Inferior Disease-specific Survival Research Articles

Racial and ethnic disparities in outcomes of diffuse large B cell lymphoma in adolescent and young adults: a SEER database analysis.

Data regarding racial disparities in the incidence, treatment, and outcomes of diffuse large B-cell lymphoma (DLBCL) is limited in the adolescent and young adult (AYA) population. We utilized the surveillance, epidemiology, and end-result (SEER) registry research plus database to evaluate racial/ethnic disparities in 8605 AYA patients with DLBCL. Race/ethnicity was categorized into three main subsets: non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), and 'other races' that included Hispanics (H), American Indian/Alaskan Native (AI/AN), Asian or Pacific Islander (A/PI). NHB were more likely to present with advanced stage disease (p < 0.001) and B symptoms (p < 0.001) and were less likely to receive chemotherapy(p < 0.001) compared to non-Hispanic white (NHW) patients and other races respectively. NHB patients had inferior 5-year disease specific survival (DSS) (70% vs 85% vs 80%, p < 0.001) and 5-year overall survival (OS) (66% vs 82% vs 77%, p < 0.001) compared to NHW and other races respectively. Black race was independently associated with both inferior DSS (HR 1.55, 95% CI 1.17-2.05, p = 0.002) and OS (HR 1.41, 95% CI 1.10-1.83, p = 0.007) after adjusting for age, gender, stage, presence of B symptoms, receipt of chemotherapy and radiation. NHB-DLBCL patients also had a lower 1-year relative survival rate (RSR) compared to NHW and other races. The low RSR in NHB patients persisted up to 5 years from diagnosis unlike NHW and other races. Our study shows that despite significant therapeutic advances in DLBCL over the last two decades, NHB AYA patients with DLBCL continue to have inferior survival outcomes compared to other ethnic and racial groups with disparities arising as early as the first year of diagnosis.

Clinical, pathological, genetics and intratumoural immune milieu of micropapillary carcinoma of the colon

AimMicropapillary carcinoma (MPC) is a recognised WHO variant of colonic carcinoma (CC), although little is known about its prognosis, immune microenvironment and molecular alterations. We investigated its clinical, pathological and...

Predictive value of FCGBP expression for treatment response and survival in rectal cancer patients undergoing chemoradiotherapy.

Despite neoadjuvant chemoradiotherapy (CRT) being the established standard for treating advanced rectal cancer, clinical outcomes remain suboptimal, necessitating the identification of predictive biomarkers for improved treatment decisions. Previous studies have hinted at the oncogenic properties of the Fc fragment of IgG binding protein (FCGBP) in various cancers; however, its clinical significance in rectal cancer remains unclear. In this study, we first conducted an analysis of a public transcriptome comprising 46 rectal cancer patients. Focusing on cell adhesion during data mining, we identified FCGBP as the most upregulated gene associated with CRT resistance. Subsequently, we assessed FCGBP immunointensity using immunohistochemical staining on 343 rectal cancer tissue blocks. Elevated FCGBP immunointensity correlated with lymph node involvement before treatment (p = 0.001), tumor invasion, and lymph node involvement after treatment (both p < 0.001), vascular invasion (p = 0.001), perineural invasion (p = 0.041), and reduced tumor regression (p < 0.001). Univariate analysis revealed a significant association between high FCGBP immunoexpression and inferior disease-specific survival, local recurrence-free survival, and metastasis-free survival (all p ≤ 0.0002). Furthermore, high FCGBP immunoexpression independently emerged as an unfavorable prognostic factor for all three survival outcomes in the multivariate analysis (all p ≤ 0.025). Enriched pathway analysis substantiated the role of FCGBP in conferring resistance to radiation. In summary, our findings suggest that elevated FCGBP immunoexpression in rectal cancer significantly correlates with a poor response to CRT and diminished patient survival. FCGBP holds promise as a valuable prognostic biomarker for rectal cancer patients undergoing CRT.

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Abstract B031: High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes

Abstract Introduction: Recent publications have identified ‘low risk’ (LR-NSMP) and ‘high risk’ no specific molecular profile (HR-NSMP) endometrial cancers (ECs). Although LR-NSMP (low grade (G1/2) estrogen receptor (ER) positive tumors have extremely low rates (&amp;lt;2%) of death from disease and are considered candidates for de-escalation of adjuvant therapy, little is known about the newly defined entity of HR-NSMP (G3 and/or ER-negative), including optimal management, with 27% of HR-NSMP patients dying from their disease We aimed to perform in-depth characterization of a cohort of HR-NSMP ECs to identify additional prognostic or predictive features that may inform management. Methods: Clinicopathologic data collection, immunohistochemistry (IHC), and next generation sequencing was performed on a cohort of 148 HR-NSMP ECs testing for associations with outcomes. Three subgroups of HR-NSMP were assessed: i) low grade without any ER expression (G1/2ER-, n=40), ii) high grade with ER (G3ER+, n=67), and iii) high grade without ER expression (G3ER-, n=41). Results: In a univariate analysis, advanced stage (III/IV), positive lymph node (LN) status, no LN assessment, and PIK3CA mutations were associated with inferior progression-free survival (PFS), disease specific survival (DSS), and overall survival (OS). HR-NSMP patients with positive LNs had a hazard ratio (HR) of death of 7.55 (95% CI: 3.41−16.73) compared to node negative. Additionally, patients with no LN assessment had an increased risk of death with a HR of 2.33 (95% CI: 1.12−4.85) compared to node negative. Within the three HR-NSMP subgroups, the worst OS (HR 7.06, CI 4.12-12.09, p&amp;lt; 0.001), DSS (HR 20.43, CI 10.14-41.19, p&amp;lt; 0.001), and PFS (HR 3.69, CI 1.59-8.63, p&amp;lt;0.001) were observed in patients with both adverse features (G3ER-). PIK3CA mutations were found in 32.7% of all HR-NSMP tumors tested (G1/2ER- 45.5%, G3ER+ 42.3%, G3ER- 6.7%) and associated with inferior OS (HR 4.84, CI 1.21-19.41, p=0.014), DSS (HR 4.84, CI 1.21-19.41, p=0.014), and PFS (HR 3.22, CI=1.08-9.66, p=0.028). There was a trend towards decreased OS and DSS in HR-NSMP patients with overexpression of HER2 IHC. L1CAM IHC overexpression and CTNNB1 mutation status were not associated with outcomes when assessed across all HR-NSMP or within subgroups. Conclusion: Among HR-NSMP ECs, the worst clinical outcomes were observed in patients harboring both high grade and ER negative tumors. In contrast to LR-NSMP ECs where patients who had no lymph node assessment had excellent outcomes mirroring node negative status, HR-NSMP patients who had no nodal assessment had a high rate of recurrence and death from disease suggesting the importance of comprehensive staging in this cohort. PIK3CA appears to be a prognostic stratification feature within HR-NSMP and represents a potential therapeutic pathway. More work is needed to understand the association of HER2 expression and ER status and whether HER2 -targeted therapies represent actionable opportunities for these patients. Citation Format: Andrea Neilson, Amy Jamieson, Derek Chiu, Samuel Leung, Amy Lum, Jennifer Pors, Stefan Kommoss, Aline Talhouk, David G. Huntsman, Naveena Singh, C. Blake Gilks, Jessica N. McAlpine. High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B031.

Neighborhood deprivation and race as predictors for cancer-related mortality in breast cancer.

174 Background: The socioeconomic status (SES) of individuals and their neighborhoods significantly influences their access to healthcare and the outcomes of their diseases. Inequities in opportunities, education, income, and infrastructure can contribute to worse prognosis and unfavorable outcomes for certain malignancies in areas with lower SES. We studied the association of race and neighborhood deprivation with the survival of breast cancer (BC). Methods: We linked the neighborhood deprivation index (NDI) data by the National Cancer Institute with the BC cohort from the SEER database diagnosed from 2010 to 2016. NDI score of each county is created using factor analysis to identify variables from 13 SES attributes from the dimensions: wealth/income, education, occupation, housing conditions. NDI was classified into quintiles (qn) (Q1 least deprived - Q5 most deprived). The association between NDI, race/ethnicity and overall survival (OS) and disease-specific survival (DSS) was analyzed using Cox multivariate regression model. All analyses were adjusted for age, race, grade, insurance, and treatments. Results: Most of the early-stage (ES) (N= 88, 572) and advanced-stage (AS) BC (N= 12336) patients (pts) were in the Q5 (ES- 27.4%, AS- 30%) qn. There was a predominance of racial minorities in Q5 and Q4 compared to Q1 qn (ES: Blacks 13-15% vs 8%, Hispanics 15% vs 6%; AS: Blacks 19-23% vs 14%, Hispanics 13% vs 7%, p&lt;0.001). Uninsured ES pts were higher in Q5 compared to Q1 qn (2.2% vs 1.7%, p&lt;0.001). Triple-negative BC was higher in Q5 compared to Q1 qn (ES: 14.5% vs 11.7%; AS: 16.5% vs 8.8%, p&lt;0.001). ES BC pts who live in Q5 qn have inferior OS and DSS compared to Q1 qn, but this trend was not observed in advanced BC (Table 1). The interaction between NDI and race for OS and DSS was significant (p-interaction 0.0030 and 0.02 respectively) for the ES BC, but not for advanced BC (p-interaction 0.67 and 0.72 respectively). In ES BC, Whites residing in Q5 qn had higher overall (OS: HR= 1.23, 95% CI= 1.14-1.34, p&lt;0.001) and disease-specific mortality (DSS: HR= 1.29, 95% CI= 1.15-1.45, p&lt;0.001) compared to Whites from Q1 qn. However, this disparity in mortality based on the NDI was not observed for Blacks with ES BC (OS: HR= 1.2, 95% CI= 0.98-1.46, p=0.06, DSS: HR= 1.2, 95% CI= 0.94-1.55, p= 0.12). Conclusions: Early-stage BC pts from areas with worse NDI have poor OS and DSS. Blacks with early-stage BC have poor OS and DSS regardless of the SES of the neighborhoods. To improve their clinical outcomes, personalized treatments are needed for Black pts with early-stage BC. Targeted investments and policies should prioritize improving the SES of neighborhoods with high deprivation to reduce healthcare disparities and enhance BC outcomes.[Table: see text]

Transcriptional subtypes of glottic cancer characterized by differential activation of canonical oncogenic programming.

There is a paucity of data concerning molecular heterogeneity among glottic squamous cell carcinoma, and the clinical implications thereof. Data corresponding to glottic squamous cell carcinoma were derived from The Cancer Genome Atlas. The Onco-GPS computational methodology was levied to derive four patterns of transcriptional activity and three functional subtypes of glottic cancer. Thirty glottic cancer samples stratified to three distinct oncogenic states (S0-S2) based on a Onco-GPS model containing four transcriptional components (F0-F3). Membership in S2 and association with transcriptional component F0 conveyed an invasive phenotype, with transcriptional activity strongly reflecting EMT programming (including TGF-B and NF-KB signaling). S2 membership also correlated with inferior disease-specific survival (HR 9.027, 95% CI 1.021-79.767), and higher incidences of extracapsular spread and perineural invasion. We present a functional taxonomy of glottic cancer, with subtypes demonstrating differential upregulation of canonical oncogenic networks and survival implications.

Effect of neighborhood deprivation index on breast cancer survival in the United States

PurposeTo analyze the association between the Neighborhood Deprivation Index (NDI) and clinical outcomes of locoregional breast cancer (BC).MethodsSurveillance, Epidemiology and End Results (SEER) database is queried to evaluate overall survival (OS) and disease-specific survival (DSS) of early- stage BC patients diagnosed between 2010 and 2016. Cox multivariate regression was performed to measure the association between NDI (Quintiles corresponding to most deprivation (Q1), above average deprivation (Q2), average deprivation (Q3), below average deprivation (Q4), least deprivation (Q5)) and OS/DSS.ResultsOf the 88,572 locoregional BC patients, 27.4% (n = 24,307) were in the Q1 quintile, 26.5% (n = 23,447) were in the Q3 quintile, 17% (n = 15,035) were in the Q2 quintile, 13.5% (n = 11,945) were in the Q4 quintile, and 15.6% (n = 13,838) were in the Q5 quintile. There was a predominance of racial minorities in the Q1 and Q2 quintiles with Black women being 13–15% and Hispanic women being 15% compared to only 8% Black women and 6% Hispanic women in the Q5 quintile (p < 0.001). In multivariate analysis, in the overall cohort, those who live in Q2 and Q1 quintile have inferior OS and DSS compared to those who live in Q5 quintile (OS:- Q2: Hazard Ratio (HR) 1.28, Q1: HR 1.2; DSS:- Q2: HR 1.33, Q1: HR 1.25, all p < 0.001).ConclusionLocoregional BC patients from areas with worse NDI have poor OS and DSS. Investments to improve the socioeconomic status of areas with high deprivation may help to reduce healthcare disparities and improve breast cancer outcomes.

SYNPO2 upregulation is an unfavorable prognostic factor for nasopharyngeal carcinoma patients.

Nasopharyngeal carcinoma (NPC) is the most common malignant neoplasm of the nasopharynx. Despite improvements in the clinical treatment strategies for NPC, NPC patients usually have poor survival rates because of late diagnosis, tumor metastasis, and recurrence. Therefore, the identification of potential diagnostic and prognostic markers for NPC is imperative. We investigated the differential expression of cell adhesion-related genes (gene ontology:0003779) and tumorigenesis-related genes (GSE12452) in patients with NPC. The correlations between synaptopodin-2 (SYNPO2) immune expression and clinicopathological features were analyzed using Pearson chi-square test. Multivariate analysis was performed using Cox proportional hazards model. SYNPO2 expression was significantly higher in NPC tumor tissues than in nontumor tissues. High SYNPO2 expression was significantly associated with the advanced disease stage (P = .006). Univariate analysis showed that high expression of SYNPO2 was associated with poor disease-specific survival, distal metastasis-free survival, and local recurrence-free survival in patients with NPC. Notably, our multivariate analysis demonstrated that high SYNPO2 expression was substantially correlated with inferior disease-specific survival (hazard ratio = 1.968, P = .012) and local recurrence-free survival (hazard ratio = 3.386, P = .001). Overall, our findings reveal that SYNPO2 may aid in the development of potential prognostic biomarkers for NPC patients.

Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

ObjectivesLow-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy. MethodsGenomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation. Results63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup. ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

Abstract 1934: Incidence and survival outcomes of younger adults with colorectal cancers by age group: a SEER analysis

Abstract Background: The incidence of colorectal cancer (CRC) is increasing in younger adults (&amp;lt;50 years). Most cases occur between 40 and 49 years. Adolescents and young adults (AYA,15-39 years) with CRC have more aggressive disease. We sought to compare the incidence and outcomes of CRC in AYA with patients in the 40-49 age group. Methods: Surveillance, Epidemiology, and End Result (SEER) was analyzed from 2000-2019. Survival outcomes were analyzed using Kaplan-Meier methods, and comparisons were made using the log-rank test. Cox regression models were used to evaluate univariate and multivariate associations with survival outcomes. SAS v9.4 (Cary, NC) and SEER*Stat v8.4 were used, with a significance level of 0.05.Results: A total of 13,877 AYA patients and 43,771 patients in the age group 40-49 years were identified. The annual incidence rate per 100,000 AYA patients increased from 3.1 in 2000 to 5.3 in 2019. In the 40-49 cohort, the annual incidence rate per 100,000 increased from 21.6 in 2000 to 28.0 in 2019. The annual percent change for incidence for the AYA cohort was higher 3.1% (95% CI 2.8,3.4) than the 40-49 cohort 1.4% (95% CI 1.2,1.6). The 2-year overall survival (OS) rate was not different among the two groups. Disease-specific survival (DSS) was slightly but significantly inferior in the AYA group, 83% (95%CI 0.82,0.83) compared to in the 40-49 cohort, 84% (95%CI 0.83,0.84). Factors associated with inferior DSS in the AYA group were male sex, black race, advanced stage, lack of chemotherapy, and longer time to treatment. Conclusion: Our study shows that the annual percent change in incidence rate was higher in AYA patients compared to those in the 40-49 age group from 2000-2019. DSS was slightly lower in AYA patients; OS was similar in both groups. Further studies are needed to understand the discrepancies. Table 1: Baseline characteristics of AYA and 40-49yr patients AYA 13877(24.1%) 40-49yr 43771(75.9%) Overall 57648(100%) P value Age at diagnosis Mean/Standard deviation 34/4.6 45.5/2.8 42.7/5.9 &amp;lt;0.001 Gender Male 51.9% 53.6% 53.2% &amp;lt;0.001 Race Non-Hispanic White 54.2% 59.4% 58.2% &amp;lt;0.001 Non-Hispanic Black 12.1% 13.3% 13% Asian or Pacific Islander 33% 26.7% 28.2% Unknown 0.6% 0.6% 0.6% Stage Localized 22.2% 26.5% 25.5% &amp;lt;0.001 Regional 31.6% 30.2% 30.6% Distant 20% 19.2% 19.4% Unstaged 1.8% 1.7% 1.7% Blank 24.4% 22.3% 22.8% Chemotherapy No/Unknown 33.8% 39.4% 38.1% &amp;lt;0.001 Citation Format: Sheeba Ba Aqeel, Adrienne Groman, Kristopher Attwood, Renuka Iyer, Sarabjit Mukherjee, Deepak Vadehra. Incidence and survival outcomes of younger adults with colorectal cancers by age group: a SEER analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1934.

Clinicopathological features and prognostic outcomes of molecularly defined entities in the new edition of the WHO classification of sinonasal carcinoma.

We investigated the clinicopathological features and prognoses of the new molecularly defined entities in latest edition of the World Health Organization (WHO) classification of sinonasal carcinoma (SNC). Integrated data were combined into an individual patient data (IPD) meta-analysis. We included 61 studies with 278 SNCs including 25 IDH2-mutant, 41 NUT carcinoma, 187 SWI/SNF loss, and 25 triple negative SNCs (without IDH2 mutation, NUTM1 rearrangement, and SWI/SNF inactivation) for analyses. Compared to other molecular groups, NUT carcinoma was associated with a younger age at presentation and an inferior disease-specific survival. Among SNCs with SWI/SNF inactivation, SMARCB1-deficient tumors presented later in life and were associated with a higher rate of radiotherapy administration. SMARCA4-deficiency was mostly found in teratocarcinosarcoma while SMARCB1-deficient tumors were associated with undifferentiated carcinoma and non-keratinizing squamous cell carcinoma. Our study facilitates our current understanding of this developing molecular-defined spectrum of tumors and their prognoses.

Abstract PD1-04: Neighborhood Deprivation Index and Survival in Breast Cancer in the United States

Abstract Introduction: Socioeconomic status (SES) of the individual and neighborhood plays an important role in patients’ (pts) access to the health system and eventually in the outcomes of their disease. Owing to the inequalities in opportunities, education, income, and developmental infrastructures, the area with deprived individual and neighborhood SES may be associated with a poor prognosis of certain malignancies and worse outcomes. We analyzed the association between Neighborhood Deprivation Index (NDI) and survival of early-stage breast cancer (BC). Methods: The NDI created by the National Cancer Institute includes variables from dimensions, such as, wealth and income, education, occupation, and housing conditions which have been used for our analysis. We analyzed the impact of NDI in quintiles (qn). We queried the SEER database from 2010-2016 for all early-stage BC pts and studied the overall survival (OS) and disease-specific survival (DSS) of BC in association with NDI. Cox multivariate regression modeling was performed to measure the association between NDI and OS/DSS. Kruskal-Wallis test was used for comparison for continuous and Chi-Square test was used for categorical variables. All analyses were adjusted for age, race, grade, insurance, surgery (SX), radiation (RN), and chemotherapy (CT). Statistics were performed using SAS. Results: Out of the 88,572 early-stage BC pts, 27.4 % (n= 24,307) were in the most deprivation (MD) qn, 26.5% (n= 23,447) were in the average deprivation (AD) qn, 17% (n= 15,035) were in the above average deprivation (AA) qn, 15.6% (n= 13,838) were in the least deprivation (LD) qn and 13.5% (n= 11,945) were in the below average deprivation (BA) qn. The median age of pts in the LD qn was 59 and MD qn was 61 yrs, p&amp;lt; 0.001. There was a predominance of racial minorities in the MD and AA qn with Blacks being 13-15% and Hispanics being 15% compared to only 8% Blacks and 6% Hispanics in the LD qn (p&amp;lt; 0.001). There was a higher percentage of uninsured pts in the MD qn compared to LD qn (2.2% vs 1.7%, p&amp;lt; 0.001). There were more rural areas in MD qn compared to LD qn (25.9% vs only 0.7%, p&amp;lt; 0.001). There were more pts with grade III disease in MD qn compared to LD qn (34% vs 31.9%, p&amp;lt; 0.001). 96.1% pts underwent SX in MD qn vs 97.1 % had SX in LD qn, p&amp;lt; 0.001. Similarly, 49.7% underwent RN in MD qn vs 56.5% had RN in the LD qn, p&amp;lt; 0.001. Greater percentage of pts received CT in MD qn compared to LD qn (44.6% vs 42.1%, p&amp;lt; 0.001). There was a higher percentage of more aggressive cancers such as triple-negative breast cancer (TNBC) and HER2 positive (HER2+) in MD qn compared to LD qn (14.5%, 17.7% vs 11.7%, 16.5% respectively, p&amp;lt; 0.001). In multivariate analysis, in the overall cohort, those who live in AA qn and MD qn have inferior OS and DSS when compared to those who live in LD qn (OS in AA: Hazard Ratio (HR) 1.3, 95% CI: 1.2-1.4; OS in MD: HR 1.2, 95% CI: 1.1-1.3; DSS in AA: HR 1.3, 95% CI: 1.2-1.5; DSS in MD: HR 1.2, 95% CI: 1.1-1.4, all p&amp;lt; 0.001). Similar results in OS and DSS were observed in hormone receptor-positive HER2 negative (HR+) and HER2+ subtypes, but not in TNBC (Table 1). The 5-year OS rates and DSS rates were also comparatively low in AA qn and MD qn compared to LD qn (OS: AA- 84%, MD- 85%, LD- 98%; DSS: AA- 91%, MD- 92%, LD- 95%, all p&amp;lt; 0.001). Conclusion: Early-stage BC pts from areas with worse NDI have poor OS and DSS, after accounting for the demographic, clinicopathological, treatment-related factors. Investments in poor-resource neighborhoods and policies focusing on improving the SES of areas with high deprivation need to be implemented to reduce health care disparities and improve breast cancer outcomes. Table: Overall Survival and Disease Specific Survival Citation Format: Arya Mariam Roy, Anthony George, Kristopher Attwood, Shipra Gandhi. Neighborhood Deprivation Index and Survival in Breast Cancer in the United States [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 PD1-04.

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.

Intratumoral neutrophil extracellular traps are associated with unfavorable clinical outcomes and immunogenic context in pancreatic ductal adenocarcinoma.

Extracellular traps (ETs) and tumor-infiltrating immune cells play crucial roles in tumor progression. However, little is known about the clinical significance of tumor-infiltrating neutrophils and macrophages and the related ETs in pancreatic ductal adenocarcinoma (PDAC). This study investigates the associations between neutrophil or macrophage infiltration or ET formation and the clinicopathological features, molecular characteristics, immune checkpoint molecules, clinical outcomes, and response to adjuvant chemotherapy (ACT) in PDAC. We performed multiplex immunofluorescence staining to detect ET formation by neutrophils or macrophages using tissue microarrays obtained from 205 patients, and analyzed the immunohistochemistry data for PD-L1, PD-L2, B7-H3, and B7-H4. The ET expression rates in macrophages and neutrophils were 23.9% and 45.4%, respectively. Patients with a high density of neutrophils or positive expression of neutrophil ETs exhibited poorer progression-free survival (PFS) and disease-specific survival (DSS), whereas macrophage ETs were not related to PFS and DSS. Neutrophil infiltration and ET formation were identified as independent prognostic predictors of DSS using univariate and multivariate Cox analyses. Patients with PDAC with lower neutrophil infiltration or negative staining for neutrophil ETs are more likely to benefit from ACT. Patients with PDAC were more accurately stratified based on the infiltration of neutrophils and presence of neutrophil ETs, and patients with low neutrophil infiltration and negative staining for neutrophil ETs showed the best survival. Patients with positive neutrophil ETs demonstrated inferior DSS compared to those with negative neutrophil ETs in the PD-L1 tumor proportion score (TPS) < 1% and PD-L1 IC < 1% subgroups. However, the positive expression of neutrophil ETs was not related to DSS in the PD-L1 TPS ≥ 1% or PD-L1 IC ≥ 1% subgroup. Our findings emphasize the potential of neutrophil infiltration and ETs as prognostic markers that could guide the formulation of more effective personalized treatments for PDAC.

Identification of a novel subtype of endometrial cancer with unfavorable outcome using artificial intelligence-based histopathology image analysis.

5594 Background: Molecular subtyping of endometrial cancer (EC), unlike histopathological evaluation, offers an objective and reproducible classification system that has strong prognostic value and therapeutic implications. The Proactive Molecular risk classifier for Endometrial cancer (ProMisE) was developed by our team as a pragmatic, cost-effective, and clinically applicable molecular classifier for EC patients. ProMisE has four subtypes: (i) POLE mutant ( POLEmut), (ii) mismatch repair deficient (MMRd), (iii) p53 abnormal (p53abn) by immunohistochemistry, and (iv) NSMP (No Specific Molecular Profile), lacking any of the defining features of the other three subtypes. While ProMisE subtypes are associated with clinical outcomes, within each subtype, there are clinical/prognostic outliers. This is particularly true within the largest ProMisE subtype; NSMP (representing ̃50% of ECs), where a subset of patients experience a very aggressive disease course, comparable to what is observed in patients with p53abn ECs. Methods: We hypothesized that objective assessment of the digitized hematoxylin and eosin (H&amp;E)-stained histopathology slides of the largest and most diverse EC subset, NSMP, could potentially identify clinical outcome outliers. As such, we developed an artificial intelligence (AI)-based image analysis model to identify the NSMP cases that had similar histopathological features to the p53abn subtype, as assessed by H&amp;E stain. We used a discovery cohort of 182 and an external validation cohort of 195 NSMP ECs. Results: Our AI-based image analysis model, based on deep convolutional neural networks, identified 21 (11.5%) out of the 182 NSMP cases with similar histopathological features as p53abn cases. We refer to these cases as ‘p53abn-like’ NSMPs. Compared to the rest of the NSMP cases, these cases had markedly inferior disease-specific survival (DSS) (10-year DSS 58.9% vs. 93.1% ( p&lt;3.44e-8)) and progression-free survival (PFS) (10-year PFS 55.1% vs. 91.4% ( p&lt;3.76e-6)). These findings were confirmed in our validation cohort, with 10.7% of the 195 patients categorized as ‘p53abn-like’ tumors with 10-year DSS of 82% vs. 51.3% ( p&lt;5.28e-5) and PFS of 89.3% vs. 56.6% (p&lt;2.15e-4). Conclusions: Utilizing an AI-based approach for histopathology image analysis, we have discovered ‘p53abn-like’ NSMPs, a novel subtype of NSMP ECs with morphological features similar to p53abn cases. ‘p53abn-like’ NSMPs exhibit similar clinical behavior as p53abn, having noticeably inferior outcome compared to the rest of the NSMP cases in two independent cohorts. These findings warrant further molecular investigation of this novel subtype of EC to identify the biological underpinning and future therapeutic strategies.

MicroRNA-182-5p and microRNA-205-5p as potential biomarkers for prognostic stratification of p16-positive oropharyngeal squamous cell carcinoma.

MicroRNAs constitute promising biomarkers. The aim was to investigate diagnostic and prognostic implications of miR-182-5p and miR-205-5p in p16-positive and p16-negative oropharyngeal squamous cell carcinomas (OPSCCs). Expression of miR-182-5p, miR-205-5p were determined via quantitative real-time-PCR in fresh frozen tissues of 26 p16-positive, 19 p16-negative OPSCCs and 18 HPV-negative oropharyngeal controls. Associations between miRNA-expression, clinicopathological characteristics and prognosis were analyzed. Higher miR-182-5p expression was associated with significant inferior disease-specific survival for p16-positive OPSCCs (HR = 1.98E+09, 95% CI 0-Inf; P= 0.028) and a similar trend was observed for p16-negative OPSCCs (HR = 1.56E+09, 95% CI 0-Inf; P= 0.051). Higher miR-205-5p expression was associated with an inferior progression-free survival (HR = 4.62, 95% CI 0.98-21.83; P= 0.034) and local control rate (HR = 2.18E+09, 95% CI 0-Inf; P= 0.048) for p16-positive OPSCCs. Results indicate that miR-182-5p and miR-205-5p can further stratify patients with p16-positive OPSCC into prognostic groups.

Value of c-MET and Associated Signaling Elements for Predicting Outcomes and Targeted Therapy in Penile Cancer.

Simple SummaryNo relevant improvement in patient outcomes could be achieved in the last decade in metastasized penile cancer due to insufficient identification of molecular hubs crucial for tumor evolution. We investigated the potential of the cellular receptor c-MET and selected other proteins linked to its activity to predict outcomes and for exploitation in targeted treatment. Assessing tumor tissue as well as primary cells both naïve and resistant to systemic drugs, we illustrate the most promising role of c-MET. Indeed, its elevated expression was strongly associated with inferior tumor-related survival. Moreover, its upregulation in treatment-resistant cell lines compared to naïve cells was observed. Treating cell lines with the c-MET inhibitors cabozantinib and tivantinib mediated an effective decrease in cell growth, while the first agent was more efficacious in the naïve cells and the second agent in the resistant cells. Therefore, c-MET blockade warrants further investigation in the setting of metastasized penile cancer.Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.

Photodynamic Therapy with Zinc Phthalocyanine Inhibits the Stemness and Development of Colorectal Cancer: Time to Overcome the Challenging Barriers?

Photodynamic therapy (PDT) is a light-based cancer therapy approach that has shown promising results in treating various malignancies. Growing evidence indicates that cancer stem cells (CSCs) are implicated in tumor recurrence, metastasis, and cancer therapy resistance in colorectal cancer (CRC); thus, targeting these cells can ameliorate the prognosis of affected patients. Based on our bioinformatics results, SOX2 overexpression is significantly associated with inferior disease-specific survival and worsened the progression-free interval of CRC patients. Our results demonstrate that zinc phthalocyanine (ZnPc)-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially decrease tumor migration via downregulating MMP9 and ROCK1 and inhibit the clonogenicity of SW480 cells via downregulating CD44 and SOX2. Despite inhibiting clonogenicity, ZnPc-PDT with 12 J/cm2 irradiation fails to downregulate CD44 expression in SW480 cells. Our results indicate that ZnPc-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially reduce the cell viability of SW480 cells and stimulate autophagy in the tumoral cells. Moreover, our results show that ZnPc-PDT with 12 J/cm2 or 24 J/cm2 irradiation can substantially arrest the cell cycle at the sub-G1 level, stimulate the intrinsic apoptosis pathway via upregulating caspase-3 and caspase-9 and downregulating Bcl-2. Indeed, our bioinformatics results show considerable interactions between the studied CSC-related genes with the studied migration- and apoptosis-related genes. Collectively, the current study highlights the potential role of ZnPc-PDT in inhibiting stemness and CRC development, which can ameliorate the prognosis of CRC patients.

Impact of Disease Extent and Distribution on Outcomes in Stage II Follicular Lymphoma Treated with Curative-Intent Radiation Therapy

Impact of Disease Extent and Distribution on Outcomes in Stage II Follicular Lymphoma Treated with Curative-Intent Radiation Therapy