Shorter Recurrence-free Survival Research Articles

Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers.

Conventional surveillance methods are poorly sensitive for monitoring appendiceal cancers (AC). This study investigated the utility of circulating tumor DNA (ctDNA) in evaluating systemic therapy response and recurrence after surgery for AC. Patients from two specialized centers who underwent tumor-informed ctDNA testing (Signatera) were evaluated to determine the association between systemic therapy and ctDNA detection. In addition, the accuracy of ctDNA detection during surveillance for the diagnosis of recurrence after complete cytoreductive surgery (CRS) for grade 2-3 ACs with peritoneal metastases (PM) was investigated. In this cohort of 94 patients with AC, most had grade 2-3 tumors (84.0%) and PM (84.0%). Fifty patients completed the assay in the presence of identifiable disease, among which ctDNA was detected in 4 of 7 (57.1%), 10 of 16 (62.5%), and 19 of 27 (70.4%) patients with grade 1, 2, and 3 diseases, respectively. Patients who had recently received systemic chemotherapy had ctDNA detected less frequently (7 of 16 [43.8%] v 26 of 34 [76.5%]; odds ratio, 0.22 [95% CI, 0.06 to 0.82]; P = .02). Among 36 patients with complete CRS for grade 2-3 AC-PM, 16 (44.4%) developed recurrence (median follow-up, 19.6 months). ctDNA detection was associated with shorter recurrence-free survival (median 11.3 months v not reached; hazard ratio, 14.1 [95% CI, 1.7 to 113.8]; P = .01) and showed high accuracy for the detection of recurrence (sensitivity 93.8%, specificity 85.0%). ctDNA was more sensitive than carcinoembryonic antigen (62.5%), CA19-9 (25.0%), and CA125 (18.8%) and was the only elevated biomarker in four (25%) patients with recurrence. This study revealed a reduced ctDNA detection frequency after systemic therapy and accurate recurrence assessment after CRS. These findings underscore the role of ctDNA as a predictive and prognostic biomarker for grade 2-3 AC-PM management.

A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol andadrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy.

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette-Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial-stromal interface zone compartments and their distribution, represented by an epithelial-stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.

Prognostic Value of HHLA2 in Patients with Solid Tumors: A Meta-Analysis.

HHLA2 is a checkpoint from the B7 family that can play a co-stimulatory or co-inhibitory role in cancer, depending on the binding receptor. The aim of this meta-analysis was to assess the relationship between HHLA2 levels and its impact on the prognosis of patients with solid cancers. The study used data from PubMed, Embase, Web of Science (WOS), Cochrane and SCOPUS databases. The R studio software was used for the data analysis. The study assessed overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS) by pooling appropriate hazard ratios (HR). Eighteen studies (2880 patients' data) were included. High expression of HHLA2 was associated with worse OS (HR = 1.58, 95% CI: 1.23-2.03), shorter RFS (HR = 1.95, 95% CI: 1.38-2.77) and worse DFS (HR = 1.45, 95% CI: 1.01-2.09) in patients with solid cancers. The current study suggests that high expression of HHLA2 is associated with poorer prognosis in patients with solid cancers.

New insights into macrophage polarization and its prognostic role in patients with colorectal cancer liver metastasis

BackgroundAs liver metastasis is the most common cause of mortality in patients with colorectal cancer, studying colorectal cancer liver metastasis (CLM) microenvironment is essential for improved understanding of tumor biology and to identify novel therapeutic targets.MethodsWe used a multiplex immunofluorescence platform to study tumor associated macrophage (TAM) polarization and adaptive T cell subtypes in tumor samples from 105 CLM patients (49 without and 56 with preoperative chemotherapy).ResultsCLM exhibited M2 macrophage polarization, and helper T cells were the prevalent adaptive T cell subtype. The density of total, M2 and TGFβ-expressing macrophages, and regulatory T cells was lower in CLM treated with preoperative chemotherapy. CLM with right-sided primary demonstrated enrichment of TGFβ-expressing macrophages, and with left-sided primary had higher densities of helper and cytotoxic T cells. In multivariate analysis, high density of M2 macrophages correlated with longer recurrence-free survival (RFS) in the entire cohort [hazard ratio (HR) 0.425, 95% CI 0.219–0.825, p = 0.011) and in patients without preoperative chemotherapy (HR 0.45, 95% CI 0.221–0.932, p = 0.032). High pSMAD3-expressing macrophages were associated with shorter RFS in CLM after preoperative chemotherapy.ConclusionsOur results highlight the significance of a multi-marker approach to define the macrophage subtypes and identify M2 macrophages as a predictor of favorable prognosis in CLM.

The prognostic and potentially immunomodulatory role of cartilage oligomeric matrix protein in patients with gastric and esophageal adenocarcinoma

BackgroundCartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment.MethodsCOMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm.ResultsThe expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma.ConclusionsExpression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.

Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

ZIP Code to Genomic Code: Neighborhood Disadvantage, Aggressive Breast Cancer Biology, and Breast Cancer Outcomes.

To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes. ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS. We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively. Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS. In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.

Abstract 7665: Detection of γ-OHPdG as a hepatocellular carcinoma recurrence biomarker by CTCs and LC-MS/MS

Abstract Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally. Recurrence risks following curative resection remain high, ~50% after three years and 75-100% over five years. A biomarker for HCC recurrence is urgently needed to help lead treatment strategies. We previously showed that hepatic γ-hydroxy-1, N2-propano-2′-deoxyguanosine (γ-OHPdG), a DNA adduct derived from lipid peroxidation, increased during hepatocarcinogenesis. Furthermore, in a retrospective study, higher γ-OHPdG levels in post-surgical liver tumor tissues were associated with poorer survival (p<0.0001) and shorter recurrence-free survival (p=0.007), suggesting that it may be a prognostic biomarker for HCC (Hepatology 2018). In this study, we aimed to test γ-OHPdG detected in livers after curative resection as a recurrence biomarker in a prospective study and, in addition, we developed a new non-invasive method for γ-OHPdG in circulating tumor cells (CTCs). This multicenter study seeks to validate γ-OHPdG as a biomarker for HCC recurrence. Methods: A total of 28 HCC patients undergoing hepatectomy at MedStar/Georgetown University Hospital, Johns Hopkins University Hospital, and the University of Maryland Medical Center were enrolled. γ-OHPdG was detected in DNA isolated from hepatic tumors and non-tumors by a previous liquid chromatograph-tandem mass spectrometry (LC-MS/MS) method and in HCC CTCs isolated from blood samples. CTCs were isolated using hepatocyte-specific rabbit anti-asialoglycoprotein-1 (ASGPR-1), followed by staining with mouse anti-γ-OHPdG antibodies. Clinical outcomes were correlated with γ-OHPdG in liver tissues and CTCs. Results: In our current cohort of 28 patients (mean age: 64.7 years; 82% male), five patients experienced HCC recurrence, with an estimated progression-free survival (PFS) rate of 85% over 8 months. γ-OHPdG levels (adducts/109 nucleotides) detected by LC-MS/MS varied widely in tumor tissues (5-56, mean: 11.8) and non-tumor tissue (7-71, mean: 20.6). Preliminary analysis showed shorter PFS associated with γ-OHPdG in non-tumors (cutoff: 16, p=0.0271). γ-OHPdG (arbitrary units x107) in CTCs also varied widely in the nucleus (0.95-18.84, mean: 2.85) and in the whole cell (0.16- 52.18, mean: 9.72). Total CTC γ-OHPdG intensity in both the nucleus (p=0.006) and in the whole cell (p=0.005) was associated with its levels in non-tumor tissue. Furthermore, a shorter PFS was associated with CTC count (cutoff: 270 cells, p=0.01), and total CTC whole cell γ-OHPdG intensity (cutoff: 21.17 × 107 arbitrary units, p=0.002). Conclusion: Preliminary results suggest that γ-OHPdG, measured in tissues by LC-MS/MS and in blood by CTC, predicts HCC recurrence. Once evaluated in all enrolled subjects, multiple variant analyses will be carried out to include stage, AFP, grade of differentiation, vascular invasion on surgical samples, and status of viral hepatitis infection. Citation Format: Mark Kuo, Merve Ozge Aktop, Elie Ghabi, Mahmoud A. Ouf, Margaret Carder, Vinona Muralidaran, Jhalen Ascue, Marketa Hlouskova, Pengfei Wu, Guang Cheng, Stephen S. Hecht, Hong-Bin Fang, Nader Hanna, Jin He, Alexander H. Kroemer, Monika Aggarwal, Aiwu R. He, Fung-Lung Chung. Detection of γ-OHPdG as a hepatocellular carcinoma recurrence biomarker by CTCs and LC-MS/MS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7665.

A new model using deep learning to predict recurrence after surgical resection of lung adenocarcinoma

This study aimed to develop a deep learning (DL) model for predicting the recurrence risk of lung adenocarcinoma (LUAD) based on its histopathological features. Clinicopathological data and whole slide images from 164 LUAD cases were collected and used to train DL models with an ImageNet pre-trained efficientnet-b2 architecture, densenet201, and resnet152. The models were trained to classify each image patch into high-risk or low-risk groups, and the case-level result was determined by multiple instance learning with final FC layer’s features from a model from all patches. Analysis of the clinicopathological and genetic characteristics of the model-based risk group was performed. For predicting recurrence, the model had an area under the curve score of 0.763 with 0.750, 0.633 and 0.680 of sensitivity, specificity, and accuracy in the test set, respectively. High-risk cases for recurrence predicted by the model (HR group) were significantly associated with shorter recurrence-free survival and a higher stage (both, p < 0.001). The HR group was associated with specific histopathological features such as poorly differentiated components, complex glandular pattern components, tumor spread through air spaces, and a higher grade. In the HR group, pleural invasion, necrosis, and lymphatic invasion were more frequent, and the size of the invasion was larger (all, p < 0.001). Several genetic mutations, including TP53 (p = 0.007) mutations, were more frequently found in the HR group. The results of stages I-II were similar to those of the general cohort. DL-based model can predict the recurrence risk of LUAD and identify the presence of the TP53 gene mutation by analyzing histopathologic features.

The impact of prognostic factors and comorbidities on survival in older adults with stage I − III cutaneous melanoma in Southwest Finland: A register study

IntroductionDespite being diagnosed with thicker and more often ulcerated melanomas, cancer-specific survival (CSS) is not necessarily inferior in older adults with melanoma compared to younger patients. Materials and MethodsOur aim was to evaluate the impact of baseline melanoma-specific prognostic factors and comorbidities on recurrence-free survival (RFS), CSS, and overall survival (OS) in patients aged 70–79 (n = 474) and ≥ 80 years (n = 286) with resected stage I − III cutaneous melanoma in Southwest Finland between January 1, 2000 and December 31, 2020. Patients were restaged according to the 8th edition of TNM classification, and comorbidities were assessed using the Charlson Comorbidity Index (CCI). ResultsPatients aged ≥80 years had thicker and more commonly ulcerated melanomas: 43.0%, 40.9%, and 16.1% of patients aged ≥80 and 56.5%, 25.3%, and 18.1% of patients aged 70–79 years were diagnosed with stage I, II, and III melanoma, respectively. Multiple comorbidities (CCI ≥2) were more common and sentinel lymph node biopsy less frequently performed in patients aged ≥80 years. RFS and CSS were similar in patients aged 70–79 years and ≥ 80 years: median RFS 13.8 years vs not reached, with the hazard ratio of melanoma recurrence or death from melanoma 1.25 (95% confidence interval [CI]: 0.91–1.71); median CSS was not reached, with the hazard ratio of death from melanoma 1.12 (95%CI: 0.81–1.75). The proportion of patients who were alive with melanoma recurrence or had died from melanoma was similar in both age groups. In multivariable analysis, higher pathological stage was the only independent risk factor for short RFS regardless of age group, sex, CCI, and tumor ulceration. Higher stage and male sex were associated with short CSS. Age ≥ 80 years, stage III disease, and CCI ≥ 2 were associated with short OS and female sex with long OS in multivariable analysis. DiscussionPathological stage was the most influential factor determining RFS and CSS in older adults with resected stage I − III melanoma. Concerning OS, age ≥ 80 years, stage III disease, and multiple comorbidities had a significant negative impact.

Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay. This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples. The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p=.009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p<.0001). ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

High Community-Level Social Vulnerability is Associated with Worse Recurrence-Free Survival (RFS) After Resection of Extremity and Truncal Soft Tissue Sarcoma.

Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1-39%, least vulnerable) to high (60-100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19-67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06-2.54) but not with OS (HR, 1.47; 95% CI 0.84-2.56). High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma.

Association of perioperative acute kidney injury with oncological outcomes in patients who undergo radical cystectomy: A multicenter retrospective study.

660 Background: Acute kidney injury (AKI) is a frequent complication in patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). Previous studies have reported that AKI during cancer treatment was associated with poor oncological outcomes in several malignancies. Moreover, we previously have reported the negative impact of neoadjuvant chemotherapy-induced AKI on oncological outcomes in patients with MIBC. However, the impact of perioperative AKI on oncological outcomes in patients who undergo RC remains unclear. Methods: This multi-institutional retrospective study included 798 patients with MIBC who underwent RC. AKI was defined according to the KDIGO criteria. Stage 1 AKI was diagnosed with an increase in serum creatinine by just 0.3 mg/dL. Patients were divided into two groups: patients who developed AKI after RC (AKI group) and patients who did not (non-AKI group). Multivariable Cox-proportional hazards regression analyses were performed to evaluate the impact of perioperative AKI on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The median age and follow-up period were 70 years and 64 months, respectively. Of the 798 patients, 408 (51%) developed AKI after RC. Approximately 73% AKI were stage 1 AKI. RFS, CSS, and OS in the AKI group were significantly shorter than those in the non-AKI group ( P = 0.003, P = 0.035, and P &lt; 0.001, respectively). After adjustment for confounding variables, AKI was significantly associated with shorter RFS (hazard ratio [HR] 1.357, P = 0.019), CSS (HR 1.345, P = 0.042), and OS (HR 1.344, P = 0.009). Conclusions: Perioperative AKI was associated with poor oncological outcomes in patients with MIBC who underwent RC. [Table: see text]

CtDNA-based minimal residual disease detection in lung cancer patients treated with curative intended chemoradiotherapy using a clinically transferable approach

BackgroundReliable biomarkers are needed to identify tumor recurrence of non-small cell lung cancer (NSCLC) patients after chemoradiotherapy (CRT) with curative intent. This could improve consolidation therapy of progressing patients. However, the approach of existing studies has limited transferability to the clinic. Materials and methodsA retrospective analysis of 135 plasma samples from 56 inoperable NSCLC patients who received CRT with curative intent was performed. Plasma samples collected at baseline, at the first check-up (average 1.6 months post-RT), and at the second check-up (average 4.5 months post-RT) were analyzed by deep sequencing with a commercially available cancer personalized profiling strategy (CAPP-Seq) using a tumor-agnostic approach. ResultsDetection of circulating tumor DNA (ctDNA) at 4.5 months after therapy was significantly associated with higher odds of tumor recurrence (OR: 5.4 (CI: 1.1–31), Fisher's exact test: p-value = 0.022), and shorter recurrence-free survival (RFS) (HR: 4.1 (CI: 1.7–10); log-rank test: p-value = 9e-04). In contrast, detection of ctDNA at 1.6 months after therapy was not associated with higher odds of tumor recurrence (OR: 2.7 (CI: 0.67–12), Fisher's exact test: p-value = 0.13) or shorter RFS (HR: 1.5 (CI: 0.67–3.3); log-rank test: p-value = 0.32). ConclusionThis study demonstrates that the detection of ctDNA can be used to identify minimal residual disease 4.5 months after CRT in NSCLC patients using a commercially available kit and a tumor-agnostic approach. Furthermore, the time point of collecting the plasma sample after CRT has decisive importance for the prognostic value of ctDNA. Micro abstractThis study analysed 135 plasma samples from 56 NSCLC patients treated with curative intent chemoradiotherapy using a tumor-agnostic approach. Detecting ctDNA at 4.5 months post-treatment was linked to higher recurrence odds, indicating ctDNA's potential as a biomarker for identifying residual disease after treatment with curative intent. Importantly, the study emphasizes the importance of timing for accurate ctDNA analysis results.

Clinical Application of the Association between Genetic Alteration and Intraoperative Fluorescence Activity of 5-Aminolevulinic Acid during the Resection of Brain Metastasis of Lung Adenocarcinoma.

The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM of lung adenocarcinoma at our institute for five years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.

A ten long noncoding RNA-based prognostic risk model construction and mechanism study in the basal-like immune-suppressed subtype of triple-negative breast cancer.

According to the Fudan University Shanghai Cancer Center (FUSCC) system, triple-negative breast cancer (TNBC) is divided into four stable subtypes: (I) luminal androgen receptor, (II) immunomodulatory, (III) basal-like immune-suppressed (BLIS), and (IV) mesenchymal-like. However, the treatment outcomes of the corresponding targeted therapies are unsatisfactory, especially for the BLIS subtype. Therefore, we aimed to identify the key long noncoding RNAs (lncRNAs) to construct a prognostic model for BLIS subtype and discover potential targets to explore potential therapeutic strategies in this study. The FUSCC cohort was used to establish a prognostic risk model via least absolute shrinkage and selection operator (LASSO) and Cox regression analysis. The Cancer Genome Atlas (TCGA) cohort was then used to evaluate and verify the model. To understand the functional aspects of the model, functional, immune landscape, mutation, and drug sensitivity analyses were performed between high- and low-risk groups. Ten prognostic-related lncRNAs identified, including C5ORF66-AS2, DIO3OS, FZD10-DT, LINC00393, LNC-ERI1-32, LNC-FOXO1-2, LNC-SPARCL1-1, HCG23, LNC-MMD-4 and LNC-TMEM106C-6, were selected for risk score system construction. The results showed that the model constructed could divide the patients with BLIS subtype into two groups of high and low risk, and patients with higher risk scores had shorter recurrence-free survival. In addition, drug sensitivity analysis identified 3 compounds, including BMS-754807, cytochalasin b, and linifanib, that could have a potential therapeutic effect on patients with the BLIS subtype. The risk prognosis model showed good prognostic value for the BLIS subtype patients, and the ten lncRNAs may be potential therapeutic targets.

Targeting PEG10 as a novel therapeutic approach to overcome CDK4/6 inhibitor resistance in breast cancer

BackgroundBreast cancer is the global leading cancer burden in women and the hormone receptor-positive (HR+) subtype is a major part of breast cancer. Though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are highly effective therapy for HR+ subtype, acquired resistance is inevitable in most cases. Herein, we investigated the paternally expressed gene 10 (PEG10)-associated mechanism of acquired resistance to CDK4/6 inhibitors.MethodsPalbociclib-resistant cells were generated by exposing human HR+ breast cancer cell lines to palbociclib for 7–9 months. In vitro mechanistic study and in vivo xenograft assay were performed. For clinical relevance, public mRNA microarray data sets of early breast cancer were analyzed and PEG10 immunohistochemical staining was performed using pre-CDK4/6 inhibitor tumor samples.ResultsWe observed that PEG10 was significantly upregulated in palbociclib-resistant cells. Ectopic overexpression of PEG10 in parental cells caused CDK4/6 inhibitor resistance and enhanced epithelial–mesenchymal transition (EMT). On the contrary, PEG10-targeting siRNA or antisense oligonucleotides (ASOs) combined with palbociclib synergistically inhibited proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice and suppressed EMT as well. The mechanistic study confirmed that high PEG10 expression suppressed p21, a natural CDK inhibitor, and SIAH1, a post-translational degrader of ZEB1, augmenting CDK4/6 inhibitor resistance. Then PEG10 siRNA combined with palbociclib suppressed cell cycle progression and EMT via activating p21 and SIAH1, respectively. Consequently, combined PEG10 inhibition and palbociclib overcame CDK4/6 inhibitor resistance. Furthermore, high PEG10 expression was significantly associated with a shorter recurrence-free survival (RFS) based on public mRNA expression data. In pre-CDK4/6 inhibitor treatment tissues, PEG10 positivity by IHC also showed a trend toward a shorter progression-free survival (PFS) with CDK4/6 inhibitor. These results support clinical relevance of PEG10 as a therapeutic target.ConclusionsWe demonstrated a novel PEG10-associated mechanism of CDK4/6 inhibitor resistance. We propose PEG10 as a promising therapeutic target for overcoming PEG10-associated resistance to CDK4/6 inhibitors.

Serial circulating tumor DNA profiling predicts tumor recurrence after liver transplantation for liver cancer.

Minimal residual disease (MRD) is proposed to be responsible for tumor recurrence. The role of circulating tumor DNA (ctDNA) to detect MRD, monitor recurrence, and predict prognosis in liver cancer patients undergoing liver transplantation (LT) remains unrevealed. Serial blood samples were collected to profile ctDNA mutational changes. Baseline ctDNA mutational profiles were compared with those of matched tumor tissues. Correlations between ctDNA status and recurrence rate (RR) and recurrence-free survival (RFS) were analyzed, respectively. Dynamic change of ctDNA was monitored to predict tumor recurrence. Baseline mutational profiles of ctDNA were highly concordant with those of tumor tissues (median, 89.85%; range 46.2-100%) in the 74 patients. Before LT, positive ctDNA status was associated with higher RR (31.7% vs 11.5%; p = 0.001) and shorter RFS than negative ctDNA status (17.8 vs 19.4months; p = 0.019). After LT, the percentage of ctDNA positivity decreased (17.6% vs 47.0%; p < 0.001) and patients with positive ctDNA status had higher RR (46.2% vs 21.3%; p < 0.001) and shorter RFS (17.2 vs 19.2months; p = 0.010). Serial ctDNA profiling demonstrated patients with decreased or constant negative ctDNA status had lower RR (33.3% vs 50.0%; p = 0.015) and favorable RFS (18.2 vs 15.0months, p = 0.003) than those with increased or constant positive ctDNA status. Serial ctDNA profiling predicted recurrence months ahead of imaging evidence and serum tumor biomarkers. ctDNA could effectively detect MRD and predict tumor recurrence in liver cancer patients undergone LT.