Inferior Recurrence-free Survival Research Articles

Survival of patients with ruptured gastrointestinal stromal tumour treated with adjuvant imatinib in a randomised trial.

Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival. We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria. Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%). About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture. NCT00116935.

A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets for breast cancer.

Adhesion G protein-coupled receptors (aGPCRs), a distinctive subset of the G protein-coupled receptor (GPCR) superfamily, play crucial roles in various physiological and pathological processes, with implications in tumor development. Despite the global prevalence of breast cancer (BRCA), specific aGPCRs as potential drug targets or biomarkers remain underexplored. UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, cBiopportal, String, GeneMANIA, DAVID, Timer, Metascape, and qPCR were applied in this work. Our analysis revealed significantly increased transcriptional levels of ADGRB2, ADGRC1, ADGRC2, ADGRC3, ADGRE1, ADGRF2, ADGRF4, and ADGRL1 in BRCA primary tumors. Further analysis indicated a significant correlation between the expressions of certain aGPCRs and the pathological stage of BRCA. High expression of ADGRA1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, and ADGRG7 was significantly correlated with poor overall survival (OS) in BRCA patients. Additionally, high expression of ADGRF2 and ADGRF4 indicated inferior recurrence-free survival (RFS) in BRCA patients. The RT-qPCR experiments also confirmed that the mRNA levels of ADGRF2 and ADGRF4 were higher in BRCA cells and tissues. Functional analysis highlighted the diverse roles of aGPCRs, encompassing GPCR signaling andmetabolic energy reserves. Moreover, aGPCRs may exert influence or actively participate in the development of BRCA through their impact on immune status. aGPCRs, particularly ADGRF2 and ADGRF4, hold promise as immunotherapeutic targets and prognostic biomarkers in BRCA.

Time dependency for HPV ctDNA detection as a prognostic biomarker for anal cancer.

3513 Background: Prior HPV infection is associated with > 90% of anal cancers, a malignancy with rising incidence in the United States. Standard treatment for localized anal cancer is concurrent chemoradiation (cRT). While detection of circulating tumor DNA (ctDNA) within weeks after surgery is linked to recurrence in other solid tumors, the optimal time point for ctDNA detection as a prognostic biomarker following cRT for HPV-associated anogenital cancers is not well characterized. We utilized a novel, highly sensitive HPV ctDNA assay to evaluate clinical outcomes according to HPV ctDNA status among patients with localized anal cancer treated with cRT. Methods: ctDNA was isolated from patients with stages I-III anal cancer treated at our institution with cRT prior to treatment, at the end of treatment (week 5), and at months 3, 6, 9, and 12 after treatment under an IRB-approved protocol. A droplet digital HPV ctDNA PCR assay evaluating HPV E6 and E7 oncogenes for 13 oncogenic HPV types was utilized for quantification of HPV ctDNA. A limit of quantification at 16 HPV copies/mL plasma was set for “HPV ctDNA detection.” Median recurrence-free survival (RFS) according to HPV ctDNA status was estimated via Kaplan-Meier and compared using a log-rank test. Associations between selected clinical factors and recurrence were evaluated with a Chi-square test, with a one-sided p < .05 considered significant. Results: Following cRT, HPV ctDNA was detected in 9/41 (22%), 4/30 (13%), 2/20 (10%), and 0/12 (0%) patients at week 5 and months 3, 6, and 12, respectively. Detection of HPV ctDNA 3 months after cRT was associated with clinical recurrence (100% versus 8%; odds ratio 88, 95% CI 4-2000; p = .006) and inferior RFS (5.9 months vs not reached (NR); hazard ratio (HR) 24, 95% CI 1.2-475; p < .001) relative to HPV ctDNA-negative status. Differences in RFS according to HPV ctDNA status were not observed at week 5/end of treatment (median RFS NR for both; HR 2.4, 95% CI .5-10; p = .15). At month 3, sensitivity and specificity for recurrence according to HPV ctDNA detection were 57% and 100%, respectively, with a PPV and NPV of 100% and 89%, respectively. Baseline clinical stage, T stage, N stage, age, and gender were not associated with clinical recurrence after cRT (p > .25 for all). Conclusions: With a novel, highly sensitive assay, detection of HPV ctDNA at 3 months after cRT was associated with RFS. Further, an HPV ctDNA-positive status outperformed baseline clinical features for prognosticating anal cancer recurrence after cRT in this retrospective series. Future clinical trials should incorporate the 3-month post-treatment time point for identification of patients with HPV-positive anal cancer at elevated risk for recurrence according to HPV ctDNA status. A clinical trial evaluating anti-PD-L1 + anti-TIGIT immunotherapy for patients with HPV-associated cancers with detected HPV ctDNA after cRT is forthcoming at our institution.

Abstract PS16-08: Histologic Pattern and Outcomes in High-Grade Metaplastic Breast Cancer Compared to Triple-Negative Ductal Breast Cancer Counterparts: A Single Institution Retrospective Study

Abstract Background Metaplastic breast cancer (MpBC) is a rare and aggressive subtype of breast cancer that presents with high tumor stage and a poor prognosis. MpBC tumors tend to have worse outcomes compared to other non-metaplastic triple-negative breast cancers (TNBC). Although MpBC has been described as chemotherapy resistant, chemotherapy remains a mainstay of treatment. MpBC tumors can be further characterized by their specific histologic pattern. The existing literature on outcomes of MpBC by histologic pattern is limited, with varying results regarding response rate and overall survival (OS). Identifying a pattern of MpBC that has better response to treatment could help tailor treatment recommendations. Methods A retrospective chart review was performed and identified 106 patients with early-stage, high-grade MpBC who were diagnosed at Levine Cancer Institute between January 1, 2010 and September 1, 2021. A matched control cohort (n=106) of patients diagnosed with non-metaplastic TNBC was selected based on propensity score matching on diagnosis date, age at diagnosis, race, pathologic staging, and tumor grade. Patient demographics, tumor characteristics, therapeutic interventions, residual cancer burden (RCB), and outcomes were collected. The associations between the histologic patterns of MpBC and disease characteristics were evaluated using chi-squared tests for categorical variables and Wilcoxon tests for continuous variables. We also examined the differences in RCB scores between the MpBC cohort and the non-metaplastic TNBC cohort who received neoadjuvant chemotherapy. Additionally, Kaplan-Meier and Cox proportional hazard analysis was performed to assess differences in recurrence free survival (RFS) and OS between the spindle cell/sarcomatous pattern versus all other patterns. Results For the entire group (n=212), median age at diagnosis was 58 years (range, 24-92); all patients were female; 66% White, 29% Black, and 5% unknown race. Most tumors were triple-negative (91%); 19%, 56% and 14% with Clinical Stage I, II, and III disease, respectively. A total of 63% of patients underwent radiation treatment and 76% received chemotherapy (43% neoadjuvant and 57% adjuvant). Recurrence after treatment occurred in 16% of all patients. In the MpBC cohort (n=106), the histologic patterns included spindle cell/sarcomatous (34%), squamous (17%), heterologous mesenchymal (31%), mixed (17%), and other (1%). Of those with MpBC who received neoadjuvant chemotherapy (n=32), RCB among the different histologic patterns was assessed. When comparing spindle cell/sarcomatous versus the other histologic patterns combined, there was no significant difference in RCB (p = 0.81), although more RCB III scores were recorded in the spindle cell/sarcomatous pattern compared to the other MpBC patterns (40% versus 30%). When assessing RFS and OS by histologic pattern in the entire MpBC cohort, spindle cell/sarcomatous tumors had inferior RFS (p = 0.0194) and OS (p = 0.0039) compared to the other MpBC patterns combined. When comparing RCB values between MpBC and non-metaplastic TNBC, there were numerically more RCB-III classes in the MpBC cohort as compared to the non-metaplastic TNBC. Conclusion MpBC is an aggressive and difficult breast malignancy to treat. Based on our single institution review, no correlation between RCB and the histologic pattern of MpBC was found, however, RFS and OS were worse among the spindle cell/sarcomatous pattern. Furthermore, the MpBC cohort had numerically higher RCB-III scores than the TNBC control cohort, which is in line with historical data. Citation Format: Ashley Matusz-Fisher, Annabel Chen, Erin Donahue, Courtney Schepel, Michelle Wallander, Chad Livasy, Richard White, Antoinette Tan, Lejla Hadzikadic-Gusic. Histologic Pattern and Outcomes in High-Grade Metaplastic Breast Cancer Compared to Triple-Negative Ductal Breast Cancer Counterparts: A Single Institution Retrospective Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-08.

Abstract PO5-02-12: Comparison of survival outcomes according to axillary ultrasonography findings and cytology results in early-stage breast cancer patients

Abstract Purpose: Axillary lymph node dissection and sentinel lymph node biopsy are associated with increased risk of post-surgical complications including lymphedema and recent trials have raised questions about the therapeutic benefit of axillary operation in early-stage breast cancer patients. While treatment options for lymph nodes with negative findings on axillary ultrasonography (AUS) or positive findings on fine needle aspiration biopsy (FNAB) are evident, data regarding lymph nodes that are suspicious on AUS but negative by FNAB are limited. Thus, we aimed to compare clinicopathological characteristics of AUS positive and FNAB negative patients with those of AUS negative or FNAB positive patients. Materials and Methods: Medical records of patients who underwent breast cancer surgery between January 2010 and December 2017 were reviewed. Patients were grouped into the following three groups: (a) negative findings on AUS, (b) suspicious findings on AUS but negative on FNAB, (c) and FNAB positive. A total of 4,506 patients were included for analysis, with 3,771 patients with no suspicious lymph nodes on AUS, 557 patients who had suspicious AUS findings but were negative on FNAB, and 178 patients with positive findings on both AUS and FNAB. Primary endpoints were disease free survival (DFS) and recurrence free survival (RFS), and secondary endpoint was overall survival (OS). Results: At a median follow-up period of 92 months, DFS and RFS was significantly higher in the AUS negative group compared to the other two groups (10-year-DFS: 91.6% vs 87.5% vs 75.7%, 10-year-RFS: 95.0% vs 89.9% vs 77.1%, p < 0.001). In terms of OS, AUS negative group and the AUS positive and FNAB negative group did not show statistically significant survival difference (10-year-OS: 94.5% vs 92.8%, p = 0.061), while the FNAB positive group showed significantly lower survival rates (10-year-OS: 81.8%, p < 0.001). Multivariable analysis revealed that not AUS positive and FANB negative but positive FNAB was significantly associated with poor RFS. Moreover, hormone receptor (HR) positive and HER2 negative subtype showed poor DFS and RFS in subgroup analysis. Conclusion: Early breast cancer patients with suspicious findings on AUS but negative FNAB results had similar OS but inferior DFS and RFS compared to those with negative features on AUS, especially in HR(+)HER2(-) subtype. While further prospective trials are warranted to determine whether additional treatment is necessary, close surveillance is recommended for this subgroup of patients. Figure1. Overall survial and Disease free survival according to axillay US and FNAB status Table1. patients' characteristics Table2. prognostic factors for overall survival and disease free survival related to axillary US and FNAB status Citation Format: Suk Jun Lee. Comparison of survival outcomes according to axillary ultrasonography findings and cytology results in early-stage breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-12.

Survival outcomes after caudate lobectomy for hepatocellular carcinoma: systematic review and meta-analysis.

Caudate lobectomy (CLB) remains the most effective treatment for caudate lobe hepatocellular carcinoma (CL-HCC). However, there is controversy regarding the survival after CLB. This meta-analysis aims to investigate the survival outcomes following CLB for the treatment of CL-HCC. In line with PRISMA and MOOSE guidelines, a search for all eligible studies was performed. The pooled estimates of survival rates and hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. Sixteen studies comprising 864 patients met the inclusion criteria. The pooled estimates of 3- and 5-year overall survival (OS) rates were 62.3% and 42.9% respectively and the pooled estimate of 3- and 5-year recurrence-free survival (RFS) rates were 39.3% and 24.4% respectively. CL-HCC showed inferior OS (HR:1.39, 95% CI: 0.91-1.88, P < 0.001) and RFS (HR:1.33, 95% CI: 1.10-1.56, P < 0.001) than other sites HCC. Isolated CLB showed better OS (HR:0.9, 95% CI:0.39-1.41, p < 0.001) and RFS (HR:0.76, 95% CI: 0.03-1.5, P = 0.04) than combined CLB. The survival outcomes for CL-HCC after CLB are lower compared to other sites HCC. Isolated CLB offers better survival outcomes compared to combined CLB. However, choosing isolated or combined approaches should be prioritized according to patient and tumour characteristics.

Clinicopathologic Significance of Quaking Expression in Hepatocellular Carcinoma.

The RNA binding protein quaking (QKI) is associated with the development and progression of tumor suppressors in various cancers. However, the clinical implications of QKI expression have not yet been fully elucidated. In this study, we aimed to investigate the clinicopathological and prognostic significance of QKI expression in hepatocellular carcinoma (HCC). We performed QKI, Zinc finger E-box-binding homeobox 1 (ZEB1), E-cadherin, and glutathione peroxidase 4 (GPX4) immunohistochemical staining on 166 HCC patient tissue samples. X-tile bioinformatics software was used to set the cut-off value for high QKI expression. Correlations between QKI expression and various clinicopathological parameters were assessed. The best cut-off value for high QKI expression was 12.5. High QKI expression was observed in 28 of 166 patients (16.9%) and was an independent prognostic factor for inferior recurrence-free survival (RFS). In addition, high ZEB1 and GPX4 expression correlated with high QKI expression, but not with the loss of E-cadherin expression. High QKI expression was identified in HCCs and associated with poor RFS. QKI might be a prognostic biomarker of HCCs associated with epithelial-to-mesenchymal transition and a potential candidate therapeutic target.

Effects of Cystic Duct Margin Involvement on the Survival Rates of Patients With Gallbladder Cancer: A Propensity Score-Matched Case-Control Study.

Background In gallbladder cancer (GBC), extrahepatic bile duct (EHBD) resection is selectively performed if gross direct extension or microscopic involvement of the cystic duct margin (CDM) is detected. Although CDMis usually sent for frozen biopsy intraoperatively in most centers, there are no studies regarding the routine use of CDM frozen biopsy irrespective of the tumor location and paucity of literature regarding the impact ofCDM status on recurrence-free and overall survival inGBC. The presence of obstructive jaundice in GBC usually indicates the involvement of EHBD or cystic duct-bile duct junction. The present study aimed to analyze the necessity of routineCDM frozen biopsy inpatients with resectable GBC withoutjaundice, regardless of the tumor location. The impact of positive CDM on survival was also evaluated. Methods This retrospective observational case-control study was conducted from May 2009 to March 2021 and included 105 patients with resectable GBC without macroscopic EHBD infiltration andjaundice. Patients were divided into CDM-negative (n=91) and CDM-positive (n=14) groups. Propensity score matchingwas performed for variables such asperformance status, tumor size, tumor-node-metastasis (TNM) stage, and adjuvant chemotherapy. After propensity score matching, 27 patients (CDM-negative=13, CDM-positive=14) were included. The primary outcome was to analyze the role of routine CDM frozen biopsy regardless of tumor location, and secondary outcomes were to study the impact of positive CDM status on survival andevaluate predictive factors for CDM positivity. A subgroup analysis was conducted to assess clinicopathologic characteristics and outcomes of the anatomical location of the tumor. Results Of 105 patients, 91 had negative CDM, and 14 had positive CDM. Among 14 patients with positive CDM, only one patient had a tumor in the fundus/body, and the remaining had a tumor involving the neck. All CDM-positive patients underwent bile duct excision with hepaticojejunostomy. Common bile duct (CBD) involvement was present in 50% of patients with positive CDM in the final histopathological examination. In the matched population, patients with positive CDM had a significantly higher rate of neck tumors (p=0.001). Recurrence-free survival (24 vs. 12 months, p=0.30) and overall survival (24.5 vs. 20 months, p=0.417) were comparable between CDM-negative and CDM-positive groups, respectively. On multivariate analysis, preoperative and intraoperative tumor location were independent predictive factors for CDM positivity. On subgroup analysis, 30 patients had tumor involving the neck of the gallbladder, and the remaining 75 had at the fundus and body of the gallbladder. Neck tumors had inferior recurrence-free survival (17 vs. 30 months, p=0.012) and overall survival (24 vs. 36 months, p=0.048) compared to non-neck tumors. Conclusions Routine use of CDM frozen analysis in patients with resectable GBC without jaundice, regardless of tumor location, can be avoided. Itcan be selectively preferred in patients with GBC involving the neck since tumor location is found to be an independent predictive factorfor CDM positivity. Positive CDM has comparable survival outcomes to negative CDM, providing a similarR0 resection rate and tumor stage.However, neck tumors have aworse prognosis than non-neck tumors.

The efficacy of re-excision after unplanned excision for synovial sarcoma

BackgroundThis investigation studied the clinical features and outcomes of synovial sarcoma (SS) patients from a single institution. MethodsA retrospective clinicopathologic study was conducted on 129 postoperative SS patients during 2003–2018. Kaplan-Meier curves and Cox proportional hazards regression (Cox) models were performed to determine the parameters associated with recurrence-free survival (RFS), metastasis-free survival (MFS), and cancer-specific survival (CSS) via univariate and multivariate analysis. The impact of unplanned excision (UE) and residual tumor in re-excision specimens was evaluated. ResultsThe 3-year RFS, MFS and 5-year CSS were 72 %, 70 %, and 76 %, respectively. Independent factors associated with significantly inferior survival included older age, UE without re-excision, UE with residual tumors, high grade, and deep tumor for RFS, trunk-related tumor, UE without re-excision, UE with residual tumors, and deep tumor for MFS, UE with residual tumors, high grade, and deep tumor for CSS. Re-excision after UE was significantly associated with better RFS (P < 0.001). Residual tumors were remarkably correlated with inferior RFS (P = 0.0012), MFS (P = 0.0016), and CSS (P = 0.048), especially in patients at stage II (MFS: P < 0.001, CSS: P = 0.0014). ConclusionUE and residual tumors have a marked impact on the long-term survival of SS patients. Primary wide excision and re-excision is especially essential for patients at stage II.

Sex Does Not Affect Survival: A Propensity Score-Matched Comparison in a Homogenous Contemporary Radical Cystectomy Cohort

ObjectivesTo determine whether biological sex affects oncological outcome after extended pelvic lymph node dissection, radical cystectomy, and urinary diversion for muscle-invasive bladder cancer, and to identify risk factors impacting outcome. Patients and MethodsWe performed a single-center, retrospective observational cohort study with prospective data collection with a propensity score matched population. A total of 1165 consecutive patients from 2000 to 2020, (317 women and 848 men) scheduled for open extended pelvic lymph node dissection, radical cystectomy, and urinary diversion for urothelial bladder cancer were included in the final analysis. Overall Survival (OS), Cancer-Specific-Survival (CSS), and Recurrence-Free-survival (RFS) were assessed with multivariable weighted Cox regression analysis as well as with propensity score matched Cox-Regression. ResultsNo significant difference was found between sexes regarding OS (HR 1.18, [0.93-1.49], P = .16), CSS (HR 0.87, [0.64-1.18], P = .38), or RFS (HR 0.80, [0.59-1.07], P = .13). These results were confirmed after propensity score matching: female sex was not associated with inferior OS (HR 1.20, [0.91-1.60], P = .19), CSS (HR 1.01, [0.75-1.35], P = .97) or RFS (HR 0.98, [0.75-1.27], P = .86). ConclusionsWe did not find a significant difference in cancer-related outcomes or overall survival after extended pelvic lymph node dissection, open radical cystectomy, and urinary diversion for urothelial cancer between males and females even after adjustment with propensity matching score for multiple factors including oncological parameters, smoking status, and renal function.

Prognostic role of the controlling nutritional status (CONUT) score in patients with biliary tract cancer: a meta-analysis

Background Previous reports have not reached consistent results regarding the prognostic significance of the controlling nutritional status (CONUT) score in biliary tract cancer (BTC). Therefore, the present meta-analysis was conducted to investigate the precise role of the CONUT score in predicting the prognosis of BTC. Methods Electronic platforms including Web of Science, PubMed, Cochrane Library, and Embase were comprehensively searched up to May 2, 2023. We also determined combined hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the role of the CONUT score in predicting the prognosis of patients with BTC. Results Ten studies involving 1,441 patients were included in the present study. Nine studies treated patients with surgical resection, and one study used percutaneous transhepatic biliary stenting (PTBS) plus 125I seed intracavitary irradiation. Based on the combined data, a higher CONUT score significantly predicted dismal overall survival (OS) (HR = 1.94, 95%CI = 1.41–2.66, p < 0.001), inferior recurrence-free survival (RFS) (HR = 1.79, 95%CI = 1.48–2.17, p < 0.001) in BTC, and low differentiation (OR = 1.57, 95%CI = 1.15–2.14, p = 0.004). Nonetheless, the CONUT score was not related to sex, lymph node metastasis, microvascular invasion, perineural invasion, distant metastasis, TNM stage, or tumor number in patients with BTC. Conclusion Higher CONUT scores significantly predicted worse OS and RFS in patients with BTC. Moreover, BTC patients with high CONUT scores tended to have poor tumor differentiation. The CONUT score could help clinicians stratify high-risk patients with BTC and devise individualized treatment plans.

Context to the Analysis of High Risk of Microvascular Invasion on Liver MRI When Considering Resection or Transplantation as Treatment Options for Hepatocellular Carcinoma.

Context to the Analysis of High Risk of Microvascular Invasion on Liver MRI When Considering Resection or Transplantation as Treatment Options for Hepatocellular Carcinoma.

Sex differences in localized gastrointestinal stromal tumor.

e23511 Background: Sex plays an important role in the incidence and prognosis of several cancer types. Male patients with gastrointestinal stromal tumors (GISTs) have inferior outcomes compared to women, but the reasons behind the sex differences are not well understood. This study aimed to investigate whether sex was a prognostic factor in localized GIST and to explore the relationship between sex and established clinical, molecular and histopathological characteristics. Methods: The study cohort is population-based and consisted of patients who underwent surgical resection of primary, non-metastatic GIST at Oslo University Hospital, Norway between January 2000 and September 2017. Recurrence-free survival (RFS) was the primary endpoint. Mutation analysis was performed by Sanger sequencing or by the AmpliSeq for Illumina Cancer Hotspot Panel version 2. Results: The study cohort comprised 409 patients, 202 women and 207 men. There were 275 gastric tumors (67.2%) and 134 non-gastric tumors (32.8%). Disease recurrence was recorded in 87 patients (21%) after a median follow-up of 64 months. Men with gastric tumors had inferior RFS compared to women (HR 2.18; 95% CI 1.07-4.45; P= 0.029), while there was no difference for non-gastric tumors (HR 0.77; 95% CI 0.44-1.33; P= 0.341). There was a substantial sex variation in the type of primary KIT mutation related to tumor location. Men with gastric tumors had a deletion or insertion-deletion that involved codons 557 and 558 (del557/558) more than twice as frequently as women (34% versus 16%; P= 0.008). Men also had slightly larger tumors (mean 6.6 cm versus 5.5 cm; P= 0.035) and more often tumors located in the upper third of the stomach, but there was no difference in mitotic count (23% versus 22% with &gt; 5 mitoses per 5 mm2). There was no difference in adjuvant imatinib treatment between men and women. No sex differences in primary mutation, tumor size or mitotic count were observed for non-gastric tumors. When KIT del557/558 mutation was included in the Cox regression analysis for gastric tumors, sex was not significantly associated with RFS (HR 1.49; 95% CI 0.70-3.18; P= 0.303), while del557/558 mutation was a strong prognostic factor (HR 6.40; 95% CI 3.17-12.94; P&lt; 0.001). Del557/558 mutation was not associated with RFS in non-gastric tumors (HR 0.67; 95% CI 0.33-1.35; P= 0.262). Conclusions: Women with localized, gastric GISTs had a lower risk of recurrence compared to men. There was no sex difference in outcome or baseline characteristics for non-gastric tumors. Men with gastric tumors more often had KIT del557/558 primary mutations, which may explain their inferior outcome. The observed sex difference in primary mutations in GISTs is unexplained and should be further explored.

Transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature in early-stage EGFR-mutant non-small-cell lung cancer.

e20571 Background: In a previous pilot study, we classified early-stage EGFR-mutant NSCLC according to two transcriptomic subtypes (i.e., terminal respiratory unit [TRU], which was related with the downregulation of a proliferative-related pathway; and non-TRU, which was related with the activation of a proliferative-related pathway) and the presence of a co-existing TP53 mutation. In turn, the clinical significance of the APOBEC mutation signature has not been elucidated clearly owing to the small sample size of the previous pilot study. Thus, this study aimed to validate the predictive value of transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature, to expand our pilot study via the use of additional samples and a long-term follow-up. Methods: We performed whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or FFPE from 101 patients with pathological stage II–IIIA non-squamous EGFR-mutant NSCLC who underwent complete resection between January 2014 and December 2020 at the Samsung Medical Center. This study evaluated the recurrence-free survival (RFS) and progression-free survival (PFS) afforded by EGFR-TKI therapy after recurrence according to transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature. Results: The median duration of the follow-up period was 54.2 months (range, 11.3–107.7 months). Six patients were excluded because of failure of the initial quality control; thus, 95 patients were included in the final analysis. The median age was 61.9 years (range, 44.7–91.0 years), and 75.8% of the patients were never-smokers. Moreover, 51.6% of the patients had stage III disease. Among the 95 patients, 47 (49.5%) patients were in the non-TRU group and 44 (46.3%) patients carried a TP53 mutation. The median RFS was 25.8 months (95% CI, 17.6–34.0 months). Patients with non-TRU and/or TP53 mutation had an inferior RFS compared with patients with TRU and wild-type TP53, regardless of the pathological stage (hazard ratio, 1.9; 95% CI, 1.4–2.7). The APOBEC mutation signature was not associated with RFS ( P = 0.17). Among the 65 patients who experienced radiological recurrence, 59 patients received EGFR-TKI therapy as the first-line treatment. The median PFS of EGFR-TKI therapy was 20.7 months (95% CI, 13.6–26.6 months). However, among these patients, those with the APOBEC mutation signature had a shorter PFS than those without this mutation signature (8.2 vs. 23.5 months, P &lt; 0.05). Conclusions: This study showed consistently that the transcriptomic subtype and TP53 mutation status were predictive factors of RFS, regardless of the pathological stage, in patients with early-stage EGFR-mutant NSCLC. Additionally, the APOBEC mutation signature may be present at the initial diagnosis of early-stage EGFR-mutant NSCLC and was associated with a poor PFS after EGFR-TKI therapy.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Prognostic Marker for the Outcome of HPV-Positive and HPV-Negative Oropharyngeal Squamous Cell Carcinoma.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in the past decades due to carcinogenic HPV infection. As this patient group suffers from considerable mortality and treatment morbidity it is important to improve prognostic strategies in OPSCC. Inflammation plays a key role in cancer and the neutrophil-to-lymphocyte ratio (NLR) in blood has been suggested as a prognostic factor for OPSCC. This study aimed to investigate the prognostic impact of NLR on overall survival (OS) and recurrence-free survival (RFS) in a retrospective cohort of 1370 patients. Included patients had pretreatment neutrophil and lymphocyte counts available, as well as a known HPV status. Patients were treated with curative intent according to Danish national guidelines. We stratified patients in groups by NLR < 2, NLR 2−4, or NLR > 4 and analyzed the influence of the NLR tertile on OS and RFS. Kaplan−Meier curves illustrated survival probability in OS and RFS in the general cohort and were stratified by HPV status. We found that an increasing NLR was associated with inferior OS (HR = 1.5 for NLR > 4) and RFS (HR = 1.6 for NLR 2−4; HR = 1.8 for NLR > 4) in multivariable analysis. The Kaplan−Meier curves displayed inferior OS and RFS with an increasing NLR for both HPV+ and HPV− patients. In conclusion, we showed that an increasing NLR is prognostic for a worse outcome of OPSCC independently of HPV status. There are possible uses of NLR in prognostication and treatment de-escalation although further studies are warranted to determine the clinical utility.

Loss of F-Box and Leucine Rich Repeat Protein 5 (FBXL5) Expression Is Associated With Poor Survival in Patients With Hepatocellular Carcinoma After Curative Resection: A Two-institute Study.

Alteration of F-box and leucine-rich repeat protein 5 (FBXL5), an iron-sensing ubiquitin ligase, might be related with carcinogenesis of hepatocellular carcinoma (HCC), by disturbing cellular iron homeostasis. However, the clinical implications of FBXL5 expression using patient samples need to be elucidated. We collected HCC tissue samples from two institutes: Samsung Medical Center (n=259) and Hallym University Sacred Heart Hospital (n=115) and evaluated FBXL5 expression using immunohistochemistry. Using cut-off values determined by X-tile software, association between FBXL5 expression and several clinicopathological parameters was investigated. For external validation, the Cancer Genome Atlas (TCGA) cohort was used. The best cutoff value for FBXL5 IHC expression associated with recurrence-free survival (RFS) was 5%. Low FBXL5 expression was found in 18.7% of the total 374 HCCs and was associated with non-viral etiology (p=0.019). Low FBXL5 expression was related with inferior disease-specific survival (DSS, p=0.002) and RFS (p=0.001) and also was an independent prognostic factor for DSS and RFS. In addition, cases with low FBLX5 mRNA levels showed inferior DSS and RFS (p<0.001 and p=0.002, respectively) compared to high FBLX5 mRNA levels in the TCGA cohort. Down-regulation of FBXL5 expression in HCCs might be associated with poor prognosis. FBXL5 might be a prognostic biomarker of HCCs and a potential therapeutic target in conjunction with iron homeostasis.

Analysis of Immune Intratumor Heterogeneity Highlights Immunoregulatory and Coinhibitory Lymphocytes as Hallmarks of Recurrence in Stage I Non–Small Cell Lung Cancer

Our understanding of the molecular mechanisms underlying postsurgical recurrence of non–small cell lung cancer (NSCLC) is rudimentary. Molecular and T cell repertoire intratumor heterogeneity (ITH) have been reported to be associated with postsurgical relapse; however, how ITH at the cellular level impacts survival is largely unknown. Here we report the analysis of 2880 multispectral images representing 14.2% to 27% of tumor areas from 33 patients with stage I NSCLC, including 17 cases (relapsed within 3 years after surgery) and 16 controls (without recurrence ≥5 years after surgery) using multiplex immunofluorescence. Spatial analysis was conducted to quantify the minimum distance between different cell types and immune cell infiltration around malignant cells. Immune ITH was defined as the variance of immune cells from 3 intratumor regions. We found that tumors from patients having relapsed display different immune biology compared with nonrecurrent tumors, with a higher percentage of tumor cells and macrophages expressing PD-L1 (P =.031 and P =.024, respectively), along with an increase in regulatory T cells (Treg) (P =.018), antigen-experienced T cells (P =.025), and effector-memory T cells (P =.041). Spatial analysis revealed that a higher level of infiltration of PD-L1+ macrophages (CD68+PD-L1+) or antigen-experienced cytotoxic T cells (CD3+CD8+PD-1+) in the tumor was associated with poor overall survival (P =.021 and P =.006, respectively). A higher degree of Treg ITH was associated with inferior recurrence-free survival regardless of tumor mutational burden (P =.022), neoantigen burden (P =.021), genomic ITH (P =.012) and T cell repertoire ITH (P =.001). Using multiregion multiplex immunofluorescence, we characterized ITH at the immune cell level along with whole exome and T cell repertoire sequencing from the same tumor regions. This approach highlights the role of immunoregulatory and coinhibitory signals as well as their spatial distribution and ITH that define the hallmarks of tumor relapse of stage I NSCLC.

Prognostic and clinicopathological significance of the Prognostic Nutritional Index in patients with gastrointestinal stromal tumours undergoing surgery: a meta-analysis

ObjectivesPrevious studies have investigated the prognostic value of the Prognostic Nutritional Index (PNI) in patients with gastrointestinal stromal tumours (GISTs). However, the results have been inconsistent. We performed a meta-analysis...

Survival after minimally invasive radical hysterectomy without using uterine manipulator for early-stage cervical cancer: A systematic review and meta-analysis.

Minimally invasive radical hysterectomy has been reported to increase the risk of cancer relapse and death compared with open surgery in women with early-stage cervical cancer. The use of a uterine manipulator is considered one of the risk factors. To investigate whether women with early-stage cervical cancer treated with minimally invasive radical hysterectomy without using uterine manipulator have oncological outcomes similar to those of open surgery. Searches were performed in MEDLINE, Embase and CENTRAL from their inception until 31 March 2022. Inclusion criteria were: (1) randomised controlled trials or observational cohort studies published in English, (2) studies comparing minimally invasive radical hysterectomy without using a uterine manipulator with open radical hysterectomy in women with early-stage cervical cancer, and (3) studies comparing survival outcomes. Two authors independently conducted data extraction and assessed study quality. We calculated the hazard ratios (HR) and the 95% confidence intervals (CI) using the inverse variance approach for survival outcome. Six observational studies with 2150 women were included. The minimally invasive surgery group had a significantly higher risk of cancer relapse compared with open surgery group (HR 1.55, 95% CI 1.15-2.10). Minimally invasive radical hysterectomy without using a uterine manipulator resulted in an inferior recurrence-free survival compared with open radical hysterectomy in the treatment of women with early-stage cervical cancer.

Circulating HPV DNA Kinetics and Clinical Outcomes in a Large Cohort of Radiotherapy-Treated p16-Positive Oropharyngeal Cancers

<h3>Purpose/Objective(s)</h3> Human papillomavirus (HPV) driven oropharyngeal cancer (OPC) has heterogeneous outcomes with a 5-year recurrence rate of up to 30% after definitive (chemo-)radiotherapy (CRT/RT). Circulating HPV DNA (ctDNA) is a convenient dynamic biomarker that can be repeatedly measured for risk stratification and response monitoring. However, the understanding of HPV ctDNA kinetics during treatment and its association with clinical and treatment factors is nascent. We characterized HPV ctDNA kinetics in the largest-to-date cohort of RT- or CRT-treated OPC. <h3>Materials/Methods</h3> Among 262 patients with p16 positive, stage I-III (TNM-8) OPC treated with standard of care curative-intent RT (n=107) or CRT (n=155), blood samples were collected at baseline (pre-treatment), week 4 of RT (mid-treatment), and 3-month follow-up (post-treatment). Early-treatment (end of week 1) blood draws were also performed in a subset of patients (n=92) with detectable baseline ctDNA. Copies of HPV-16 ctDNA were quantified using a previously validated multiplex droplet digital PCR assay and normalized to plasma volume. Primary outcome was recurrence-free survival (RFS) and secondary outcomes were progression-free survival (PFS) and overall survival (OS). <h3>Results</h3> With median follow up of 42.0 months (range: 3.5-77.5), 3-year RFS was 88%. Pre-treatment HPV ctDNA was detected in 220 (84%) patients and ranged from 0.32 to 2.4 × 10^5 copies/mL in plasma. Baseline ctDNA level was moderately associated with T category (median copies/mL: 350 in T1-2 and 730 in T3-4, p = 0.011) and strongly associated with N category (N0: 83, N1: 357, N2: 609, N3: 5903, p < 0.001). Among patients with detectable pre-treatment ctDNA, clearance (undetectable ctDNA) occurred in 3.5%, 14.3%, and 90.7% of early-, mid-, and post-treatment samples, respectively. Clearance at each timepoint was consistently associated with longer RFS, PFS, and OS, though the study was only powered to detect significant differences at post-treatment. 3-year RFS, PFS, and OS were 91.0%, 88.5%, and 92.1% respectively if ctDNA was cleared post-treatment, versus 62.2%, 50.6%, and 56.0% if ctDNA was not cleared. As a continuous variable, log-transformed ctDNA levels were independently prognostic of RFS (adjusted for disease stage) at early-treatment (Cox proportional hazards HR: 1.37, 95% CI: 1.01-1.86, p = 0.046) and post-treatment (HR: 1.30, 95% CI: 1.08-1.56, p = 0.0047), but not at pre- or mid-treatment. An increase (peak) in ctDNA level from pre-treatment to early-treatment was associated with inferior RFS (p=0.18), PFS (p=0.03), and OS (p=0.03). <h3>Conclusion</h3> Detectability of HPV ctDNA during and post-treatment is prognostic of recurrence and survival in RT-treated p16+ OPC. Quantitative ctDNA levels at early-treatment and post-treatment are prognostic, independent of disease stage. Early-treatment ctDNA kinetics show promise as a potential dynamic biomarker of treatment response.