Worst Disease-free Survival Research Articles

Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p≤.05. Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p<.001), hormone receptor-positive (p<.001), and node-positive (p=.003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p<.001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p=.014) and TN and luminal A-like in HER2-0 (p=.019) showed the worst DFS. In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Prognostic Factors for Triple-Negative Breast Cancer with Residual Disease after Neoadjuvant Chemotherapy

Valid factors to evaluate the prognosis of triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) are still lacking. We performed this study to explore prognostic factors focusing on genetic alterations and clinicopathology features in non- pathologic complete response (pCR) TNBC patients. Patients initially diagnosed with early-stage TNBC, treated with NAC, and who had residual disease after primary tumor surgery at the China National Cancer Center during 2016 and 2020 were enrolled. Genomic analyses were performed by targeted sequencing for each tumor sample. Univariable and multivariable analyses were conducted to screen prognostic factors for the survival of patients. Fifty-seven patients were included in our study. Genomic analyses showed that TP53 (41/57, 72%), PIK3CA (12/57, 21%), and MET (7/57, 12%), and PTEN (7/57, 12%) alternations commonly occurred. The clinical TNM (cTNM) stage and PIK3CA status were independent prognostic factors of disease-free survival (DFS) (p < 0.001, p = 0.03). A prognostic stratification indicated that patients with clinical stages I &II possessed the best DFS, followed by those with clinical stage III & wild-type PIK3CA. In contrast, patients with clinical stage III & the PIK3CA mutation had the worst DFS. In TNBC patients with residual disease after NAC, prognostic stratification for DFS was observed by combining the cTNM stage and PIK3CA status.

Prognostic value of myosteatosis and systemic inflammation in patients with resectable gastric cancer: A retrospective study.

The association between systemic inflammation and myosteatosis upon diagnosis of gastric cancer (GC) and whether these factors could predict survival outcomes is not clear. Our aim was to explore the association between systemic inflammation and myosteatosis upon diagnosis of GC, specially whether the co-occurrence of these factors could predict survival outcomes. Computed tomography (CT) was performed at the level of the third lumbar vertebra for body composition analysis in 280 patients with GC. Myoesteatosis was defined as the lowest tertile of the muscle radiodensity distribution or based on clinical significance using optimal stratification analysis. Inflammatory indexes were measured, including the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte and lymphocyte-to-monocyte ratios. Patients with low skeletal muscle (SM) radiodensity were more likely to be older than 65 years, have a higher body mass index and have diabetes. They also had higher intermuscular visceral and subcutaneous adipose tissue areas and indexes. The highest tertile of SM radiodensity was associated with better disease-free survival (DFS) (HR = 0.51, 95% CI [0.31, 0.84], ptrend = 0.020) and overall survival (OS) (HR = 0.49, 95% CI [0.29, 0.82], ptrend = 0.022). Patients with NLR > 2.3 and myosteatosis had the worst DFS and OS (HR = 2.77, 95% CI [1.54, 5.00], p = 0.001; HR = 3.31, 95% CI [1.79, 6.15], p < 0.001, respectively). Co-occurrence of myosteatosis and inflammation increased disease progression and death risk by almost three times. These regularly obtained biomarkers might improve prognostic risk prediction in resectable GC.

Lung Metastasectomy from Colorectal Cancer, 10-year Experience in a South American Cancer Center

PurposeThis study aimed to describe the survival outcomes and factors associated with prognosis in patients undergoing pulmonary metastasectomy with colorectal cancer (CRC) in a cancer center in South America.Material and methodsA retrospective analysis of patients that underwent lung metastasectomy due to CRC at National Cancer Institute (INC), Colombia between 2007 and 2017 was performed and Kaplan-Meier survival analysis along with log-rank test and Cox regression multivariate analysis were completed.ResultsSeventy-five patients with colorectal adenocarcinoma were included in the study. Of them, 57.3% were women with a median age of 62 years [interquartile ranges (IQR): 18.5]. For 45.3% the adenocarcinoma was located in the rectum and 29.3% had stage IV at diagnosis. 56% had a history of controlled extrapulmonary metastasis and 20% of the cases had a history of the metastasis of the liver. The median follow-up was 36.8 months (IQR: 27.4). Three-year and five-year overall survival (OS) was 57.5% [95% confidence interval (CI), 47.0–70.4] and 33.2% (95% CI, 23.4–47.2), respectively. Patients with bilateral, more than one pulmonary metastasis, abnormal postmetastasectomy carcinoembryonic antigen (CEA), history of liver metastasis, and disease-free interval (DFI) ≤12 months had worse OS. Three-year and five-year disease-free survival (DFS) was 30.1% (95% CI, 20.8–43.6) and 21.6% (95% CI, 13.0–35.9), respectively. Bilateral, more than one pulmonary metastasis, and patients with stage IV at diagnosis had the worst DFS. Multivariate analysis in the Cox regression model showed that abnormal postmetastasectomy CEA [Hazard Ratio (HR):1.97, 95% CI, 1.01–3.86, p = 0.045] and DFI ≤ 12 months (HR: 3.08, 95% CI, 1.26–7.53, p = 0.014) were independent factors for worst OS.ConclusionsThe OS found falls within the wide range described in the world literature but interestingly it falls at the bottom end of this range. The factors associated with worst survival were identified as bilateral, more than one pulmonary metastasis, abnormal postmetastasectomy CEA, history of liver metastasis, and DFI ≤12 months.Contribution to the fieldPulmonary metastasectomy is the standard of care in patients with metastatic CRC. However, the literature supporting this conduct is based on retrospective studies and the only randomized controlled trial conducted to date was stopped due to poor recruitment. Limited information is available in South America about survival and factors associated with prognosis in patients with metastatic CRC. While this study is another series that adds to the many studies across the world that describe the use of pulmonary metastasectomy in CRC, it presents critical data as it is one of the few studies carried out in South America. As described in a wide range of world literature, OS found falls in patients that underwent lung metastasectomy due to CRC however; interestingly, in the South American population analyzed here it falls at the bottom end of this range. This may be explained by a large number of patients included with a history of extrapulmonary metastasis as well as may reflect inadequate patient access to reference cancer centers in Colombia. Factors associated with worst survival in our population were bilateral, more than one pulmonary metastasis, abnormal postmetastasectomy CEA, history of liver metastasis, and interval from diagnosis to development of pulmonary metastasis ≤12 months.

Combining Pre- and Postoperative Lymphocyte-C-Reactive Protein Ratios Can Better Predict Hepatocellular Carcinoma Prognosis After Partial Hepatectomy.

BackgroundVarious preoperative inflammatory indicators have been identified as potential predictors of poor prognosis in patients with hepatocellular carcinoma (HCC), but the role of postoperative inflammatory indicators remains unclear. This study aimed to explore the prognostic value of the postoperative lymphocyte–C-reactive protein ratio (PostLCR) on its own and combined with preoperative LCR (PreLCR).MethodsA total of 290 patients with primary HCC were retrospectively enrolled in the study. Univariate analysis was used to identify factors significantly associated with poor disease-free survival (DFS) and overall survival (OS), then multivariate analysis was performed to identify independent prognostic indicators of poor survival. Prognostic models based on preoperative, postoperative, and both types of indicators were then constructed, and their predictive performance were evaluated using time-dependent receiver operating characteristic curves and the concordance index (C-index).ResultsPreLCR and PostLCR levels correlated with DFS and OS more strongly than other pre- and postoperative inflammatory indicators, respectively. Decreased PreLCR and PostLCR were independent prognostic factors for both DFS and OS, while HCC patients with decreased PreLCR and PostLCR had worse prognosis than patients with increased PreLCR and PostLCR. Patients into three groups based on their cut-off values of PreLCR and PostLCR, Kaplan–Meier survival analysis indicated that HCC patients with low PreLCR and PostLCR had the worst DFS and OS. The combined model showed better predictive performance at 1 and 3 years post-surgery than individual pre- and postoperative models, the American Joint Committee on Cancer/Tumor-Node-Metastasis (8th edition) staging system and the Barcelona Clinic Liver Cancer system. The combine model demonstrated a markedly superior C-index compared with the other models in DFS and OS.ConclusionOur study showed PreLCR and PostLCR are independent predictors of DFS and OS in HCC patients after partial hepatectomy. Models that include both PreLCR and PostLCR can predict prognosis better than well-established clinical staging systems.

Immunoarchitectural patterns as potential prognostic factors for invasive ductal breast cancer

Currently, tumor-infiltrating lymphocytes (TILs) in invasive breast cancers are assessed solely on the basis of their number, whereas their spatial distribution is rarely investigated. Therefore, we evaluated TILs in 579 patients with invasive breast cancer of no special type (IBC-NST) with a focus on their spatial distributions in tumor center (TC) and invasive margin (IM). We also assessed a new factor, namely para-tumor infiltrating lymphocytes (PILs) in the para-tumor lobular area (Para). Five immunoarchitectural patterns (IPs) were observed, which were significantly associated with clinicopathological features, especially molecular subtypes, histological grades, clinical stages, and programmed death-ligand 1 (PD-L1) expression. High-TIL density (IP1/2) correlated with favorable disease-free survival (DFS) in TNBC patients (p = 0.04), but opposite results were observed for luminal B subtype patients (both the lowest TIL and PIL densities (IP5) correlated with good DFS, p = 0.013). Luminal B patients with high TILs in the IM and low TILs in the TC (IP3) exhibited the worst DFS, whereas those with low TILs (similar to IP5) and high PILs (IP4) exhibited poor DFS. We also identified TIL subpopulations with significantly different IPs. Our findings suggest that IP can be a potential prognostic factor for tumor immunity in IBC.

Breast Cancer Classification Based on Tumor Budding and Stem Cell-Related Signatures Facilitate Prognosis Evaluation.

BackgroundTumor budding (TB) is emerging as a prognostic factor in multiple cancers. Likewise, the stemness of cancer cells also plays a vital role in cancer progression. However, nearly no research has focused on the interaction of TB and tumor stemness in cancer.MethodsTissue microarrays including 229 cases of invasive breast cancer (BC) were established and subjected to pan-cytokeratin immunohistochemical staining to evaluate molecular expression. Univariate and multivariate analyses were applied to identify prognostic factors of BC, and the Chi-square test was used for comparison of categorical variables.ResultsHigh-grade TB was significantly associated with T stage, lymph node metastasis, tumor node metastasis (TNM) stage, epithelial-mesenchymal transition, and poor disease-free survival (DFS) of BC patients. We also found that the prognostic value of TB varied widely among different subtypes and subgroups. Cox regression analysis then showed that TB grade was an independent prognostic factor. Moreover, cancer stem cell (CSC) markers CD44 and ALDH1A1 were significantly higher in high-grade TB tumors. Consequently, patients were classified into high CSC score subgroup and low CSC score subgroups. Further research found that CSC scores correlated with clinicopathological features and DFS of BC patients. Based on TB grade and CSC scores, we classified BC patients into TBlow-CSCslow (type I), TBlow-CSCshigh (type II), TBhigh-CSCslow (type III), and TBhigh-CSCshigh (type IV) subgroups. Survival analysis showed that patients in the type I subgroup had the best DFS, whereas those in the type IV subgroup had the worst DFS. Finally, a TB-CSC-based nomogram for use in BC was established. The nomogram was well calibrated to predict the probability of 5-year DFS, and the C-index was 0.837. Finally, the area under the curve value for the nomogram (0.892) was higher than that of the TNM staging system (0.713).ConclusionThe combination of TB grade with CSC score improves the prognostic evaluation of BC patients. A novel nomogram containing TB grade and CSC score provides doctors with a candidate tool to guide the individualized treatment of cancer patients.

Can we use Ki67 expression to predict prostate cancer aggressiveness?

specialists have an urge for biomarkers that can discriminate indolent prostate cancer from aggressive tumors. Ki67 is a proliferation marker, and its expression is associated with the aggressiveness of several cancers. analyze the expression of Ki67 in prostate cancer samples correlating with the aggressiveness of the disease. Ki67 mRNA levels were determined utilizing data from a TCGA cohort (Tumor(n)=492 and control(n)=52). The protein expression was determined on 94 biopsies from patients by immunohistochemical assay. in mRNA, the Ki67 upregulation is associated with cancer tissue (p<0.0001) and worst disease-free survival (p=0.035). The protein upregulation is associated with increase of the ISUP score (p<0.0001), cancer stage (p=0.05), biochemical recurrence (p=0.0006) and metastasis (p<0.0001). We also show a positive correlation between Ki67 expression and ISUP score (r=0.5112, p<0.0001) and disease risk stratification (r=0.3388, p=0.0009). Ki67 expression is a factor independently associated with biochemical recurrence (p=0.002) and metastasis (p<0.0001). Finally, the patients with high Ki67expression shows better survival regarding biochemical recurrence (p=0.008) and metastasis (p=0.056). Patients with high Ki67 expression are 2.62 times more likely to develop biochemical recurrence (p=0.036). Ki67 upregulation is associated with prostate cancer aggressiveness.

Association of KRAS Variant Subtypes With Survival and Recurrence in Patients With Surgically Treated Intrahepatic Cholangiocarcinoma

KRAS variants are associated with tumor progression; however, the prevalence of KRAS variant subtypes and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection are largely unknown. To explore the prognostic association of KRAS variant subtypes with survival and recurrence in patients with ICC. In this cohort study, patients who underwent curative resection for ICC from January 2009 through December 2016 at a single hospital in China were recruited, and whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify KRAS variants. Kaplan-Meier and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Data were analyzed from April 2020 to January 2021. Hepatectomy in patients with ICC. The association of KRAS variant subtypes with OS and DFS. Of 1024 included patients with ICC, 621 (60.6%) were male, and the mean (SD) age was 59.2 (10.2) years. A total of 14 different subtypes of KRAS somatic variants affecting 127 patients (12.4%) were identified. G12D was the most frequent allele in this cohort, accounting for 55 of 127 identified KRAS variants (43.3%), followed by G12V (25 [19.7%]), G12C (9 [7.1%]), and G13D (8 [6.3%]). Compared with patients with wild-type KRAS, patients with variant KRAS were more likely to have high levels of carbohydrate antigen 19-9 (92 of 127 [72.4%] vs 546 of 897 [60.9%]; P = .01) and γ-glutamyltransferase (72 of 127 [56.7%] vs 420 of 897 [46.8%]; P = .04). Multivariable analysis revealed that G12 KRAS variants but not non-G12 KRAS variants were independently associated with worse OS (hazard ratio [HR], 1.69; 95% CI, 1.31-2.18; P < .001) and DFS (HR, 1.47; 95% CI, 1.16-1.88; P = .002). Among the patients with G12 KRAS variants, the G12V KRAS variant was the strongest prognostic determinant for the worst OS (HR, 3.05; 95% CI, 1.94-4.79; P < .001) and DFS (HR, 1.79; 95% CI, 1.13-2.85; P = .01). In this cohort study, the distribution of KRAS variant subtypes was characterized in a large cohort of patients with ICC from China. The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.

Clinical Significance of Cyclin Expression Profiling in Ocular Surface Squamous Neoplasia.

Ocular surface squamous neoplasia (OSSN) can recur, metastasize, and even cause death. Cyclins regulate the cell cycle progression at different phases and its dysregulation is associated with uncontrollable cell growth and malignant transformation of the cell. Overexpression of cyclin has been reported in various malignancies and is associated with poor prognosis. However, the role of cyclins in OSSN remains unexplored. This study has been designed to assess the prognostic significance of cyclin (cyclin B1, E1, and D1) immunoexpression in 100 OSSN patients. The targeted proteins demonstrated overexpression of cyclin B1, cyclin E1, and cyclin D1 in 55%, 37%, and 56% OSSN cases prospectively. A gradual and significant increase in the cyclin B1 (P=0.01) and cyclin D1 (P=0.005) expression was seen from Tis to the T4 category. Overexpression of cyclin B1 was associated with poor disease-free survival and worst prognosis in both early (P=0.03) as well as advanced T staged (P=0.038) OSSN patients. Overexpression of cyclin E1 was associated with worst disease-free survival (P=0.01) and poor prognosis in advanced stage OSSN patients. Our findings suggest that cyclin B1 and cyclin E1 have prognostic relevance in OSSN patients, and therefore are recommended for detecting high-risk category cases. A significant increase in the expression of cyclins from early to advanced stage indicates that cyclins play an important role in the pathogenesis of OSSN patients.

Miller–Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy

IntroductionHR+/HER2− breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2− non-pCR populations, it is essential to accurate identification new prognostic markers.Materials and MethodsThe study retrospectively analyzed 105 stage II–III patients who were diagnosed with HR+/HER2− BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller–Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.ResultsAmong the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1–2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4–5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10–0.80; p = 0.018]. DFS was longer in the good response (MP grades 3–4) group than in the poor response (MP grades 1–2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05–0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9–75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.ConclusionThe study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

Association of sarcopenia and expression of interleukin-23 in colorectal cancer survival

The relationship between sarcopenia and interleukin-23 (IL-23) has not been reported. We designed this study to investigate this relationship and the association of sarcopenia and interleukin-23 with poor prognosis of colorectal cancer. We used the %FINDCUT SAS macro to determine the cutpoints of the skeletal muscle index (SMI) to define sarcopenia in colorectal cancer patients. Immunohistochemical staining was performed to detect high and low IL-23 expression in cancer samples. Clinicopathological features were also recorded. The prognosis of the 5-year disease-free survival and overall survival were analyzed using univariate and multivariate methods. A total of 114 patients with colorectal cancer were enrolled. The mean age was 63.2 years. Forty-six (40%) patients were female. Sarcopenia was defined as less than 50cm2/m2 for men and 32cm2/m2 for women and 52(46%) patients were defined as having sarcopenia. Sarcopenia was significantly associated with poor 5-year disease-free survival and overall survival (p=0.003 and p=0.001, respectively). Multivariate adjustment demonstrated that sarcopenia was an independent predictor of the 5-year disease-free survival (hazard ratio=1.827, p=0.024) and overall survival (hazard ratio=3.669, p<0.001). A lower SMI was detected in patients with high IL-23 expression (p=0.045). After grouping the patients with sarcopenia and IL-23 expression, the patients with sarcopenia and high IL-23 expression had the worst disease-free survival (p=0.013) and overall survival (p=0.007). This is the first study to explore the significant association between IL-23 expression and sarcopenia in colorectal cancer. Sarcopenia combined with IL-23, as an inflammatory marker, significantly predicted poor survival.

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122.

Simple SummaryTargeting epigenetic alterations in hepatocellular carcinoma (HCC) provides therapeutic options in addition to traditional treatments. The aim of our study was to evaluate the potential of targeting histone methyltransferase G9a in the development of a therapeutic target. We confirmed the prognostic values of mRNA and protein levels of G9a expression in HCC respectively from public database and tissue microarray. We also confirmed the aggressive phenotypes supported by G9a in both HBV+ and HBV− HCC cells. The identification of a regulation axis between liver-specific tumor suppressor miR-122 and G9a further supported the important roles of G9a during the tumorigenesis and progression of HCC. Combination of lower miR-122 and higher G9a levels may provide prognostic potential for poor clinical outcomes and therapeutic potential for epigenetic targeting therapies.Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV−)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists.

Immunotyping in tubo-ovarian high-grade serous carcinoma by PD-L1 and CD8+ T-lymphocytes predicts disease-free survival.

PD-L1 immune checkpoint inhibitor expression was evaluated in high-grade serous carcinoma (HGSC) ovary in the context of the overall immune landscape to determine its prognostic value. Consecutive cases of HGSC, 50 who underwent upfront surgery followed by adjuvant chemotherapy (HGSC-U) and 50 who underwent neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (HGSC-PC) were selected. In HGSC-PC cases, the pre-NACT ascitic fluid cell blocks were included. Tumor-infiltrating lymphocytes (TILs) were scored, hotspots chosen for tissue microarray construction and immunohistochemistry performed and scored for CD4 and CD8 lymphocyte subsets, CD68+ tumor-associated macrophages (TAMs), PD-1 and PD-L1 expression. HGSC-post-chemotherapy showed increased TILs, predominantly CD8+T-lymphocytes, compared to HGSC-U. HGSC showed PD-L1 expression on tumor cells and/or TAMs in 60% cases with a linear correlation to CD4+, CD8+ TIL levels. Concordant PD-L1 expression was seen in matched pre- and post-NACT tumor cells. HGSC-PC showed higher expression of PD-L1. There was no association of PD-L1 cumulative proportion score or tumor cell score with outcome. Taking a cutoff for PD-L1 CPS at 10%, immunotype I (PD-L1+/CD-8+), corresponding to tumors with adaptive immune evasion, showed worst disease-free survival compared to all other immunotypes (p=0.03) and was more significant (p=0.01) when compared to immunotype III (PD-L1+/CD8-). Immunotyping based on PD-L1/CD8+ expression correlates to prognosis and outcome.

Obesity and high neutrophil-to-lymphocyte ratio are prognostic factors in non-metastatic breast cancer patients.

Obesity has been associated with an increased risk of breast cancer recurrence and death. Some readily available biomarkers associated with systemic inflammation have been receiving attention as potential prognostic indicators in cancer, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). This study aimed to explore the correlation between body mass index (BMI) and invasive breast cancer and the association of NLR, PLR, and BMI with breast cancer outcomes. We undertook a retrospective study to evaluate patients treated for breast cancer over 14 years. Clinicopathological data was obtained before receiving any treatment. Of the 1664 patients included with stage I-III, 567 (34%) were obese (BMI≥30 kg/m2). Obese patients had larger tumors compared to non-obese patients. Higher BMI was associated with recurrence and worse survival only in patients with stage I disease. NLR and PLR were classified into high and low level groups. The NLRhigh (NLR>4) was found to be an independent prognostic factor for recurrence and mortality, while the PLRhigh (PLR>150) group had no impact on survival. A subgroup of patients with NLRhigh and BMIhigh had the worst disease-free survival (P=0.046), breast cancer-specific survival (P<0.001), and overall survival (P=0.006), compared to the other groups. Patients with early-stage breast cancer bearing NLRhigh and BMIhigh had worse outcomes, and this might be explained by the dysfunctional milieu of obesity in adipose tissue and its effects on the immune system. This study highlights the importance of lifestyle measures and the immune system interference with clinical outcomes in the early breast cancer setting.

Prognostic Impact of Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma Patients.

Tumor-infiltrating lymphocytes (TILs) has been shown to be associated with the prognosis of many tumors, yet few studies have investigated their roles in laryngeal squamous cell carcinoma (LSCC). We aim to investigate the prognostic values of tumor-infiltrating CD3+ /CD4+ /CD8+ /Foxp3+ T-cells and neutrophils in LSCC patients that received total or partial laryngectomy. Retrospective case series of LSCC patients who underwent total or partial laryngectomy from 2013 to 2014 at Eye, Ear, Nose, and Throat Hospital of Fudan University. In our study, 41 tumor tissues from patients with LSCC were retrospectively assessed using immunohistochemistry for CD3+ /CD4+ /CD8+ /Foxp3+ T-cells and CD66b+ neutrophils. Overall survival (OS) and disease-free survival (DFS) were recorded using Kaplan-Meier methods. Generally, patients with high density of TILs (CD3, CD4, CD8) showed improved OS or DFS. Specifically, high density of CD3+ TILs were associated with better OS, yet poorer OS and DFS for CD66b+ neutrophils. Patients with an Immunoscore of 0-1 experienced the worst OS and DFS, compared with Immunoscore 2-4 (P = .0111 for OS, P = .0391 for DFS). In Cox proportional hazards analysis adjusted for N stage and T stage, only stroma CD66b+ neutrophils densities were able to predict OS, with odds ratios of 4.819 (95% confidence interval [CI] 1.149-20.206; P = .032*), and DFS 2.888 (95% CI 1.043-7.997; P = .041*). The density of TILs and CD66b+ neutrophils may help predict the prognosis of patients with LSCC after surgery. 3 Laryngoscope, 131:E1249-E1255, 2021.

Overexpression of VEGF165 is associated with poor prognosis of cervical cancer

Cervical cancer is a major health hazard to Indian women. Human papillomavirus (HPV) infection is an established risk factor for cervical carcinogenesis. However, understanding the cervical cancer biology beyond HPV infection is very crucial to predict aggressive behavior, prognosis, treatment response and survival. In the present study, we explored the role of vascular endothelial growth factor A (VEGFA) isoforms, VEGFC and VEGFD in cervical cancer progression and its association with HPV 16 and 18 infections. A total of 110 cervical cancer tissues and 50 normal cervical tissues were collected for the study. Reverse transcription-polymerase chain reaction was employed to analyze tissue VEGFA isoforms, VEGFC and VEGFD expression. VEGF165 was significantly higher, whereas VEGFC and VEGFD were significantly lower in malignant cervical carcinoma tissues as compared to normal cervix tissues. Expression levels of VEGF121 and VEGFC were significantly associated with type of tumor growth while VEGF165 was significantly associated with lymph node metastasis. VEGF165 transcript levels were significantly higher in patients with squamous cell carcinoma (SCC) and developed recurrence. Most strikingly, higher VEGF165 expression was significantly associated with worst disease-free survival (DFS) specifically in patients with SCC. Association of VEGF165 with lymph node metastasis, disease recurrence and worst DFS indicated that VEGF165 is an important prognostic factor in cervical carcinogenesis.

Abstract 6458: Adverse recurrence prognostic implications of tumor CD47 expression in resected non-small cell lung cancer

Abstract Background: Immunotherapy is one of the most promising advances in the field of oncology. However, limited information exists regarding characterization of the tumor associated macrophages (TAMs) related immune microenvironment in patients with non-small cell lung cancer(NSCLC), by which it may possible to predict the efficacy of novel immunotherapies. Method: 191 resected NSCLC specimens were retrospectively studied for the CD47 expression &amp; PD-L1 expression which were examined using immunohistochemistry (IHC). The infiltration of macrophages (M2-macrophages &amp; M1-macrophages) and CD8+T-lymphocytes were evaluated using dual-IF staining. 46 cases of pulmonary infectious diseases were used as the control group. Targeted sequencing was performed on all 191 specimens using NovoSeq 6000 system. Bioinformatics analysis including somatic variant detection and statistical analysis were subsequently carried out. Finally, the pattern of immune infiltrates was depicted and their prognostic role of was assessed. Results: Using IHC 2/3+ as cutoff, the prevalence of CD47 positive (CD47pos) expression in NSCLC was 33.0% (63/191), significantly higher than that in non-tumor lung tissues (17.4%, 8/46, Chi-squared test p-val=0.038). CD47pos expression was significantly higher in female, non-smoking, and adenocarcinoma (LUAD) patients (p-val=0.020, p-val&amp;lt;0.001, and p-val&amp;lt;0.001, respectively). With somatic mutations integrated, CD47pos expression significantly correlates with EGFR mutation (p-val&amp;lt;0.001). When patients were stratified by LUAD and squamous cell carcinoma (LUSC), statistical correlation between EGRE mutation and CD47pos expression remains in LUAD (adjusted p-val=0.002) and LUSC patients group (adjusted p-val=0.0499). The expression of CD47 (H-score) in NSCLC was negatively correlated with both tumor PD-L1 expression (tumor proportion score, TPS) (p-val=0.0346) and tumor mutation burden (TMB) (p-val=0.0107). CD47pos expression independently correlates with worse disease free survival (DFS) for NSCLC patients in multivariate Cox regression (p-val=0.035). When CD47 and M2 were combined as combinatorial biomarkers, four groups of patients can be significantly separated with negative CD47(CD47neg) expression / absence of M2 in tumor area being best DFS and CD47pos expression / M2 in tumor area being worst DFS. To link the pattern of immune infiltrates with patient better DFS, we performed an unsupervised clustering using major immune components (CD47, PD-L1, CD8, M1 and M2). 191 patients were clustered into three groups and patient's DFS of each group was significantly differentiated (Log-rank p-val=0.041). Briefly, the group of patients with worst DFS is characterized with high infiltration of M1 and M2 in tumor area. Conclusions: To the best of our knowledge, this is the first study that extensively investigated the major immune modulators along with their association with genotype in NSCLC cohort. We elucidated the demographic characteristics, molecular characteristics, and immuno-microenvironment characteristics of CD47 expression in NSCLC. We further identified the tumor CD47pos expression as an independent adverse recurrence prognostic factor in NSCLC. Our study illustrates the idea of ‘precision medicine' by stratification of patients based on immuno-microenvironment characteristics. Citation Format: Yan Xu, Ji Li, Bing Tong, Shuang Wang, Wei Zhong, Minjiang Chen, Jing Zhao, Mengzhao Wang. Adverse recurrence prognostic implications of tumor CD47 expression in resected non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6458.

Tumor-associated macrophages in classical Hodgkin lymphoma: hormetic relationship to outcome

Commonly attributed to the prevalence of M2 macrophages, tumor-associated macrophages (TAM) are linked to poor outcome in Hodgkin lymphoma (HL). MYC is supposed to control the expression of M2-specific genes in macrophages, and deficiency in MYC-positive macrophages inhibits tumor growth in mouse models. To verify this hypothesis for HL, seventy-six samples were subjected to immunohistochemical double staining using CD68 or CD163 macrophage-specific antibodies and a reagent detecting MYC. For each cell population, labelled cells were grouped according to low, intermediate and high numbers and related to disease-free survival (DFS) and overall survival (OS). MYC+ cells accounted for 21% and 18% of CD68+ and CD163+ cells, respectively. Numbers of MYC− macrophages were significantly higher in EBV+ cases while no differences were observed for MYC+ macrophages between EBV+ and EBV− cases. Cases with highest numbers of macrophages usually showed worst DFS and OS. In most scenarios, intermediate numbers of macrophages were associated with better outcome than very low or very high numbers. Our observations are reminiscent of the “hormesis hypothesis” and suggest that a relative lack of TAM may allow HL growth while macrophages display an inhibitory effect with increasing numbers. Above a certain threshold, TAM may again support tumor growth.

Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.

Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs.Methods: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors.Results: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer.Conclusions: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.