recurrence. These data support integration into post-treatment management to reduce diagnostic uncertainty and guide timely care.

Background: The incidence and mortality of anal squamous cell carcinoma (ASCC) are rising, with greater than 80% of cases linked to human papillomavirus (HPV), primarily HPV16. Post-treatment surveillance can be challenging due to the limitations of anoscopy, digital anal rectal exam (DARE), and imaging. Plasma tumor tissue modified viral (TTMV)-HPV DNA has shown strong sensitivity, specificity, and predictive value in detecting the recurrence of HPV-driven oropharyngeal cancer. Here, we investigate the ability of TTMV-HPV DNA for the early recurrence detection of ASCC. Methods: This retrospective clinical case series included 117 patients with HPV-driven ASCC across 7 U.S. centers, monitored with TTMV-HPV DNA during routine clinical care between March 2020 and June 2024. Physician-reported clinical data and biomarker testing data were combined to create a comprehensive, longitudinal dataset for evaluating test performance metrics. Results: Patients had a median age of 63 years and median post-diagnosis follow-up of 19 months. HPV status was primarily confirmed by TTMV-HPV DNA (52%) or p16 immunohistochemistry (39%). Of those tested for TTMV-HPV DNA pretreatment, 85% had a positive result. TTMV-HPV DNA clearance during or within three months post-treatment was associated with significantly better recurrence-free survival. The per-patient surveillance sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 82.8%, 98.4%, 96.0%, and 92.5%. Of 24 patients with a documented recurrence and a positive TTMV-HPV DNA test, the test was the first evidence of recurrence in 14 patients (58.3%), with a median lead time of 59 days (range: 10–536). TTMV-HPV DNA accurately resolved 94.3% of cases with indeterminate clinical findings. Conclusions: TTMV-HPV DNA testing provides a sensitive and specific approach for detecting patients with recurrent ASCC and resolving the status of patients with indeterminate clinical findings.

Abstract Purpose: Squamous cell carcinoma of the anus (SCCA) is primarily driven by human papillomavirus (HPV) infection. Up to 30% of patients experience recurrence, necessitating improved surveillance strategies. Liquid biopsies have shown promise as a tool in oncology. This study investigates the clinical performance of circulating tumor tissue modified viral (TTMV)- HPV DNA in the post-treatment surveillance of SCCA. Patients and methods: This central IRB-approved retrospective cohort study included 117 patients diagnosed with HPV-driven SCCA from seven U.S. centers who had ≥1 TTMV-HPV DNA tests (NavDx®, Naveris, Inc., Waltham, MA) performed between March 2020 and June 2024. TTMV-HPV DNA for HPV subtypes 16, 18, 31, 33, and 35 were analyzed using droplet digital PCR. The diagnostic accuracy of TTMV-HPV DNA was evaluated by comparing test results with clinical evidence of SCCA recurrence determined through anoscopy, radiology, and/or tissue biopsy. Recurrence is defined as either a positive biopsy or subsequent salvage therapy. Results: Patients were primarily female (73%) with a median age 63 years. Median follow-up after initial treatment was 19 months. Forty-seven patients (40%) had pretreatment TTMV-HPV DNA testing, with a baseline detectability of 85.1% (40/47, 95% CI: 74.9–95.3). Of these, 24 were re-tested within 3 months post-treatment and 18 had undetectable TTMV-HPV DNA (75%). Those patients whose scores became undetectable had significantly longer recurrence-free survival than those whose scores remained detectable (log-rank test, p=0.01). One hundred and four patients (89%) underwent post-treatment testing, of which 91 provided relevant data for the analysis. Of these 91 patients, 27 (29.7%) experienced recurrence. Post-treatment testing demonstrated a per- patient sensitivity of 85.7% (24/28, 95% CI: 72.8-98.7). Of four patients with a false negative test, only one had biopsy-confirmed recurrence, whereas the remaining recurrences were not biopsied prior to starting salvage treatment. The positive predictive value of a single positive test was 97.6% (40/41; 95% CI: 92.8–100.0). One patient remains in active follow-up. Of the true positive post-treatment tests, 58% (14/24) predicted recurrence before clinical detection, with a median lead time of 59 days (range: 10–536). There were 141 negative post-treatment tests across 66 patients. This yielded a per-test specificity and negative predictive value of 99.3% (136/137, 95% CI: 97.8-100.0) and 97.2% (136/140, 95% CI: 94.9-99.9), respectively. Indeterminate TTMV-HPV DNA tests were rare (5/268,1.9%). However, clinically indeterminate findings (CIFs) were common, with 141 post-treatment CIFs identified across 52/117 patients (44.4%). TTMV-HPV DNA testing was able to correctly predict recurrence status in 94.3% of CIF cases. Conclusion: TTMV-HPV DNA testing is a sensitive and specific surveillance method for detecting early recurrence of HPV-driven SCCA. Citation Format: Shane Lloyd, Rafi Kabarriti, James Jabalee, Tyler Slater, Corbin Jacobs, Sean Inocencio, Michael Rutenberg, Chance Matthiesen, Kasha Neff, Gene-Fu F Liu, Tiffany M Juarez, Catherine DV Fitz, Stanley Liauw. Plasma-based circulating tumor tissue modified viral (TTMV)-HPV DNA for detection of recurrent HPV-driven anal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B018.

Abstract Background Immunosuppressive regimens associated with organ transplantation increase the risk of developing cancer. Transplant candidates and recipients with prostate cancer are often treated, even if low-risk features would ordinarily justify active surveillance. Methods Using SEER-Medicare, we identified 163 676 men aged 66 years and older diagnosed with nonmetastatic prostate cancer. History of solid organ transplant was identified using diagnosis or procedure codes. A propensity score-matched cohort was identified by matching transplanted men to nontransplanted controls by age, race, region, year, T-stage, grade, comorbidity, and cancer therapy. Fine-Gray competing risk models assessed associations between transplant status and prostate cancer-specific mortality (PCSM) and overall mortality (OM). Results We identified 620 men (0.4%) with transplant up to 10 years before (n = 320) or 5 years after (n = 300) prostate cancer diagnosis and matched them to 3100 men. At 10 years, OM was 55.7% and PCSM was 6.0% in the transplant cohort compared with 42.4% (P < .001) and 7.6% (P = .70) in the nontransplant cohort, respectively. Adjusted models showed no difference in PCSM for transplanted men (hazard ratio = 0.88, 95% confidence interval = 0.61 to 1.27, P = .70) or differences by prostate cancer therapy. Among 334 transplanted men with T1-2N0, well or moderately differentiated “low-risk” prostate cancer, PCSM was similar for treated and untreated men (hazard ratio = 0.92, 95% confidence interval = 0.47 to 1.81). Conclusions Among men aged 66 years and older with prostate cancer, an organ transplant is associated with higher OM but no observable difference in PCSM. These findings suggest men with prostate cancer and previous or future organ transplantation should be managed per usual standards of care, including consideration of active surveillance for low-risk cancer characteristics.

24 Background: The use of radical prostatectomy (RP) as initial treatment of high-risk/locally-advanced prostate cancer is increasing but patients (pts) with adverse pathologic features such as positive surgical margins or T3 disease have up to 70% recurrence risk. These high-risk pts may be managed with adjuvant radiotherapy (ART) or early salvage radiotherapy (ESRT). The optimal timing of post-operative radiotherapy is unclear. Methods: Individual data from 1566 consecutive pts with pT2N0M0/R1 or pT3N0M0/R0-1 disease who underwent post-prostatectomy ART or ESRT (1987-2013) at 10 academic centers were pooled. Post-irradiation freedom from biochemical failure (FFBF), freedom from distant metastases (FFDM), prostate-cancer specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier and multivariate competing-risks regression (MVA) analyses. Propensity score (PS) matching was used to account for covariates potentially associated with treatment allocation. All outcomes were measured from the date of surgery to address lead time bias. Results: After PS-matching, median follow-up after surgery was 66 vs. 73 months for the ART and ESRT groups, respectively, and baseline characteristics were well-matched. ART was associated with higher FFBF (12-yr: 69% vs. 43%; log-rank P < 0.0001), FFDM (12-yr: 95% vs. 85%; log-rank P = 0.03), PCSS (12-yr: 99% vs. 94%; log-rank P = 0.048), and OS (12-yr: 91% vs. 79%; log-rank P = 0.01). ART, lower Gleason score, lower T-stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on MVA for BF. Sensitivity analysis demonstrated that the decreased risk of BF associated with ART remained significant unless more than 56% of ART pts were cured by surgery alone. This threshold is greater than the estimated 12-yr FFBF of 46% after RP alone as determined by a contemporary nomogram. Conclusions: To the best of our knowledge, this represents the largest multi-institutional study to date comparing ART to ESRT. ART was associated with reduced biochemical recurrence, distant metastases, and death compared to ESRT for high-risk pts, pending prospective validation.

9 Background: Early salvage radiation therapy (SRT) following radical prostatectomy (RP) has been shown to reduce biochemical recurrence and distant metastases. We aim to identify factors predictive of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) from a consortium database from 10 academic institutions. Methods: 2,454 node-negative patients (pts) with detectable post-prostatectomy PSA ( ≥ 0.01 ng/mL) treated with SRT ± neoadjuvant/concurrent androgen deprivation therapy (N/C ADT) were included. Cumulative incidence and Kaplan-Meier methods were used to estimate rates of PCSM and ACM, respectively. Univariate and multivariable analyses (MVA) were performed by competing risks regression and Cox proportional hazards methods for PCSM and ACM. Results: Median follow-up was 5 years from SRT completion and 8 years from date of RP; 24% had pathologic Gleason score (GS) of ≤ 6, 56% GS 7, and 19% GS ≥ 8; 56% extraprostatic extension (EPE), 18% seminal vesicle invasion (SVI), 58% positive surgical margins, and 16% received N/C ADT. Median age at RP and SRT were 62 years (IQR 56-66) and 64 years (59-69), respectively. Median SRT dose was 66 Gy (IQR 65-68) and median pre-SRT PSA was 0.5 ng/mL (IQR 0.3-1.1). MVA performed from SRT completion date demonstrated higher pre-SRT PSA (HR = 2.1), higher GS (GS 7 vs. ≤ 6: HR 2.0; GS ≥ 8 vs. 6: HR 3.3) , SVI (HR 2.5), year of SRT (2000-2004, 1995-1999, 1985-1994 vs. 2005-2012; HR 2.9, HR 2.5, HR 3.6, respectively) were significantly associated with higher PCSM. These same variables were all significantly associated with higher PCSM and ACM rates calculated from both SRT completion date and date of RP. Conclusions: Initiation of early SRT at lower post-operative PSA levels following RP is associated with reduced risk of PCSM and ACM, even when calculated from RP date to account for lead time bias. Other factors significantly associated with PCSM include higher GS, SVI, and earlier year of SRT. [Table: see text]

Purpose: To present the most updated American College of Radiology consensus guidelines formed from an expert panel on treatment of locally advanced, high-risk prostate cancer Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Results: The panel summarized the most recent and relevant literature on the topic and voted on 4 clinical variants illustrating the appropriate management of locally advanced, high-risk cancer. Numerical rating and commentary reflecting the panel consensus was given for each treatment approach in each variant. Conclusions: Aggressive local approaches including surgery followed by adjuvant XRT, beam combined with androgen deprivation therapy, and beam combined with brachytherapy have resulted in unpresented success in locally advanced, high-risk prostate cancer. By combining most recent medical literature and expert opinion, this guideline can aid clinicians in the appropriate integration of available therapeutic modalities.

Purpose We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. Methods Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. Results Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). Conclusion Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.