No Evidence Of Disease Research Articles

BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL as urinary marker for bladder cancer: Final results of a German multicenter study

Introduction and objectiveBTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL are urinary-based rapid tests. This multicenter study is the first study comparing all available rapid tests on a large cohort of bladder cancer patients and healthy controls in one setting. MethodsIn total 732 urine samples (second morning urine) in a real-world assessment have been analyzed. We evaluated clinical samples from 464 patients with histologically confirmed urothelial tumors of the urinary bladder (17 solitary CIS, 189 low-grade, 187 high-grade nonmuscle invasive, 71 high-grade muscle invasive), 77 patients with No Evidence of Disease (NED), and from 191 healthy controls. Urine samples were analyzed by the BTA stat®, NMP22® BladderChek®, UBC® Rapid Test point-of-care (POC) system using the concile Omega 100 POC reader, and CancerCheck® UBC® rapid VISUAL. Sensitivities and specificities were calculated by contingency analyses. ResultsAll investigated urinary markers detected more pathological concentrations in urine of bladder cancer patients compared to tumor-free patients. The calculated diagnostic sensitivities for BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, CancerCheck® UBC® rapid VISUAL, and cytology were 62.4%, 13.4%, 58.2%, 28.6%, 36.2% for low-grade, 83.4%, 49.5%, 84.5%, 63.1%, 71.2% for high-grade nonmuscle invasive, and 95.8%, 35.2%, 76.1%, 50.7%, 67.7% for high-grade muscle-invasive bladder cancer. The specificity was 67.9%, 95.5%, 79.4%, 94.4%, and 83.7%, respectively. The area under the curve (AUC) after receiver operating characteristics (ROC) analysis for high-grade non–muscle-invasive tumors was 0.757, 0.725, 0.819, 0.787, and 0.774, respectively. ConclusionsThe analysis of more than 700 urine samples offers an objective view on urine-based rapid diagnostics. Elevated pathological concentrations of markers in urine of bladder cancer patients were detected in all investigated tests. The highest sensitivities for high-grade non–muscle-invasive tumors were calculated for BTA stat® and UBC® Rapid Test, whereas NMP22® BladderChek®, and cytology showed the highest specificities. BTA stat® and UBC® Rapid Test have the potential to be used as a clinical valuable urinary protein biomarker for the detection of high-grade non–muscle-invasive bladder cancer patients and could be included in the management of these tumors.

Combined detection of SDC2/ADHFE1/PPP2R5C methylation in stool DNA for colorectal cancer screening.

Colorectal cancer (CRC) is a disease of global concern, and its increasing incidence suggests the need for early and accurate diagnosis. The aim of this study was to investigate the value of combined detection of SDC2, ADHFE1 and PPP2R5C gene methylation in stool samples for early CRC screening. Stool samples from patients with CRC (n = 105), advanced adenoma (AA) (n = 54), non-advanced adenoma (NA) (n = 57), hyperplastic or other polyps (HOP) (n = 47) or no evidence of disease (NED) (n = 100) were collected from September 2021 to September 2022. The methylation levels of SDC2, ADHFE1 and PPP2R5C were quantified by quantitative methylation-specific polymerase chain reaction (qMSP), and faecal immunochemical testing (FIT) was performed. The diagnostic value was assessed using reporter operating characteristic (ROC) curve analysis. The sensitivity of combined detection of SDC2/ADHFE1/PPP2R5C methylation in predicting CRC (0-IV) was 84.8%, the specificity was 98.0%, and the AUC was 0.930 (95% CI 0.889-0.970). Compared to FIT and serum tumour biomarkers, it showed better diagnostic performance for different stages of CRC. The results of this study verified that the methylation levels of SDC2, ADHFE1 and PPP2R5C in stool DNA were significantly increased in CRC patients. Combined detection of SDC2/ADHFE1/PPP2R5C methylation is a potential non-invasive diagnostic method for CRC and precancerous lesion screening. Chinese Clinical Trials Registry, ChiCTR2100046662, registered on 26 May 2021, prospective registration.

First report of tumor-informed circulating tumor DNA in fibrolamellar carcinoma in adolescents and young adults: 51 patients.

3034 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare form of primary liver cancer (50-200 cases/year), unrelated to hepatocellular carcinoma. The only established standard of care is surgery. However, recurrence is at least 80%, even with R0 surgery, suggesting that FLC is best thought of as a systemic disease instead of a surgical disease. Systemic therapies in retrospective studies of more than 25 show immunotherapy and chemotherapy combinations have promise. Circulating “tumor-informed” tumor DNA (ctDNA) is a tool for tracking microscopic systemic disease, serving as a marker of systemic involvement, has shown success in management of other cancers. FLC has never been studied using this technology. Our retrospective study of 51 patients over a 2.5-year period is the first attempt to understand if ctDNA can be helpful in the management of FLC. Methods: All patients consented to blood draws on a 1-3 monthly basis, according to the company (Signatera) protocol. All patients had regular imaging reviewed by the FibroFighters Foundation National Tumor Board. Complete response (CR), Partial response (PR) (> 30% decrease), Progressive Disease (PD) (> 20% increase), and Stable Disease (SD) (neither PD/PR/CR) were recorded according RECIST 1.1. The imaging closest in time to the blood draw was used for correlation purposes. “Negative” is defined as a value = 0.00. “Positive” is defined as a value > 0.00. Results: Fifty-one FLC patients (26M, 25F, median age 23, range 10-56), 92% stage (III/IV), consented to ctDNA “blood biopsies,” (n=226 samples, mean 4.4/patient, range 1-11). Negative values correlated with no evidence of disease (NED) on imaging 78% of the time, positive values with disease 94% [PPV/NPV/sens/spec of 0.78/0.94/0.93/0.81]. NPV and sens increased to almost 100% with a ctDNA threshold of > 1.0 at the expense of a lower PPV and spec. However, consecutive negative ctDNA values correlated with radiologic NED 86% [PPV/NPV/sens/spec = 0.86/0.84/0.77/0.91] without a single PD in this cohort (n=64). A “downward trend or slope” on consecutive values predicted Objective Response (CR+PR) and Disease Control (CR+PR+SD) at 68% and 96% [PPV/NPV/sens/spec of 0.68/0.49/0.36/0.78 and 0.96/0.26/0.36/0.94, respectively], while an “upward trend” performed less well to predict relapse [PPV/NPV/sens/spec = 0.54/0.98/0.94/0.81]. Conclusions: In this first exploration of 51 young FLC patients, and 226 tissue-informed cell free ctDNA data points, “Positive” and “Negative” values overall performed well for predicting RECIST 1.1 “disease” or “NED” respectively, especially for consecutive values of zero, where no progressions were observed in 64 distinct FLC scenarios. A downward trend or “slope” performed better than an upward trend to predict objective response (PR+CR) versus relapse (PD).

Circulating tumor DNA guided therapeutic strategies for colorectal cancer patients with multiple small pulmonary-limited nodules: An open-label, prospective, phase II cohort study.

e15645 Background: The clinical diagnosis and treatment of small pulmonary nodules (suspected to be lung metastases) in advanced colorectal cancer (CRC) patients remain controversy. Previous studies have shown that tumor-informed circulating tumor DNA (ctDNA) testing with blood sample can sensitively detect recurrence or metastasis of CRC patients. This study was designed to explore the clinical value of tumor-informed ctDNA test in metastatic CRC patients with small pulmonary-limited nodules. We aimed to identify the low-risk patients for de-escalation therapy, as well as high-risk patients with no evidence of disease (NED) for escalation therapy. Methods: This is an ongoing, open-label, prospective and phase II cohort study (NCT 05495672). According to the longest diameter of the pulmonary nodule, patients were divided into two cohorts: Cohort 1(0-1cm) and Cohort 2 (1-2cm). Tumor-informed ctDNA test (OriMIRACLE S) would be performed every three months until progression or 2 years. The treatment strategy of each patient is decided by a multidisciplinary team depending on ctDNA and lung CT scan results. In general, negative minimal residual disease (MRD) patients will receive only regular follow-up. Patients with positive MRD will receive intensive examination and local treatments for pulmonary nodules such as surgery, radio frequency ablation or stereotactic body radiotherapy combined with or without systemic therapeutic treatment, aiming to achieve NED or cure. Results: From June 2022 to December 2022, a total of 26 patients were screened in the group, one patient was eliminated (with extrapulmonary metastasis), and a total of 25 patients were successfully enrolled. At present, 1 patient died (by acute intestinal perforation), 4 patients were excluded from the group (with the emergence of extrapulmonary metastasis), and a total of 20 patients were in the group. The positive rate of MRD in baseline were 4/11(36.4%) for Cohort 1 and 10/14 (71.4%) for Cohort 2, respectively. Notably, in Cohort 1, 3 of 4 patients with positive MRD at baseline were examined extrapulmonary metastasis during the follow-up examination. Conclusions: Our preliminary results suggested that the positive rate of MRD were higher in Cohort 2 than Cohort 1. Patients with pulmonary nodule less than 1 cm tended to develop extrapulmonary metastasis if baseline MRD was positive. In such circumstances, more intensive follow-up examination is suggested to prevent early disease progression. Clinical trial information: NCT05495672 .

Immunological signature of patients with thymic epithelial tumors and Good syndrome: Correlation with clinical outcome.

e20648 Background: Thymic epithelial tumors (TETs) are extremely rare and heterogenous neoplasms, associated with immune dysregulation. Recognized prognostic factors are TNM stage and the Masaoka-Koga classification. To the best of our knowledge, no study has been conducted to investigate the correlation between immunophenotype, level of cytokines, chemochines and clinical outcome in TETs patients. The aim of this study was to evaluate the correlation of immunological signature and long-term outcome in patients with TETs and Good Syndrome (GS). Methods: From May 2019 to October 2022, consecutive patients with TETs and GS, referred to the Rare Tumors Coordinating Center of Campania Region (CRCTR) of Federico II of Naples, were enrolled. The immunophenotype of monocytes, neutrophils, eosinophils, CD4+ T cells, CD8 + T cells, B-cells, NK cells and NKT-cells, T regulatory cells, and the evaluation of serum levels of cytokines, chemokines and growth factors were assessed using the 8-color immunophenotyping kit, Treg detection kit and pre-formed Kits by Bioplex multiplex, respectively. D’Agostino-Pearson normality test was used to evaluate whether the continuous data were normally distributed, and a two-tailed t-test for independent samples was used. Overall survival (OS) analysis was performed generating Kaplan-Meier curves and Cox Univariate models for the considered categorical stratifications. p-values < 0.05 were considered statistically significant. Results: A total of 24 consecutive TETs patients were included in the study: 13 (54.17%) patients were male and 11 (48.83%) were female, with a median age of 54.96 ± 9.6 years. Tumor histology included 20 thymoma, and 4 thymic carcinoma. Autoimmune diseases were found in 13 patients all of whom had thymoma. At the time of this analysis, 5 (20.83%) patients had no evidence of disease (NED) by imaging and were in follow-up, 17 (70.83%) patients were still alive. The analysis of leucocytes did not show statistically significant association with clinical outcome of TETs patients. On the contrary, a statistically significant correlation between serum concentration of IL-6 and OS was found with lower levels of IL-6 associated with poorer prognosis (HR: 9.654; p = 0.016). In addition, we found a statistically significant reduction of IL-2 (p = 0.04), IL-15 (p = 0.048), IL-5 (p = 0.03) and VEGF (p = 0.01) serum levels in patients with evidence of disease, as compared to NED patients. Conclusions: Overall, these findings suggest that measurement of IL-6 levels may be a useful parameter for identifying TETs patients with GS who have more aggressive diseases. Our preliminary data may be useful in the clinical management of this complex disease. Further studies are needed to better understand the pathophysiology and clinical implications of immunophenotype alterations in TETs patients.

Post CAR T-cell therapy outcomes and management in HSCT-naive patients: a single-center experience

BackgroundTisagenlecleucel (tisa-cel) is increasingly being used in hematopoietic stem cell transplantation (HSCT)-naive patients. Outcomes for HSCT patients following chimeric antigen receptor (CAR) T-cell therapy demonstrate low relapse rates; however, a significant number of patients who receive tisa-cel can maintain remission without an HSCT. Multiple factors are considered when choosing whether or not to proceed with HSCT.MethodsWe retrospectively reviewed 31 patients who had received tisa-cel at our institution and who were transplant naive at the time of infusion. The aim was to determine the rate and timing of consolidative HSCT, factors that led to HSCT, and overall survival.ResultsThree of the 31 patients were non-responders to tisa-cel and ultimately died of disease. Twelve of the 28 responders remain alive with no evidence of disease (NED) without subsequent therapy. Of these patients, 5 of the 12 had isolated extramedullary acute lymphoblastic leukemia (ALL) (CNS, n = 4; testes, n = 1) and 2 of the 12 had Down syndrome, so no transplantation was planned. In the remaining 5 of 12 patients, close monitoring for signs of relapsed ALL, using serial next-generation sequencing (NGS) minimal residual disease (MRD) and lymphocyte subpopulation measurements, was performed. Owing to continued negative findings, no HSCT was chosen. Ultimately, 43% (12 of 28) of responders proceeded to HSCT, with three receiving tisa-cel as a planned bridge to HSCT as a result of CD22 negativity and/or provider preference (two patients survived with NED); three proceeded to HSCT as a result of early loss of B-cell aplasia (BCA) (all survived with NED); and six had salvage HSCT following relapse (three patients survived with NED and one patient was alive in relapse). Three of the 28 patients died following relapse post CAR T-cell therapy without HSCT. The final patient had an isolated extramedullary soft tissue CD19+ relapse 1 year post tisa-cel treatment, and is now NED without HSCT and persistent BCA.ConclusionClose monitoring of NGS results and BCA, as well as consideration of the site of the disease, can spare a subset of patients HSCT with the maintenance of leukemia-free remission, while still allowing for later HSCT in others. In our cohort, only a small subset of patients was unable to proceed to HSCT following relapse post-CAR T-cell therapy.

Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial.

Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.

Retrospective analysis of colorectal cancer patients with metachronous initially unresectable liver metastases (and no other) achieving no evidence of disease after first-line comprehensive therapy: a multicenter real-world study.

To explore the optimal timing of locoregional therapy in patients with colorectal cancer (CRC) recurrence after radical resection and initially unresectable liver metastases but no other metastases and whether maintenance therapy should be performed after achieving no evidence of disease (NED). This study was jointly carried out in six medical institutions in China to collect the clinical data of patients with primary CRC from January 2015 to December 2021. Research participants were identified according to the inclusion criteria of this study for statistical analysis of the clinical characteristics and recurrence time. 625 patients CRC with metachronous initially unresectable liver metastases but no other metastases were enrolled. Multivariate analysis showed that the number of metastases in the liver and the time from the start of first-line chemotherapy to locoregional therapy significantly affected the progression-free survival (PFS, P < 0.05) following the first-line treatment, and continued maintenance therapy reduced the risk of tumor progression in the patients (P < 0.05). Furthermore, stratified analysis showed that the median PFS of patients with 3-5 metastases in the liver was maximized when the time from the start of first-line chemotherapy to locoregional therapy was 3-4months. Patients with > 6 metastases in the liver should extend the duration between the start of first-line chemotherapy and locoregional therapy to more than four months. Similarly, with the significant increase in the number of metastases in the liver, subsequent maintenance therapy significantly extended the PFS of the patients. The overall therapeutic plan in patients with CRC recurrence after radical resection and initially unresectable liver metastases but no other metastases should consider the individual patients' situations, especially the number of metastases in the liver at initial recurrence.

Mitomycin Gel (UGN-101) as a Kidney-sparing Treatment for Upper Tract Urothelial Carcinoma in Patients with Imperative Indications and High-grade Disease

BackgroundIntracavitary UGN-101 is approved for the treatment of low-grade noninvasive upper tract urothelial carcinoma (UTUC). Post-commercialization studies underscore the benefit of UGN-101 administration for patients with imperative indications for whom radical nephroureterectomy (RNU) is not a viable option. ObjectiveTo describe the use, efficacy, and safety of UGN-101 in patients with UTUC with imperative indications for renal preservation, including high-grade disease. Design, setting, and participantsPatients receiving UGN-101 with imperative indications were retrospectively analyzed using a multicenter centralized registry from 15 high-volume academic and community centers. Outcome measurements and statistical analysisWe defined imperative indications as patients with a solitary kidney, the presence of chronic kidney disease (CKD) with a glomerular filtration rate <30 ml/min, bilateral UTUC, and patients unfit for or unwilling to undergo surgical extirpation. Tumor characteristics, disease progression/recurrence, and adverse events were recorded on a per–renal-unit basis. Results and limitationsUGN-101 was instilled into 52 renal units (38%) in 48 patients for imperative indications, including 29 patients (56%) with a solitary kidney, 11 kidneys (21%) in the setting of bilateral UTUC, six patients (12%) with CKD, and six patients (12%) who were unfit for or unwilling to undergo RNU. Twelve renal units had biopsy-proven high-grade papillary disease. Tumors were completely ablated before induction therapy in 34% of cases, while 66% had tumor present. Following induction therapy, 17 patients (40%) had no evidence of disease (NED) on ureteroscopy, 88% of whom maintained this status at median follow-up of 10.8 mo. In the cohort with high-grade disease, five patients (45%) had NED at initial post-induction primary disease evaluation. Adverse events included pyelonephritis (8%), ureteral stenosis (8%), anemia (6%), and acute renal failure (4%). Limitations include the retrospective study design, the lack of long-term follow up, and patient selection bias. ConclusionsIntracavitary therapy with UGN-101 in patients with UTUC and imperative indications shows promise as a kidney-sparing treatment modality. While long-term follow-up is needed, this intracavitary treatment may help in prolonging time to RNU and delaying the morbidity of hemodialysis in this comorbid population. Patient summaryWe reviewed results for patients with cancer in the upper urinary tract and an additional condition that would not allow kidney removal who received treatment with a gel called UGN-101. Our results suggest that UGN-101 shows promise as a kidney-sparing treatment. It may delay the time until kidney removal is needed in these patients and avoid the negative effects associated with dialysis.

Precision fluoropyrimidines dosing in a compound heterozygous variant carrier of the DPYD gene: a case report.

Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging. We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up. Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs.

Abstract P2-11-06: Plasma assay of methylated DNA markers (MDM) detects patients with metastatic breast cancer (MBC) compared to healthy controls and treated breast cancer patients with no evidence of disease

Abstract Objective: Aberrantly methylated DNA may be used to detect minimal residual disease or early recurrence in breast cancer. As a 1st step, we aimed to develop an MDM panel to delineate between healthy women, stage I-III breast cancer in remission with no evidence of disease (NED), and metastatic breast cancer (MBC). Methods: We prospectively enrolled patients into 3 groups: healthy controls (adult females with a normal mammogram in past 12 months with no history of breast cancer), NED [stage I-III breast cancer with no clinical evidence of recurrence 6 months - 3 years post-treatment (adjuvant endocrine therapy allowed)], and MBC (collected either at initial diagnosis of untreated metastatic disease or radiographic progression). DNA was extracted from 6 mL of plasma derived from blood collected in LBgard tubes (Exact Sciences Corp., San Diego CA), and was bisulfite-treated and assayed by target enrichment long-probe quantitative amplified signal (TELQASTM) method for a panel of 15 previously identified MDMs [Table], normalized by the control gene, B3GALT6. Areas under the receiver operating characteristic curve (AUC) were calculated for each MDM to assess discrimination of MBC from other groups. With 60 patients per group, we had greater than 80% power to detect a difference of 0.20 from the null AUC of 0.7. Results: We tested samples from 60 MBC (10 untreated, 50 recurrent), 60 NED, and 60 healthy women. The median age was 63 (IQR, 55-72) and was not different between groups. The NED group was all hormone-receptor (HR) positive, with 47 (78%) being human epidermal growth factor receptor 2 negative (HER2-) and 13 (22%) HER2+; 48 (80%) were stage I and 9 (15%) were N+. The MBC group had 35 (58%) patients with HR+/HER2- tumors, 11 (18%) HR+/HER2+, and 6 (10%) HR-/HER2-, 4 (7%) HR-/HER2+, with 4 (7%) unknown. Of the 41 MBC whose original stage and nodal status were known 9 (22%) were stage I and 22 (54%) were N+. The markers were able to discriminate between MBC and NED patient samples with AUCs from 0.97 to 0.72. AUCs for 10/15 MDMs (ITPRIPL1, EMX1, C17orf64, OSR2, TRIM67, CHST2, IFFO1, TRH, FAM59B, and MPZ) were &amp;gt;0.90. No difference in MDMs was observed between the healthy and NED groups. Conclusions: MDMs, assayed from plasma, appear highly discriminant for metastatic breast cancer cases in comparison to control patients with NED or healthy controls. Further clinical validation of this MDM panel in a larger cohort is warranted. Table 1. Plasma MDM discrimination of metastatic breast cancer (MBC) from healthy controls and previously treated breast cancer patients with no evidence of disease (NED) Citation Format: Karthik V. Giridhar, Fergus J. Couch, Jason P. Sinnwell, Seth W. Slettedahl, William R. Taylor, Douglas W. Mahoney, Patrick H. Foote, Maria C. O’Connell, Mariah J. Robran, Mary E. Devens, Anna M. Gonser, Nicole Larson, Karen A. Doering, Kelli N. Burger, Michael Kaiser, Hatim Allawi, Kathryn Ruddy, Janet Olson, John B. Kisiel. Plasma assay of methylated DNA markers (MDM) detects patients with metastatic breast cancer (MBC) compared to healthy controls and treated breast cancer patients with no evidence of disease [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-06.

Phase 3 LITESPARK-022: Pembrolizumab (pembro) plus hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan as adjuvant treatment for clear cell renal cell carcinoma (ccRCC).

TPS748 Background: Treatment with the PD-1 inhibitor pembro produced significant improvement in disease-free survival after surgery for patients (pts) with ccRCC in the phase 3 KEYNOTE-564 trial. Based on these results, pembro was approved by the US Food and Drug Administration and the European Medicines Agency for adjuvant treatment of pts with RCC at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. Despite advances in the treatment landscape for RCC, more effective adjuvant treatment strategies are needed for pts at risk of recurrence after surgery. HIF-2α is an established oncogenic driver in ccRCC, and promising antitumor activity in advanced ccRCC and von Hippel-Lindau disease–associated RCC has been demonstrated with the HIF-2α inhibitor belzutifan. The multicenter, double-blind, randomized, phase 3 LITESPARK-022 study (NCT05239728) will evaluate the efficacy and safety of pembro plus belzutifan compared with placebo plus pembro as adjuvant treatment following nephrectomy in pts with ccRCC. Methods: Key eligibility criteria include adults with histologically or cytologically confirmed intermediate-high risk, high risk, or M1 with no evidence of disease (NED) RCC with a clear cell component; pts with no prior systemic therapy, nephrectomy, and/or metastasectomy ≤12 weeks before randomization; and pts who are tumor free per computed tomography/magnetic resonance imaging. Approximately 1600 pts will be randomly assigned to receive belzutifan 120 mg orally once daily plus pembro 400 mg intravenously (IV) every 6 weeks (Q6W) for ≤9 administrations (~54 weeks) or oral placebo plus pembro 400 mg IV Q6W for ≤9 administrations (~54 weeks) or until verified disease recurrence by blinded independent central review, start of new anticancer treatment, unacceptable toxicity, or decision to withdraw. Stratification factors are tumor grade (1 or 2 vs 3 or 4) and risk type (intermediate-high risk versus high risk versus M1 NED). Pts will be radiologically evaluated Q12W from randomization through year 2, Q16W in years 3 to 5, and Q24W in years 6 and beyond. Adverse events will be monitored throughout the study and for 30 days following cessation of study treatment (90 days for serious adverse events). The primary end point is disease-free survival. Secondary end points include overall survival, safety, disease recurrence–specific survival, and patient-reported outcomes. Recruitment is underway in Asia, Australia, Europe, North America, and South America. © 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT05239728 .

Aggressive Pursuit of No Evidence of Disease Status in Hepatoblastoma Improves Survival: An Observational Study

BackgroundThe utility of repeated surgical interventions in hepatoblastoma to achieve no evidence of disease (NED) is not well-defined. We examined the effect of aggressive pursuit of NED status on event-free (EFS) and overall survival (OS) in hepatoblastoma with subgroup analysis of high-risk patients. MethodsHospital records were queried for patients with hepatoblastoma from 2005 to 2021. Primary outcomes were OS and EFS stratified by risk and NED status. Group comparisons were performed using univariate analysis and simple logistic regression. Survival differences were compared with log-rank tests. ResultsFifty consecutive patients with hepatoblastoma were treated. Forty-one (82%) were rendered NED. NED was inversely correlated with 5-year mortality (OR 0.006; CI 0.001–0.056; P < .01). Ten-year OS (P < .01) and EFS (P < .01) were improved by achieving NED. Ten-year OS was similar between 24 high-risk and 26 not high-risk patients when NED was attained (P = .83). Fourteen high-risk patients underwent a median of 2.5 pulmonary metastasectomies, 7 for unilateral disease, and 7 for bilateral, with a median of 4.5 nodules resected. Five high-risk patients relapsed, and three were salvaged. ConclusionsNED status is necessary for survival in hepatoblastoma. Repeated pulmonary metastasectomy and/or complex local control strategies to obtain NED can achieve long-term survival in high-risk patients. Level of evidenceLevel III – Treatment Study - Retrospective Comparative Study.

Circulating tumor DNA (ctDNA) informs clinical practice in patients with recurrent/metastatic gastroesophageal cancers.

427 Background: Gastric and esophageal cancers (GECs) together account for a significant global burden in terms of new diagnoses and deaths. Over the last several years, the utility of ctDNA has ranged from estimating tumor burden and characterizing the genomic landscape of tumor biology and response to therapy in the metastatic setting to detection of minimal residual disease (MRD) and cancer surveillance in the locally advanced setting. We have previously studied the role of a commercial ctDNA assay for MRD detection and surveillance in locally advanced GECs. Herein, we present our experience with the same ctDNA assay in advanced stage settings for GECs. Methods: In this retrospective analysis of real-world data obtained from commercial circulating tumor DNA (ctDNA) testing, 53 patients with recurrent/ metastatic esophageal cancer were analyzed. A total of 216 plasma samples were collected between 10/29/2008 and 08/23/2022. The patients were divided into 3 cohorts: Cohort A (N=30) included patients with stage II/III disease who had confirmed clinical recurrence (R). Cohort B (N=25) included recurrent and Stage IV patients who achieved a state of no evidence of disease (NED) on imaging. Cohort C (N=5) included recurrent and Stage IV patients who transiently achieved NED on imaging. A personalized, tumor-informed multiplex PCR-based next-generation sequencing assay (Signatera) was used to quantify ctDNA either postoperatively, on adjuvant or palliative therapy, or during active surveillance. Results: Of 53 patients, 30 patients with recurrent stage II/III esophageal cancer had ctDNA status available postoperatively within 150 days of confirmed clinical recurrence. Cohort A: Among these cases, 25 patients were ctDNA-positive ahead of clinical recurrence (sensitivity 83.3%) with a median of 31 days (range: 1-147 days). Cohort B: Next, we explored the correlation between ctDNA status and imaging, wherein, 96% (24/25) of patients showed a significant correlation between ctDNA status (positive or negative) and disease status by imaging (Fisher exact test p=0.0001). Of the 23 patients, 17 patients were ctDNA-negative and showed NED on imaging (negative predictive value of 100%; 17/17). Cohort C: 100% of patients (N=6) who demonstrated recurrent disease on imaging after NED were ctDNA-positive prior to imaging (positive predictive value of 100%). Conclusions: Our data demonstrate the utility of ctDNA in accurately predicting disease progression and support the potential use of ctDNA to inform treatment decisions or prompt early radiographic imaging. ctDNA may ultimately supersede traditional radiographic surveillance with the advantage of being minimally invasive and cost-effective in monitoring patients during/post-treatment.

Effect of dynamic circulating tumor DNA minimal residual disease detection on recurrence surveillance and second resection rate after curative intent resection of colorectal liver metastasis: A prospective cohort study.

242 Background: Recurrence rates after curative intent resection of colorectal cancer liver metastases (CRLM) are nearly 50%. Standard of care surveillance includes intensive computed tomographic (CT) imaging and CEA measurements. However, recurrence detection often happens too late to resume a second resection. Previous studies have shown that circulating tumor DNA (ctDNA) detection, as a biomarker of minimal residual disease (MRD), is a robust prognostic factor for patients with colorectal cancers. Here, we performed a prospective study to explore the potential use for improving postoperative CRLM surveillance by dynamic ctDNA detection and its impact on the second resection of recurrent patients. Methods: Enrolled patients received curative intent resection of CRLM and were confirmed at the status of no evidence of disease (NED) by CT about one month after surgery. All patients received stand-of-care postoperative surveillance and serial plasma samples were collected, including presurgical and postsurgical samples (4-6 weeks after surgery) and every 3rd month until relapse or up to 24 months after resection. A personalized tumor-informed assay (Signatera/HuaJianwei bespoke multiplex-PCR NGS) was used to quantify ctDNA in plasma samples. Results: A total of 318 plasma samples from 60 patients recruited from July 2020 to July 2021 were included in our analysis. Twenty-five (41.6%) patients received neoadjuvant chemotherapy, and 46 patients (76.7%) received adjuvant chemotherapy after surgery. The median follow-up time was 18.0 months (range, 7.5 to 25.3 months). ctDNA was detectable in 58/60 (96.7%) patients before surgery, in 35/60 (58.3%) patients after surgery, and in 23/58 (39.7%) patients at the end of treatment (EOT). Patients with ctDNA/MRD positive status post-surgery or EOT experienced a significant shorter recurrence-free survival (RFS) than patients with negative ctDNA/MRD [hazard ratio (HR) 4.2; P &lt; 0.001 and HR 9.8; P &lt; 0.001]. The recurrence rate in MRD-positive patients (aka. positive predictive value, PPV) was 91.4% (32/35) at post-surgery and 91.3% (21/23) at EOT, respectively. In 93.0% of postoperative MRD-positive patients, ctDNA detected early relapse with a lead time up to 9.0 months (median 3.4 months) compared with standard radiological imaging. Among 40 patients with recurrence, the total secondary resection rate was 52.5% (21/40) with 40% (21/40) cases reached secondary NED. While among 24 recurrent cases with only liver metastases, the secondary resection rate was 66.7% (16/24) with 58.3% (14/24) cases reached secondary NED. Conclusions: Postoperative ctDNA status is strongly associated with shorter RFS. Serial ctDNA monitoring assists early detection of relapse, and therefore, improves patient outcomes by secondary resection. Clinical trial information: ChiCTR2000035677 .

MiR-551a and miR-551b-3p target GLIPR2 and promote tumor growth in high-risk head and neck cancer by modulating autophagy

The potential role for microRNA (miRNA) in the metastatic process that occurs in head and neck squamous cell carcinoma (HNSCC) was examined. miRNA was extracted from surgically excised tumor samples from 41 HNSCC cancer patients diagnosed with distant metastasis (DM) and from 53 patients who displayed no evidence of disease (NED) for a minimum of two years a minimum of two years after treatment with post-operative radiotherapy (PORT). A comparative two-way ANOVA of miRNA expression between DM and NED specimens identified 28 differentially expressed miRNAs with a false discovery rate (FDR) < 0.2 and fold change > 1.5. Two miRNA, miR-551a and miR-551b-3p, which share the same seed sequence, were associated with the DM group and with poor survival. Cell proliferation, migration, and invasion assays using the HN5 and UMSCC-17B HNSCC cell lines were performed after transfecting mimics or inhibitors of these miRNA uncovered an oncogenic role for miR-551a and miR-551b-3p. Furthermore, it was determined that miR-551a and miR-551b-3p directly target GLIPR2 mRNA, a negative regulator of autophagy. Overexpression of GLIPR2 reduced proliferation, migration and invasion of HNSCC cells. In addition, overexpression of miR-551a and miR-551b-3p increased radioresistance while GLIPR2 overexpression increased the radiosensitivity of HNSCC cell lines. These results propose that the miR-551a, miR-551b-3p and GLIPR2 axis plays an important role in tumor growth, invasion and metastasis, at least in part by modulating autophagy and that the proliferative and pro-survival roles of miR-551a and miR-551b-3p may represent potential therapeutic targets by inhibiting autophagy through the regulation of GLIPR2 expression in HNSCC.

Response to Surgery Assessments for Sparing Radioiodine Remnant Ablation in Intermediate-Risk Papillary Thyroid Cancer.

Using response to surgery when tailoring radioiodine (RAI) therapy for papillary thyroid cancer (PTC) is valued but lacks prospective validation. To spare RAI thyroid remnant ablation among patients with intermediate-risk PTCs using 3-tiered assessments with response to surgery highlighted, in addition to the risk of the recurrence stratification and TNM staging. Patients with no evidence of disease (NED) identified as excellent response (ER) or indeterminate response (IDR) to surgery were spared from RAI thyroid remnant ablation after informed consent and prospectively enrolled under active surveillance. Those involved in other trials or without sufficient follow-up data were excluded. Dynamic responses were followed and compared longitudinally. The main outcome measures were NED presenting as durable ER or IDR for over 12 months. Of the enrolled 215 patients, 47.4% (102/215) ER and 52.6% (113/215) IDR were identified regarding RAI decision-making. After a median of 23.6 (interquartile range 13.8-31.6) months, the share of ER increased to 82.8% (178/215) and IDR decreased to 16.3% (35/215), with 85 patients shifting from IDR to ER over time, only 0.5% (1/215) structural incomplete response and 0.5% (1/215) biochemical incomplete response observed. Successful remnant ablation was observed in 27.7% (26/94) of the patients completing 2 diagnostic whole-body scans after a median interval of 13.0 months, indicating a theranostic effect. In the 173 patients followed for over 12 months, the NED rate did not differ between ER and IDR subgroups (100% vs 97.9%, P = .20). Through the 3-tiered assessments with response to surgery highlighted, postoperative ER and IDR spared from RAI remnant ablation may indicate similar favorable responses in intermediate-risk patients with PTC during 23.6 months of follow-up.

C-Reactive Protein Pretreatment-Level Evaluation for Ewing's Sarcoma Prognosis Assessment-A 15-Year Retrospective Single-Centre Study.

A pathological/inflamed cellular microenvironment state is an additional risk factor for any cancer type. The importance of a chronic inflammation state in most diffuse types of tumour has already been analysed, except for in Ewing's sarcoma. It is a highly malignant blue round cell tumour, with 90% of cases occurring in patients aged between 5 and 25 years. Worldwide, 2.9 out of 1,000,000 children per year are affected by this malignancy. The aim of this retrospective study was to analyse the role of C-reactive protein (CRP) as a prognostic factor for Ewing's sarcomas. This retrospective study at Klinikum rechts der Isar included 82 patients with a confirmed Ewing's sarcoma diagnosis treated between 2004 and 2019. Preoperative CRP determination was assessed in mg/dL with a normal value established as below 0.5 mg/dL. Disease-free survival time was calculated as the time between the initial diagnosis and an event such as local recurrence or metastasis. Follow-up status was described as death of disease (DOD), no evidence of disease (NED) or alive with disease (AWD). The exclusion criteria of this study included insufficient laboratory values and a lack of information regarding the follow-up status or non-oncological resection. Serum CRP levels were significantly different in patients with a poorer prognosis (DOD) and in patients who presented distant metastasis (p = 0.0016 and p = 0.009, respectively), whereas CRP levels were not significantly different in patients with local recurrence (p = 0.02). The optimal breakpoint that predicted prognosis was 0.5 mg/dL, with a sensitivity of 0.76 and a specificity of 0.74 (AUC 0.81). Univariate CRP analysis level &gt;0.5 mg/dL revealed a hazard ratio of 9.5 (95% CI 3.5-25.5). In Ewing's sarcoma cases, we consider a CRP pretreatment value &gt;0.5 mg/dL as a sensitive prognostic risk factor indication for distant metastasis and poor prognosis. Further research with more data is required to determine more sensitive cutoff levels.

Cost-effectiveness of minimally invasive partial nephrectomy and percutaneous cryoablation for cT1a renal cell carcinoma.

There is growing evidence that partial nephrectomy (PN) and percutaneous cryoablation (PCA) yield comparable outcomes for patients with cT1a renal cell carcinoma (RCC), although the cost-effectiveness of both treatments still needs to be assessed. To perform a cost-effectiveness analysis of PN and PCA for patients with cT1a RCC. A decision analysis was created over a 5-year span from a healthcare payer's perspective computing expected costs and outcomes of PN and PCA in terms of quality-adjusted life-years (QALYs) and incremental cost-effectiveness (ICER). After each treatment, the following states were modelled using data from the recent literature: procedural complications, no evidence of disease (NED), local recurrence, metastases, and death from RCC- or non-RCC-related causes. Probabilistic and deterministic sensitivity analyses were performed. PCA and PN yielded health benefits of 3.68 QALY and 3.67 QALY. Overall expected costs were $20,491 and $26,478 for PCA and PN. On probabilistic sensitivity analysis, PCA was more cost-effective than PN in 84.78% of Monte Carlo simulations. PCA was more cost-effective until its complication risk was at least 38% higher than PN. PCA was more cost-effective than PN when (i) PCAs annual local recurrence risk was < 3.5% higher than that of PN in absolute values; (ii) PCAs annual metastatic risk was < 1.0% higher than that of PN; or (iii) PCAs annual cancer-specific mortality risk < 0.65% higher than that of PN. PCA remained cost-effective until its procedural cost is above $13,875. PCA appears to be more cost-effective than PN for the treatment of cT1a RCC, although the currently available evidence is of limited quality. PCA may be the better treatment strategy in the majority of scenarios varying procedural complications, recurrence, metastatic risk, and RCC-mortality in clinically plausible ranges. • For patients with cT1a RCCs, PCA yields a comparable health benefit at lower costs compared to PN, making PCA the dominant and therefore more cost-effective treatment strategy over PN. • PCA was more cost-effective than PN when (i) PCAs annual local recurrence risk was < 3.5% higher than PN in absolute values; (ii) PCAs annual metastatic risk was < 1.0% higher than PN; or (iii) PCAs annual cancer-specific mortality risk < 0.65% higher than PN. • PCA is more cost-effective than PN for the treatment of cT1a RCC, and it remained so in the majority of scenarios varying procedural complications, recurrence, metastatic risk, and RCC mortality.

PP06 Presentation Time: 9:50 AM: Biochemical Failure-Free Survival Rates After Brachytherapy with I-125, Pd-103, or Cs-131 for Intermediate-Risk Prostate Cancer: Phase II Trial

<h3>Background</h3> Iodine (I)-125 is traditionally used for low-dose-rate (LDR) brachytherapy for prostate cancer, but emerging data support the use of cesium (Cs)-131 or palladium (Pd)-103 as well. Although the safety and effectiveness of these three isotopes for intermediate risk prostate cancer have been established, the relative efficacy of each is unknown. <h3>Purpose</h3> To compare biochemical outcomes after I-125, Pd-103, or Cs-131 brachytherapy as definitive treatment for intermediate-risk prostate cancer. <h3>Materials and Methods</h3> This prospective phase II trial evaluated ultrasound-guided LDR brachytherapy monotherapy as definitive treatment for intermediate-risk prostate cancer at a single institution in 2006-2013. The choice of isotope and corresponding prescribed dose was made sequentially (starting with I-125, D=144 Gy; followed by Pd-103, D=125 Gy; then Cs-131, D=115 Gy. Patients had intermediate-risk disease (Gleason score [GS] 6 or 7 [3+4 or 4+3]), no evidence of nodal or metastatic disease, and no prior hormonal or radiation therapy. Follow-up visits were every 4 months for the first year after the implant, every 6 months for the next 5 years, and yearly thereafter, with prostate-specific antigen (PSA) levels measured at each visit. Biochemical failure (BCF) was defined per the Phoenix criteria as an increase in PSA value to nadir +2 ng/dL or radiologic or histologic evidence of recurrence with increasing PSA value. Patients were considered to have no evidence of disease (NED) if the PSA was <0.2 ng/dL at the specified time. Treatment efficacy was defined as time to BCF and the presence or absence of NED at a given time. Kaplan-Meier analysis was used to estimate BCF-free survival rates by isotope, with between-group differences assessed with log-rank tests. One-way analysis of variance was used to compare time to BCF between groups. Simple linear regression was used to determine the influence of isotope on achieving NED. <h3>Results</h3> Of the 300 patients in this trial (median age 64.9 years), 100 were treated with Cs-131, 98 with I-125, and 102 with Pd-103. Eleven patients (3.7%) had GS 6 disease, 236 (78.7%) had GS 7 (3+4) disease, and 53 (17.7%) had GS 7 (4+3) disease; 195 (65.0%) had favorable intermediate-risk, and 105 (35.0%) had unfavorable intermediate-risk disease. The median follow-up time was 8.7 years. During follow-up, 27 patients (9.0%) experienced BCF, 7 (7%) in the Cs-131 group, 13 (13.3%) in the I-125 group, and 7 (7.1%) in the Pd-103 group. Among those 27 patients with BCF, 10 (37.0%) received salvage therapy with surgery, brachytherapy, radiation therapy, or cryotherapy. The BCF-free survival rates were 93% for those treated with Cs-131, 86.7% for I-125, and 93.1% for Pd-103 (p=0.86) (Figure); the median time was not reached because of the short follow-up and the limited number of events. Follow-up data were available for 101 patients at 8.7 years; 100 patients (99%) had NED. Although 36 patients (12%) died during the study, only 1 death (0.3%) was related to prostate cancer. <h3>Conclusions</h3> No significant differences in efficacy were found among Cs-131, Pd-103, and I-125 for LDR brachytherapy monotherapy for intermediate-risk prostate cancer. The choice of isotope should be based on dosimetric advantages, estimated risk of toxicity, and quality-of-life profile. A larger randomized trial is needed to assess potential differences in efficacy among isotopes.