Poor Disease-free Survival Research Articles

ROS is a master regulator of in vitro matriptase activation.

Matriptase is a type II transmembrane serine protease that is widely expressed in normal epithelial cells and epithelial cancers. Studies have shown that regulation of matriptase expression and activation becomes deranged in several cancers and is associated with poor disease-free survival. Although the central mechanism of its activation has remained unknown, our lab has previously demonstrated that inflammatory conditions such as intracellular pH decrease strongly induces matriptase activation. In this investigation, we first demonstrate clear matriptase activation following Fulvestrant (ICI) and Tykerb (Lapatinib) treatment in HER2-amplified, estrogen receptor (ER)-positive BT474, MDA-MB-361 and ZR-75-30 or single ER-positive MCF7 cells, respectively. This activation modestly involved Phosphoinositide 3-kinase (PI3K) activation and occurred as quickly as six hours post treatment. We also demonstrate that matriptase activation is not a universal hallmark of stress, with Etoposide treated cells showing a larger degree of matriptase activation than Lapatinib and ICI-treated cells. While etoposide toxicity has been shown to be mediated through reactive oxygen species (ROS) and MAPK/ERK kinase (MEK) activity, MEK activity showed no correlation with matriptase activation. Novelly, we demonstrate that endogenous and exogenous matriptase activation are ROS-mediated in vitro and inhibited by N-acetylcysteine (NAC). Lastly, we demonstrate matriptase-directed NAC treatment results in apoptosis of several breast cancer cell lines either alone or in combination with clinically used therapeutics. These data demonstrate the contribution of ROS-mediated survival, its independence of kinase-mediated survival, and the plausibility of using matriptase activation to indicate the potential success of antioxidant therapy.

The prognostic value of the advanced lung cancer inflammation index in patients with gastrointestinal malignancy

BackgroundSystemic inflammation is crucial for the development and progression of cancers. The advanced lung cancer inflammation index (ALI) is considered to be a better indicator of systemic inflammation than current biomarkers. However, the prognostic value of the ALI in gastrointestinal neoplasms remains unclear. We performed the first meta-analysis to explore the association between ALI and gastrointestinal oncologic outcomes to help physicians better evaluate the prognosis of those patients.MethodsEligible articles were retrieved using PubMed, the Cochrane Library, EMBASE, and Google Scholar by December 29, 2022. Clinical outcomes were overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS).ResultsA total of 18 articles with 6898 patients were included in this meta-analysis. The pooled results demonstrated that a low ALI was correlated with poor OS (HR = 1.914, 95% CI: 1.514–2.419, P < 0.001), DFS (HR = 1.631, 95% CI: 1.197–2.224, P = 0.002), and PFS (HR = 1.679, 95% CI: 1.073–2.628, P = 0.023) of patients with gastrointestinal cancers. Subgroup analysis revealed that a low ALI was associated with shorter OS (HR = 2.279, 95% CI: 1.769–2.935, P < 0.001) and DFS (HR = 1.631, 95% CI: 1.197–2.224, P = 0.002), and PFS (HR = 1.911, 95% CI: 1.517–2.408, P = 0.002) of patients with colorectal cancer. However, the ALI was not related to CSS in the patients with gastrointestinal malignancy (HR = 1.121, 95% CI: 0.694–1.812, P = 0.640). Sensitivity analysis supported the stability and dependability of the above results.ConclusionThe pre-treatment ALI was a useful predictor of prognosis in patients with gastrointestinal cancers.

Glasgow Prognostic Score Predicts Survival and Recurrence Pattern in Patients With Hepatocellular Carcinoma After Hepatectomy.

The prognostic significance of the Glasgow Prognostic Score (GPS) on outcomes of liver resection for hepatocellular carcinoma (HCC) remains unclear; the aim of the study was to assess its significance. A total of 480 patients with HCC who underwent liver resection with curative intent at the Yokohama City University Hospital and Medical Center were enrolled in the study. Patients were classified into three groups: GPS-0, C-reactive protein (CRP) ≤1.0 mg/dl serum albumin ≥3.5 g/dl; GPS-1, CRP >1.0 mg/dl or serum albumin <3.5 g/dl; and GPS-2, CRP >1.0 mg/dl, serum albumin <3.5 g/dl. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. The recurrence pattern was also investigated using GPS. Of the 480 patients, 382 (79.6%), 81 (16.9%), and 17 (3.5%) were assigned to GPS-0, GPS-1, and GPS-2, respectively. Elevated GPS, indocyanine green retention rate at 15 min, and protein induced by vitamin K antagonist-II (PIVKA-II) were significantly associated with a poor OS. Elevated GPS, alpha-fetoprotein, and PIVKA-II were significantly associated with a poor DFS by multivariate analysis. The number of patients with liver-only recurrence in GPS-0, GPS-1, and GPS-2 was 179 (86.1%), 40 (78.4%), and 9 (69.2%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-0, GPS-1, and GPS-2 groups, was 33 (17.9%), 11 (27.5%), and 8 (88.9%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-2 group was significantly higher (p<0.001). Preoperative GPS is a useful predictor of OS and recurrence pattern after liver resection with a curative intent for HCC.

Macrophage numbers in the marginal area of sarcomas predict clinical prognosis

Even when treated comprehensively by surgery, chemotherapy, and radiotherapy, soft-tissue sarcoma has an unfavorable outcome. Because soft-tissue sarcoma is rare, it is the subject of fewer clinicopathological studies, which are important for clarifying pathophysiology. Here, we examined tumor-associated macrophages in the intratumoral and marginal areas of sarcomas to increase our knowledge about the pathophysiology. Seventy-five sarcoma specimens (not limited to a single histological type), resected at our institution, were collected, and the number of CD68-, CD163-, and CD204-positive macrophages in the intratumoral and marginal areas was counted. We then performed statistical analysis to examine links between macrophage numbers, clinical factors, and outcomes. A high number of macrophages positive for all markers in both areas was associated with worse disease-free survival (DFS). Next, we divided cases according to the FNCLCC classification (Grade 1 and Grades 2/3). In the Grade 1 group, there was no significant association between macrophage number and DFS. However, in the Grade 2/3 group, high numbers of CD163- and CD204-positive macrophages in the marginal area were associated with poor DFS. By contrast, there was no significant difference between the groups with respect to high or low numbers of CD68-, CD163-, or CD204-positive macrophages in the intratumoral area. Multivariate analysis identified the number of CD163- and CD204-positive macrophages in the marginal area as an independent prognostic factor. Macrophage numbers in the marginal area of soft-tissue sarcoma may better reflect clinical behavior.

Tumor burden score dictates prognosis of patients with combined hepatocellular cholangiocarcinoma undergoing hepatectomy.

The prognostic value of the tumor burden score (TBS) in patients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains unknown. This study aimed to investigate the impact of TBS on long-term outcomes after surgery. Patients who underwent radical-intent resection between June 2013 and December 2019 were retrospectively reviewed. Kaplan-Meier curves were used to analyze patient survival, and disease-free survival (DFS) and overall survival (OS) were examined in relation to TBS. A total of 178 patients were included in this study, with 119 in the training cohort and 59 in the validation cohort. Kaplan-Meier curves showed that TBS was a strong prognostic indicator in patients with cHCC-CCA. Elevated TBS was associated with poorer DFS and OS (both P-value < 0.001) and was identified as an independent prognostic indicator. In addition, the prognostic value of TBS outperformed tumor size and number alone, microvascular invasion, and lymph node invasion. The prognostic significance of TBS was confirmed by the internal validation cohort. The present study suggested the significance of tumor morphology in assessing the prognosis of patients with cHCC-CCA who undergoing curative resection. The TBS is a promising prognostic index in patients with cHCC-CCA. Elevated TBS was related to a lower long-term survival rate and was identified as an independent risk factor for poor DFS and OS. Further research is needed to verify our results.

A pan-cancer analysis of the prognostic and immunological roles of matrix metalloprotease-1 (MMP1) in human tumors.

Cancer remains the leading killer of human health worldwide. It has been shown that matrix metalloproteinase-1(MMP1) is related to poor prognosis in cancers such as BRCA, CESC and COAD. However, systematic pan-cancer analysis about the prognostic and immunological roles of MMP1 has not been explored. Here, the purpose of this study was to investigate the prognostic and immunological roles of MMP1 in pan-cancer and confirm cancer-promoting effect in pancreatic cancer. In our study, bioinformatics were first used to analyze data from multiple databases. Then, several bioinformatics tools were utilized to investigate the role of MMP1 in 33 tumor types. Finally, molecular biology experiments were carried out to prove the cancer-promoting effect of MMP1 in pancreatic cancer. MMP1 expression was higher in tumor tissues than in control tissues in most tumor types. High expression of MMP1 was associated with poor overall survival (OS) and disease-free survival (DFS) in some tumor types. Further analysis of MMP1 gene mutation data showed that MMP1 mutations significantly influenced the prognosis of STAD. In addition, MMP1 expression was closely related to cancer-associated fibroblast (CAFs) infiltration in a variety of cancers and played an important role on immune infiltration score, tumor mutational burden (TMB) and microsatellite instability (MSI). Gene Ontology enrichment analysis indicated that these 20 genes were mainly related to extracellular structure organization/extracellular matrix organization/extracellular matrix disassembly/collagen metabolic process in the enriched biological processes. Finally, molecular biology experiments confirmed the cancer-promoting effect of MMP1 in pancreatic cancer. Our pan-cancer analysis comprehensively proved that MMP1 expression is related with clinical prognosis and tumor immune infiltration, and MMP1 can become a prognostic and immunological biomarker.

Inflammatory and Nutritional Status Influences Outcomes of Minimally Invasive Esophagectomy.

The potential association between severe postoperative complications (SPC) and the oncological outcomes of esophageal squamous cell carcinoma (ESCC) patients according to the different Naples Prognostic Score (NPS) of the inflammatory nutritional status after minimally invasive esophagectomy (MIE) is unclear. Kaplan-Meier survival analysis was used to evaluate overall survival (OS) and disease-free survival (DFS) between with or without SPC (Clavien-Dindo grade ≥ III) in low NPS status (NPS = 0 or 1) and high NPS status (NPS = 2 or 3 or 4) patients. Cox multivariable analysis was carried out to analyze the various independent factors of OS and DFS, and a nomogram based on SPC was established. A total of 20.7% (125/604) ESCC patients developed SPC after MIE. Patients with SPC exhibited poor 5-year OS and DFS compared to those without SPC (all P < 0.001). Further analysis revealed that SPC significantly reduced OS and DFS in patients with high NPS status (all P < 0.001) but had little effect on the prognosis of patients with low NPS status (all P > 0.05). Multivariable Cox analysis revealed that SPC could be an independent influence indicator for OS and DFS in patients with high NPS status. Therefore, a novel nomogram combining SPC and tumor-node-metastasis (TNM) staging has been developed, which was found to be relatively more accurate in predicting OS and DFS than TNM staging alone. Severe complications can adversely affect the long-term oncological outcome of ESCC patients with high systemic inflammatory response and malnutrition after MIE.

The upregulation of CLGN in hepatocellular carcinoma is potentially regulated by hsa-miR-194-3p and associated with patient progression.

Patients with hepatocellular carcinoma (HCC) have poor prognosis, especially in advanced stages. Targeted therapy is the main treatment for advanced HCC patients, but the optimal targets for HCC remain poorly understood. The main purpose of this study was to identify potential novel prognostic markers and therapeutic targets. Firstly, differentially expressed genes (DEGs) in HCC were identified from the Gene Expression Omnibus (GEO) database. The expression, significance in prognosis, and potential mechanisms of DEGs were analyzed using GEPIA, TIMER, HPA, Kaplan Meier Plotter, CBioPortal, miRWalk, TargetScan, and ENCORI databases. Immunohistochemical staining was used to determine the protein expression levels of potential candidate genes. The mRNA levels of MND1, STXBP6, and CLGN were significantly increased in HCC (p< 0.01). HCC patients with elevated CLGN mRNA levels had poorer overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS) (p < 0.05). Higher MND1 mRNA levels significantly correlated with poorer DFS in HCC patients (p< 0.05). However, there was no significant correlation between STXBP6 expression and prognosis of HCC (p> 0.05). Further analysis revealed that patients with elevated CLGN mRNA expression in advanced pathology stages had poorer prognosis (p< 0.01). In addition, CLGN protein levels were elevated in HCC compared to their levels in normal tissues. The mRNA levels of CLGN had no significant correlation with the abundance of six common tumor infiltrating lymphocytes in HCC (COR < 0.5). Moreover, the mutation rate of CLGN was less than 1% in HCC patients (10/1089). Finally, the expression level of hsa-miR-194-3p in HCC was significantly lower than that in normal tissues (p < 0.05), and prognosis of HCC with low expression of hsa-miR-194 was poor (p < 0.05). The upregulation of CLGN in HCC is significantly associated with poor patient prognosis, especially in the advanced stages, and may be regulated by hsa-miR-194-3p. These findings suggest that CLGN may be closely related to the progression of HCC, and is a potential therapeutic target and prognostic indicator for patients with advanced HCC.

Depletion of PSMD14 suppresses bladder cancer proliferation by regulating GPX4.

The aim of this study was to investigate the role of deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in patients with bladder cancer. From 2016 to 2018, 181 patients diagnosed with primary bladder cancer at the Affiliated Hospital of Qingdao University were recruited. The expression of PSMD14 in bladder cancer tissues was tested by immunochemistry. The association between PSMD14 expression and clinical and pathological data and outcomes of bladder cancer patients was determined. Overexpression and knockdown cells were constructed to evaluate the effects of PSMD14 on proliferation of bladder cancer cells. Our results showed that PSMD14 was significantly overexpressed in bladder cancer tissues compared to adjacent non-tumor tissues (76.24% vs 23.76%, P = 0.02). The expression of PSMD14 was significantly higher in patients with larger tumor diameters (85.14% vs 70.09%, P = 0.019) and patients with a family history of cancer (92.16% vs 70.00%, P = 0.002). Patients with high expression of PSMD14 had poor disease-free survival (DFS) (HR = 2.89, 95% CI [1.247-6.711], P = 0.013). Gain and loss of function experiments demonstrated that PSMD14 deficiency inhibited bladder cancer cell proliferation. Additionally, depletion of PSMD14 suppressed bladder cancer cell growth via down-regulation of GPX4, and the promotion of PSMD14-induced cell growth was observably reversed by the GPX4 inhibitor RSL3. We determined that PSMD14 is highly expressed in bladder cancer tissues, and that PSMD14 expression correlated with poor disease-free survival. Depletion of PSMD14 could inhibit the proliferation of bladder cancer cells through the downregulation of GPX4. Therefore, PSMD14 may be an effective target for the treatment of bladder cancer.

HRCT1, negatively regulated by miR-124-3p, promotes tumor metastasis and the growth of gastric cancer by activating the ERBB2-MAPK pathway.

Gastric cancer is the fourth leading cause of cancer-related deaths worldwide. And patient outcomes are poor due to tumor relapse and metastasis. To develop new therapeutic strategies, it is of great importance to explore the mechanism underlying the progression of gastric cancer. Primary gastric cancer samples with lymph node metastases (LNM) and without LNM were subjected to mRNA microarray assay. The differentially expressed genes were confirmed by RT-qPCR. HRCT1 protein expression was further detected using an immunohistochemistry (IHC) assay. In vitro and in vivo assays were performed to investigate the role of HRCT1 in tumor invasion, metastasis, and proliferation. The expressions of the downstream target genes of HRCT1 were detected by microarray, RT-qPCR and Western blot assays. Dual-luciferase reporter and Western blot assays were carried out to identify miRNAs target to HRCT1. HRCT1 was upregulated in gastric cancer, and high expression of HRCT1 was associated with poor overall survival (OS) and disease-free survival (DFS). Moreover, HRCT1protein expression was an independent predictor for poor OS and DFS. HRCT1 could promote gastric cancer cells' migration, invasion, and proliferation in vitro as well as tumor metastasis and growth in vivo. Notably, our data showed that HRCT1 promoted gastric cancer progression by activating the ERBB2-MAPK signaling pathway. At least partially, the expression of HRCT1 could be negatively regulated by miR-124-3p. The upregulated expression of HRCT1 predicts poor survival for patients with gastric cancer. HRCT1 promotes tumor progression by activating the ERBB2-MAPK pathway. HRCT1, negatively regulated by miR-124-3p, may be a potential therapeutic target for patients with gastric cancer.

Perineural Invasion Predicts Local Recurrence and Poor Survival in Laryngeal Cancer.

(1) Background: Perineural invasion (PNI) in head and neck cancer is associated with a poor prognosis; however, the effect of PNI on the prognosis of laryngeal cancer remains under debate. This retrospective study aimed to investigate the effect of PNI in fresh or salvaged larynges on survival in patients who had undergone laryngectomy for squamous cell carcinoma. (2) Methods: This study enrolled 240 patients diagnosed with laryngeal cancer who had undergone open surgery at Seoul St. Mary's Hospital, Korea. The effects of PNI, other histopathologic factors, and treatment history on survival and recurrence patterns were assessed. (3) Results: PNI was observed in 30 of 240 patients (12.5%). PNI (HR: 3.05; 95% CI: 1.90-4.88; p = 0.01) was a significant predictor of poor 5-year disease-free survival. In fresh cases, preepiglottic invasion (HR: 2.37; 95% CI: 1.45-3.88; p = 0.01) and PNI (HR: 2.96; 95% CI: 1.62-2.96; p = 0.01) were negative prognostic factors for 5-year disease-free survival. In the salvage group, however, only PNI (HR: 2.74; 95% CI: 1.26-5.92; p = 0.01) was a significant predictor of disease-free survival. Further, PNI significantly influenced high local recurrence (HR: 5.02, 95% CI: 1.28-9.66; p = 0.02). (4) Conclusions: Independent of treatment history, PNI is a prognostic factor for poor survival and local recurrence in laryngeal cancer.

FGFR1 is an important prognostic factor in oral leukoplakia and tongue squamous cell carcinoma.

Fibroblast growth factor receptor 1 is a potential prognostic factor for tongue squamous cell carcinoma and is associated with oral epithelial dysplasia grade in oral leukoplakia. Thirty cases of tongue squamous cell carcinoma and 30 cases of oral leukoplakia were analyzed. Fibroblast growth factor receptor 1 and phosphorylated Akt protein expression were analyzed by immunohistochemistry and quantified using a digital algorithm. Fibroblast growth factor receptor 1 gene amplification was analyzed by fluorescent in situ hybridizationin the tongue squamous cell carcinoma cases. Clinical appearance and dysplasia grade were correlated with oral leukoplakia malignant transformation. Oral leukoplakia cases presenting high fibroblast growth factor receptor 1 expression showed a higher risk of malignant transformation (p=0.016, HR: 7.3, 95% CI: 1.4-37.4). Phosphorylated Akt showed faint to no expression in oral leukoplakia, which did not correlate with dysplasia grade or malignant transformation. High expression of fibroblast growth factor receptor 1 and phosohorylated Akt were associated with poor overall survival and disease-free survival in tongue squamous cell carcinoma, although only fibroblast growth factor receptor 1 expression was significantly associated with poor overall survival (p=0.024; HR: 4.9, 95% CI: 1.2-19.9). Cases presenting double fibroblast growth factor receptor 1/phosphorylated Akt overexpression (n=8) showed markedly impaired overall survival (p=0.020; HR: 6.4, 95% CI: 1.3-31.1) and disease-free survival (p=0.001, HR: 13.0, 95% CI: 3.0-55.7). Fibroblast growth factor receptor 1 amplification was observed in 16.6% of tongue squamous cell carcinoma cases, being correlated with vascular and neural invasion (p=0.001 and 0.017, respectively), but not with fibroblast growth factor receptor 1 protein expression, overall survival, or disease-free survival. Fibroblast growth factor receptor 1 protein expression is an important prognostic factor in oral leukoplakia and tongue squamous cell carcinoma.

Digital Image Analysis of Ki67 Heterogeneity Improves the Diagnosis and Prognosis of Gastroenteropancreatic Neuroendocrine Neoplasms

Ki67 is a reliable grading and prognostic biomarker of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). The intratumor heterogeneity of Ki67, correlated with tumor progression, is a valuable factor that requires image analysis. The application of digital image analysis (DIA) enables new approaches for the assessment of Ki67 heterogeneity distribution. We investigated the diagnostic utility of Ki67 heterogeneity parameters in the classification and grading of GEP-NENs and explored their clinical values with regard to their prognostic relevance. The DIA algorithm was performed on whole-slide images of 102 resection samples with Ki67 staining. Good agreement was observed between the manual and DIA methods in the hotspot evaluation (R2 = 0.94, P < .01). Using the grid-based region of interest approach, score-based heat maps provided a distinctive overview of the intratumoral distribution of Ki67 between neuroendocrine carcinomas and neuroendocrine tumors. The computation of heterogeneity parameters related to DIA-determined Ki67 showed that the coefficient of variation and Morisita-Horn index were directly related to the classification and grading of GEP-NENs and provided insights into distinguishing high-grade neuroendocrine neoplasms (grade 3 neuroendocrine tumor vs neuroendocrine carcinoma, P < .01). Our study showed that a high Morisita-Horn index correlated with poor disease-free survival (multivariate analysis: hazard ratio, 56.69), which was found to be the only independent predictor of disease-free survival in patients with GEP-NEN. These spatial biomarkers have an impact on the classification and grading of tumors and highlight the prognostic associations of tumor heterogeneity. Digitization of Ki67 variations provides a direct and objective measurement of tumor heterogeneity and better predicts the biological behavior of GEP-NENs.

Low Pretreatment Albumin-to-Globulin Ratios Predict Poor Survival Outcomes in Patients with Head and Neck Cancer: A Systematic Review and Meta-analysis.

Background: Studies have indicated that a low albumin-to-globulin ratio (AGR) before treatment is linked to poor prognosis of many cancers, but the prognostic impact of AGR remains controversial in head and neck cancer (HNC). This meta-analysis examined the prognostic value of AGR in HNC. Methods: We systematically searched the Embase, PubMed, and Cochrane library for relevant articles from inception to July 22, 2022. Studies conducted from 2000 to 2022 exploring the prognostic value of AGR in HNC were retrieved. We employed a random-effects model and calculated pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) to examine the associations of AGR with survival outcome. Results: Our analysis included nine studies involving 3211 patients with HNC. The pooled results revealed significant associations between low pretreatment AGRs and poor disease-free survival (HR = 1.97, 95% CI 1.58-2.45, p < 0.001), distant metastasis-free survival (HR = 1.64, 95% CI 1.25-2.16, p < 0.001), overall survival (HR = 2.18, 95% CI 1.65-2.88, p < 0.001), T3-T4 status (OR = 2.22, 95% CI 1.43-3.44, p < 0.001), stage III-IV disease (OR = 2.62, 95% CI 1.62-4.23, p < 0.001), and lymph node metastasis (OR = 1.95, 95% CI 1.29-2.82, p = 0.001) in patients with HNC. Conclusion: AGR can serve as a prognostic biomarker in managing HNC, and a low pretreatment AGR is strongly associated with adverse survival outcomes and advanced cancer status. Additional large-scale prospective trials must be conducted to assess the validity of our findings.

The prognostic value of TMB in early-stage non-small cell lung cancer: a systematic review and meta-analysis.

Tumor mutation burden (TMB) has been validated as a predictive biomarker for immunotherapy response and survival in numerous cancer types. Limited data is available on the inherent prognostic role of TMB in early-stage tumors. To evaluate the prognostic role of TMB in early-stage, resected non-small cell lung cancer (NSCLC). Systematic review and meta-analysis of pertinent prospective and retrospective studies. Publication search was performed in PubMed, Embase, Cochrane Library, and Web of Science databases. Based on the level of heterogeneity, a random- or fixed-effects model was used to calculate pooled effects of hazard ratio (HR) for overall survival (OS) and disease-free survival (DFS). The source of heterogeneity was investigated using sensitivity analysis, subgroup analysis, and publication bias assessment. Ten studies comprising 2520 patients were included in this analysis. There was no statistically significant difference in OS (HR, 1.18, 95% CI, 0.70, 1.33; p 0.53, I2 = 80%; phet < 0.0001) and DFS (HR, 1.18, 95% CI, 0.91, 1.52; p = 0.53, I2 = 75%; phet = 0.0001) between the high-TMB and low-TMB group. Subgroup analyses indicated that East Asian ethnicity, and TMB detected using whole exome sequencing, and studies with <100 patients had poor DFS in the high-TMB group. The inherent prognostic role of TMB is limited in early-stage NSCLC. Ethnic differences in mutation burden must be considered while designing future trials on neoadjuvant immunotherapy. Further research in the harmonization and standardization of panel-based TMB is essential for its widespread clinical utility.Registration: CRD42023392846.

Difference in prognostic impact of lateral pelvic lymph node metastasis between pre- and post-neoadjuvant chemoradiotherapy in rectal cancer patients.

The prognostic significance and treatment of lateral pelvic lymph node metastasis (mLPLN) in rectal cancer patients receiving neoadjuvant chemoradiotherapy (nCRT) are not well understood. In this study, we evaluated the impact of mLPLN identified in imaging modality on outcomes. Between January 2008 and December 2016, 1,535 patients who underwent radical resection following nCRT were identified. The association between mLPLN and disease-free survival (DFS), overall survival (OS), local recurrence-free survival (LRFS), and pelvic recurrence-free survival (PRFS) was analyzed, along with risk factors associated with OS and DFS. Overall, 329 (21.4%) of the 1,535 patients experienced disease recurrence; 71 (4.6%) had local recurrence, 25 (1.6%) had pelvic recurrence, and 312 (20.3%) had distant recurrence. The pre- and post-nCRT mLPLN (-) groups had better DFS, LRFS, PRFS, and OS than the (+) groups. LPLN sampling (LPLNs) was implemented in 24.0% of the pre-nCRT mLPLN (+) group and in 28.8% of the post-nCRT mLPLN (+) group. There was no significant difference in OS and LRFS between LPLNs group and no LPLNs group in pre- and post-nCRT mLPLN (+) groups. Pre-nCRT mLPLN was associated with poor OS (hazard ratio [HR], 1.43; P = 0.009) and post-nCRT mLPLN was associated with poor DFS (HR, 1.49; P = 0.002). Pre- and post-nCRT mLPLN (+) have different prognostic effects. Post-nCRT mLPLN appears to be more important for disease control. However, pre-nCRT mLPLN should not be disregarded when devising a treatment strategy since it is an independent risk factor for OS.

High Expression of DNTTIP1 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

Invasion and metastasis led to poor prognosis and death of clear cell renal cell carcinoma (ccRCC) patients. The deoxynucleotidyl transferase terminal interacting protein 1 (DNTTIP1) was reported to promote multiple tumor progression. However, there is no research about DNTTIP1 in ccRCC. Kaplan-Meier survival analysis, multivariate analysis demonstrated the prognostic indicator in overall survival (OS) and disease-free survival (DFS) of ccRCC with DNTTIP1 expression in the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC). Receiver operator characteristic (ROC) curve analyzed diagnostic ability of DNTTIP1 in TCGA-KIRC and validation dataset. The quantitative real-time polymerase chain reaction (qRT-PCR) detected the DNTTIP1 expression in renal cancer tissues, and the Office of Cancer Clinical Proteomics Research (CPTAC) verified the protein expression of DNTTIP1. Moreover, nomogram predicted the role of DNTTIP1 in ccRCC patient. Single-sample Gene Set Enrichment Analysis (SsGSEA) and GSEA evaluated the pathogenesis role of DNTTIP1 in TCGA-KIRC. DNTTIP1 expression was higher in ccRCC tumor tissues. High expression of DNTTIP1 was associated with poor OS (HR = 1.618, P < 0.0001), and poor DFS (HR = 1.789, P < 0.0001). SsGSEA and GSEA showed DNTTIP1 was associated with hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, G2M checkpoint. DNTTIP1 had a positive correlation with EMT biomarkers in ccRCC, and might be an effective target for ccRCC. This study provided that higher expression of DNTTIP1 predicted poor prognosis in ccRCC, and DNTTIP1 might be a novel detection biomarker and therapeutic target of tumor malignant in the future.

Abstract C047: UBE2C a poor prognostic biomarker in Black women with estrogen receptor positive (ER+) breast cancer in TCGA

Abstract Introduction: The majority of estrogen receptor positive (ER+) breast cancer carry a good prognosis; however, there is a subset, luminal B breast cancer (LBC), that is highly aggressive. LBC is more common in Black/African American (BAA) women who have a four-times higher death rate from ER+ breast cancer compared to other races. There is evidence that LBC shares biologic similarities with triple negative breast cancer (TNBC); common differentially expressed genes have been identified in TNBC and LBC, particularly among BAA women. Specifically, ubiquitin-conjugating enzyme 2C (UBE2C) expression is elevated in both. UBE2C is a driver of the cell cycle and involved in Wnt/β-catenin signaling, epithelial to mesenchymal transition (EMT), invasion and metastasis. Here we interrogate the association of UBE2C mRNAseq expression with survival in BAA women with ER+ breast cancer in The Cancer Genome Atlas (TCGA). Methods: TCGA Breast (BRCA) cohorts were queried to investigate the differential UBE2C mRNA seq expression in normal vs tumor patient samples in the general breast cancer population and specifically in the ER+ patients. Expression was also compared across races (BAA vs. White). Kaplan-Meier (KM) curves were generated to determine overall survival by gene expression using median as threshold. Results: In TCGA, compared to normal (n=112), UBE2C mRNAseq expression was statistically significantly higher in tumor in all breast cancer patients (n=1092) as well as specifically in the ER+ cohort (n=805). UBE2C mRNAseq expression was higher in the ER- (n=237) compared to the ER+ breast cancer patients (n=805) (p=3.7e-45). Expression was also significantly higher in the progesterone receptor (PR) negative (n=342) compared to the PR positive patients (n=697) (p=1.89e-40). Higher UBE2C mRNAseq expression was associated with poorer disease-free survival in all breast cancer patients as well as specifically in the ER+ patients. When examining the BAA population compared to White, UBE2C mRNA seq expression was significantly higher among BAA (n=183) compared to White (n=753) patients (FC=1.9; p=6.02e-15). Genes involved in cell cycle pathways were significantly correlated with UBE2C mRNAseq expression among BAA ER+ patients (n=110) including CDCA5 (p=1.42e-26, r=0.81), CDK2 (p=1.13e-05, r=0.41), and CDK4 (p=4.67e-06, r=0.42). The proliferation gene MKI67 was also significantly correlated with UBE2C mRNA seq expression (p=6.24e-18, r=0.71). UBE2C mRNAseq high expression was significantly associated with poor progression-free survival for BAA patients with breast cancer (n=179, p= 0.0353). UBE2C mRNAseq high expression was positively associated with African ancestry and negatively associated with European ancestry. Conclusion: UBE2C is a poor prognostic marker in BAA women with ER+ breast cancer using the TCGA dataset. UBE2C plays an integral role in the cell cycle. Given the prevalence of resistance to cell cycle targets, such as CDK 4/6 inhibitors, UBE2C demonstrates a potential drug target to improve outcomes in LBC and mitigate disparities. Citation Format: Veronica Jones, Yate-Ching Yuan, Melissa Davis, Victoria Seewaldt, Rick Kittles. UBE2C a poor prognostic biomarker in Black women with estrogen receptor positive (ER+) breast cancer in TCGA [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C047.

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma.

Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.

Pregnancy-associated breast malignancy mostly presents with an aggressive type of breast cancer

Published reports on the prognosis of pregnancy-associated breast cancer are controversial. This study aims to determine the histopathological features of pregnancy-associated breast carcinoma (PABC) and the outcomes of patients with breast cancer during pregnancy and lactation among Turkish women. The study retrospectively analyzed 29 patients diagnosed with pregnancy-associated breast malignancies who underwent surgery between January 1989 and March 2021. Demographic and pathological data were obtained to evaluate the clinicopathological and prognostic characteristics of the patients. The median age was 36 years (range: 26–42 years). Of the 29 patients with breast cancer, 13 (44.8%) were diagnosed during pregnancy, and the remaining 16 (55.2%) were diagnosed during lactation. Most patients had clinical tumor stage (cT) cT2–3 (n = 20, 69%) disease, and 15 patients had clinically node (cN)-positive disease (N1 and N2, 51.7%). The majority (n = 19, 65.5%) had invasive ductal carcinoma with high Ki-67 scores (&gt;20%). Patients with lactation-associated breast cancer were more likely to have a family history of breast cancer (44% vs. 8%, p = 0.04) than those with pregnancy-associated breast cancer. Notably, symptom duration ≥6 months and presenting with cT3–4 or cN(+) disease were associated with poor disease-free and disease-specific survival. However, no difference could be found in outcome among patients with pregnancy- and lactation-associated breast cancer. PABC mostly presents with aggressive tumor molecular subtypes with high Ki-67 scores and more advanced stages associated with poor outcome, possibly due to delayed diagnosis. Therefore, prompt early diagnosis and awareness of this disease might improve survival.