Aggressive Tumor Characteristics Research Articles

When basal cell carcinomas became giant: an Italian multicenter study.

Giant basal cell carcinoma (GBCC) is a basal cell carcinoma (BCC) enlarged in a diameter more than 5cm. Since GBCCs are a highly infrequent entity and the occurrence rate is approximately 0.5-1% out of all BCC types, only anecdotal cases are reported, and causes and characteristics inducing development of this tumor are not defined. Evaluate causative factors and clinico-histological characteristics of GBCCs. The study is a 6-month, hospital-based case series study performed in 12 Italian dermatologic centers. A total of 59 cases and 458 control BCCs were collected. No significant differences existed between the two groups if we take into account social or cultural factors. The average duration of GBCCs is considerably longer than controls. GBCCs are located on unexposed areas while BCCs are on areas not usually covered by clothes. Superficial histological subtype was more frequent in the BCCs group, while infiltrative in GBCCs. GBCCs showed significantly higher local invasiveness, and greater metastatic capacity. More than half of GBCCs had been previously treated with one or more treatments. Patients with GBCCs appear to belong to two categories: (i) those who present with GBCC due to delay in accessing medical attention, and (ii) those who have BCCs previously treated with inappropriate strategies. Only very few cases can be carried out with intrinsic biological features of tumor aggressiveness. Social and cultural conditions do not appear to be involved in the development of GBCCS. These observations may help clinicians in selecting correct therapeutic strategies in the treatment of BCCs, which give rise to GBCC.

Histology of Hepatocellular Carcinoma: Association with Clinical Features, Radiological Findings, and Locoregional Therapy Outcomes.

Objective:The objective of the study was to investigate whether hepatocellular carcinoma (HCC) histology is associated with clinical and computed tomographic/magnetic resonance imaging features and locoregional therapy (LRT) outcomes.Subjects and Methods:This single-center retrospective study included 124 consecutive patients (92 men, median age 59 years) with 132 HCC diagnosed by biopsy between 2008 and 2017 before LRT. Patients underwent chemoembolization (n = 51, 41%), ablation (n = 41, 33%), yttrium-90 radioembolization (n = 17, 13%), and chemoembolization/ablation (n = 15, 12%). Barcelona clinic liver cancer (BCLC) stage was 0/A (n = 48, 38%), B (n = 33, 26%), C (n = 27, 22%), and D (n = 16, 13%). Edmondson-Steiner (ES) grade and cytology were correlated with baseline features and radiologic response using logistic regression. Time to progression (TTP) and transplant-free survival (TFS) were analyzed using Cox proportional hazard models.Results:High ES grade was associated with α-fetoprotein (AFP) >50 ng/ml (odds ratio [OR] 4.6, 95% confidence interval [CI]: 1.5–13.9; P < 0.01), tumor diameter >5 cm (OR 3.1, 95% CI: 1.1–9.0; P < 0.05), infiltrative appearance (OR 5.0, 95% CI: 1.5–16.2; P < 0.01), and BCLC Stage C (OR 4.5, 95% CI: 1.3–16.4; P = 0.02). Clear-cell subtype was associated with non-viral cirrhosis (OR 5.3, 95% CI: 1.6–17.2; P < 0.01) and atypical enhancement (OR 3.1, 95% CI: 1.0–9.3; P < 0.05). AFP, BCLC Stage B, and diameter were associated with reduced TTP and TFS (P < 0.05). Neither ES grade nor clear-cell subtype was associated with objective response (OR 2.3, 95% CI: 0.7– 7.4; P = 0.15 and OR 1.1, 95% CI: 0.4–3.4; P = 0.87, respectively), TTP (P > 0.20), or TFS (P > 0.90) on univariate or stratified analysis.Conclusion:Histologic grade is associated with aggressive tumor features, while clear-cell HCC is associated with non-viral cirrhosis and atypical enhancement. Unlike AFP, BCLC stage, and tumor size, histologic features were not associated with LRT outcomes, supporting biopsy deferral for imaging diagnosed HCC.

Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC. We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group. Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (P Interaction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = -0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02-1.06; P = 0.001), but not in luminal tumors or TNBCs (P Interaction = 0.04). The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.

Stromal reprogramming: A target for tumor therapy

Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within the tumor microenvironment (TME) with multi-faceted roles that are endowed with tumor aggressive features. They can instruct and shape the stroma of tumor into being a highly qualified bed for cellular recruitment, differentiation and plasticity in the host tissue or secondary organ/s. In this Review, we have a discussion over CAF reprogramming as a general concept, inducers and outcomes, pursued by suggesting potential strategies to combat this key promoter of tumor.

Guideline-concordant endometrial cancer treatment and survival in the Women's Health Initiative Life and Longevity After Cancer study.

In the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) cohort, we examined predictors of guideline-concordant treatment among endometrial cancer (EC) survivors and associations between receipt of guideline-concordant treatment and survival. Receipt of guideline-concordant EC treatment was defined according to year-specific National Comprehensive Cancer Network (NCCN) guidelines. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for predictors of guideline-concordant treatment receipt. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs for relationships between guideline-concordant treatment and overall survival using Cox proportional hazards regression. We included 629 women with EC, of whom 83.6% (n = 526) received guideline-concordant treatment. Receipt of guideline-concordant treatment was less common among women with nonendometrioid histology (OR = 0.24, 95% CI = 0.13-0.45) but was more common among women living in the Midwest (OR = 2.09, 95% CI = 1.06-4.12) or West (OR = 3.02, 95% CI = 1.49-6.13) compared to the Northeast. In Cox regression models adjusted for age, histology and stage, receipt of guideline-concordant EC treatment was borderline associated with improved overall survival (HR = 0.80, 95% CI = 0.60-1.01) in the overall population. Guideline-concordant treatment was also linked with better overall survival among women with low-grade uterine-confined endometrioid EC or widely metastatic endometrioid EC. Guideline-concordant treatment varies by some patient characteristics and those women in receipt of guideline-concordant care had borderline improved survival. Studies evaluating regional differences in treatment along with randomized clinical trials to determine appropriate treatment regimens for women with aggressive tumor characteristics are warranted.

Adjuvant chemotherapy and survival among patients 70\u2009years of age and younger with node-negative breast cancer and the 21-gene recurrence score of 26\u201330

BackgroundThe benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18–30, particularly those with RS 26–30, are not known.MethodsUsing the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18–30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox’s proportional hazards model.ResultsAmong the breast cancer patients with the RS 18–30, 21% of them had RS 26–30. Compared to breast cancer patients with RS 18–25, patients with RS 26–30 had more aggressive tumor characteristics and chemotherapy use and increased risk of breast cancer-specific mortality and overall mortality. In breast cancer patients who were aged ≤ 70 years and had RS of 26–30, chemotherapy administration was associated with a 32% lower risk of breast cancer-specific mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47–0.99) and a 42% lower risk of overall mortality (HR, 0.58; 95% CI, 0.44–0.76). Survival benefits were most pronounced in breast cancer patients who were younger or had grade III tumor.ConclusionsThe 21-gene RS of 18–30 showed heterogeneous outcomes, and the RS 26–30 was a significant prognostic factor for an increased risk of mortality. Adjuvant chemotherapy could improve the survival of node-negative, hormone receptor-positive, and HER2-negative breast cancer patients with the 21-gene RS 26–30 and should be considered for patients, especially younger patients or patients with high-grade tumors.

1203P - Preliminary results of STELLAR-001, a dose escalation phase I study of the anti-C5aR, IPH5401, in combination with durvalumab in advanced solid tumours

1203P - Preliminary results of STELLAR-001, a dose escalation phase I study of the anti-C5aR, IPH5401, in combination with durvalumab in advanced solid tumours

The splicing FK506-binding protein-51 isoform plays a role in glioblastoma resistance through programmed cell death ligand-1 expression regulation

Gliomas aberrantly express programmed cell death ligand-1 (PD-L1), which has a pivotal role in immunoevasion. The splicing isoform of FKBP5, termed FKBP51s, is a PD-L1 foldase, assisting the immune checkpoint molecule in maturation and expression on the plasma membrane. The concept that PD-L1 supports tumor-intrinsic properties is increasingly emerging. The aim of the present work was to confirm the pro-tumoral effect of PD-L1 on human glioma cell survival, stemness capacity and resistance, and to address the issue of whether, by targeting its foldase either chemically or by silencing, the aggressive tumor features could be attenuated. PD-L1-depleted glioma cells have a reduced threshold for apoptosis, while PD-L1 forced expression increases resistance. Similar results were obtained with FKBP51s modulation. The ability of PD-L1 to counteract cell death was hampered by FKBP51s silencing. PD-L1 expression was particularly high in glioma cells with a cancer-stem-cell profile. Moreover, PD-L1 sustained the spheroid formation capability of glioma cells. Targeting of FKBP51s by small-interfering RNA (siRNA) or the specific inhibitor SAFit2, reduced the number of formed spheroids, along with PD-L1 expression. Finally, in an orthotopic mouse model of glioblastoma, daily treatment with SAFit2 significantly reduced tumor PD-L1 expression, and tumor growth. In treated mice, caspase-3 activation and reduced vimentin expression were observed in excised tumors. In conclusion, targeting of FKBP51s hampers PD-L1 and its pro-tumoral properties, thereby affecting the self-renewal and growth capacities of glioblastoma cells in vitro and in vivo.

Loss of ATRX expression predicts worse prognosis in pulmonary carcinoid tumors

Loss of alpha thalassemia/mental retardation syndrome X-linked (ATRX), a chromatin regulator, is associated with worse prognosis in pancreatic neuroendocrine tumors. We investigated ATRX expression in pulmonary carcinoid tumors (PCT) and its diagnostic and prognostic role in these patients. Resected PCTs (1997-2017) were reviewed. Tumors were staged according to 8th UICC/AJCC system. ATRX nuclear expression was recorded independently by 2 reviewers. A cutoff of ≤5% of nuclear ATRX expression was statistically established as loss of expression. One-hundred-fifteen patients (72 women [63%]; median age of 60.5 years [interquartile range, 50.8-71.5]) harbored 69 (60%) typical and 46 (40%) atypical PCTs. Median tumor size was 2.3 cm (interquartile range, 1.6-3.8 cm). Loss of ATRX expression was associated with atypical PCTs (OR 7.4 [95% CI, 2.6-23, P < .001]), when adjusted for lymphovascular invasion and perineural invasion. ATRX expression predicted atypical PCT with sensitivity of 37% (95% CI, 24%-52%), specificity of 92% (95% CI, 86%-98%), AUC of 0.62 (95% CI, 0.52-0.72). Loss of ATRX expression was associated with shorter disease-specific survival (HR = 11, 95% CI, 1.8-68, P = .01), after adjusting for lymphovascular invasion and presence of metastatic disease at time of diagnosis. Interobserver agreement on ATRX expression by two reviewers was substantial (κ = 0.72 [95% CI, 0.60-0.80]). ATRX expression is more commonly lost in atypical than in typical PCT, and is associated with more aggressive tumor characteristics and shorter disease-specific survival.

Trastuzumab-Induced Cardiomyopathy.

Trastuzumab targets the human epidermal growth factor receptor 2 (HER2). Its overexpression occurs in 25% of breast cancers and is associated with aggressive tumor characteristics and poor prognosis in absence of targeted therapy. Trastuzumab dramatically improves HER2-positive breast cancer outcomes; however, its clinical use is associated with left ventricular dysfunction and heart failure. Patients receiving trastuzumab or other HER2-targeted therapies undergo routine cardiac function assessment. Holding and/or stopping trastuzumab treatment in the setting of left ventricular dysfunction is recommended. This article summarizes the role of trastuzumab in cancer treatment, the mechanisms of trastuzumab-induced cardiotoxicity, recent clinical investigations, and current controversies.

Discrimination of low- and high-grade appendiceal mucinous neoplasms by targeted sequencing of cancer-related variants

DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). There were significantly more damaging variants in high-grade versus low-grade tumor cohorts. Both cohorts contained damaging, heterozygous germline variants (catenin β1; notch receptor 1 and 4) in pathways associated with cell-lineage specification (WNT, NOTCH). Damaging, somatic KRAS proto-oncogene, GTPase mutations were present in both cohorts, while somatic GNAS complex locus mutations were confined to low-grade neoplasms. Variants predominantly affected transcription factors, kinases, and stem cell signaling molecules in canonical pathways including epithelial to mesenchymal transition, stem cell pluripotency, p53, PTEN, and NF-қB signaling pathways. High-grade tumors demonstrated MYC proto-oncogene, bHLH transcription factor (MYC) and death domain associated protein (DAXX) amplification and damaging somatic variants in tumor protein p53 (TP53), likely to amplify an aggressive phenotype. Damaging APC, WNT signaling pathway regulator (APC) deletions were identified in metastatic tissue of both cohorts suggesting a role in invasive disease. Our data suggest that germline dysregulation of WNT and/or NOTCH pathways predisposes patients toward a secretory cell phenotype (i.e., goblet-like cells) upon acquisition of somatic KRAS mutations. Additional somatically acquired variants activating oncogenes MYC and DAXX and inhibiting the critical tumor suppressor, tumor protein TP53, were consistent with manifestation of a high-grade phenotype. These additional changes within the epithelial to mesenchymal transition signaling network (WNT, NOTCH, RAS/ERK/PI3K, PTEN, NF-қB), produce aggressive high-grade tumor characteristics by actively driving cells towards dedifferentiation, proliferation, and migration.

PDZ and LIM domain protein 4 suppresses the growth and invasion of ovarian cancer cells via inactivation of STAT3 signaling

AimsPDZ and LIM domain protein 4 (PDLIM4) is frequently repressed in cancer tissues. However, the expression and role of PDLIM4 in ovarian cancer has not been addressed. Main methodsIn this study, we examined the expression and prognostic significance of PDLIM4 in ovarian cancer. The function of PDLIM4 in ovarian cancer cell growth, invasion, and tumorigenesis was further explored. Key findingsPDLIM4 is downregulated in ovarian cancer compared to adjacent normal ovarian tissues. Downregulation of PDLIM4 is correlated with advanced tumor stage and lymph node metastasis. Low PDLIM4 expression is significantly associated with shorter overall survival in patients with ovarian cancer (P = 0.0136). Biologically, PDLIM4 overexpression suppresses the proliferation, colony formation, migration, and invasion of both CAOV3 and SKOV3 ovarian cancer cells, compared to empty vector-transfected cells. Consistently, in vivo data show that PDLIM4 overexpression inhibits the growth of SKOV3 xenograft tumors. Mechanistic investigation reveals that overexpression of PDLIM4 blocks the phosphorylation of STAT3 and represses STAT3-dependent transcriptional activation. Moreover, ectopic expression of PDLIM4 downregulates the expression of CCND1 and MMP9 in ovarian cancer cells. Rescue experiments demonstrate that overexpression of constitutively active STAT3 reverses PDLIM4-induced anticancer effects on ovarian cancer cells. SignificanceOverall, PDLIM4 downregulation is associated with aggressive tumor features and poor prognosis in ovarian cancer patients. PDLIM4 suppresses ovarian cancer cell growth and invasion by inhibiting STAT3 signaling. This study provides a potential therapeutic target for ovarian cancer.

Clinicopathological and epidemiological significance of breast cancer subtype reclassification based on p53 immunohistochemical expression

TP53 mutations are common in breast cancer and are typically associated with more aggressive tumor characteristics, but little is known about the clinicopathological and epidemiological relevance of p53 protein expression, a TP53 mutation surrogate, in breast cancer subtypes. In this study of 7226 Chinese women with invasive breast cancer, we defined breast cancer subtypes using immunohistochemical (IHC) measures of hormone receptors and HER2 in conjunction with histologic grade. p53 expression status was then used to further stratify subtypes into p53-positive and p53-negative. Odds ratios (ORs) and 95% confidence intervals (CIs) in case-only logistic regression analyses were used to examine heterogeneity across different subtypes. The frequency of p53 protein expression varied by breast cancer subtype, being lowest in the luminal A-like and highest in the triple-negative and HER2-enriched subtypes (P-value < 0.01). In luminal A-like and B-like/HER2-negative subtypes, p53 positivity was associated with early-onset tumors, high grade, high proliferative index, and basal marker (CK5/6 and EGFR) expression. Further, compared with luminal A-like/p53-negative patients, A-like/p53-positive patients were more likely to be parous [adjusted OR parous vs. nulliparous = 2.67 (1.60, 4.51); P-value < 0.01] and to have breastfed [adjusted OR ever vs. never = 1.38 (1.03, 1.85); P-value = 0.03]. p53 positivity was not associated with examined clinical and risk factors in other tumor subtypes. Overall, these findings suggest that p53 expression, which is readily available in many settings, can be used to identify phenotypes of luminal A-like breast cancer with distinct clinical and epidemiological implications.

Abstract 2436: Systematic computational analysis of histologic-genomic associations in triple-negative infiltrating ductal carcinomas of the breast

Abstract Background: Triple-negative breast cancer (TNBC) is characterized by rapid progression and lack of therapeutic targets. There is a pressing need for in-depth characterization of the biological correlates (and potential prognostic biomarkers) in TNBC. We performed a systematic analysis of genomic correlates of histologic markers of tumor aggressiveness and immune infiltration in 125 infiltrating ductal TNBC patients from The Cancer Genome Atlas. Methods: Fully-convolutional networks of the VGG16-FCN8 architecture were trained to classify various tissue regions in H&amp;E slides (0.956 AUC on unseen slides), and morphologic descriptors of tumor aggressiveness, invasion, and immune infiltration were extracted from predictions. Expression levels of 17,052 genes were entered into sample purity-adjusted linear regression models, and a Gene Set Enrichment Analysis was performed using the model coefficients to find gene set-level associations. Results: Significant associations are summarized in Table 1. Expression of mTOR pathway genes (especially HIGD1C and PDE6H) is positively associated with large, dense tumor nests with a smooth tumor-stroma boundary. Boundary complexity is also positively associated with the oxidant stress response of NFE2L2. In contrast, some genes downregulated by the TGF-β pathway (including FGF6, PSG2 and CHRNG) are associated with a large tumor nest phenotype. The cell cycle regulator E2F1 (through PRM1, KRT72, and DBF4) is associated with dense immune infiltration, a known marker of good prognosis, and also small tumor nest size. Conclusion: mTOR and NFE2L2-mediated mechanisms are significantly associated with features of tumor aggressiveness in TNBC, while E2F and some TGF-β targets are associated with morphological markers of less aggressive tumors. Further research is needed to elucidate the biological basis of these associations and their potential significance in therapeutic targeting of TNBC. Table 1:Significant histologic-genomic associations in infiltrating-ductal TNBC.Histologic phenotype (feature description)Enriched gene set (MSigDB Oncogenic Signatures)Gene set descriptionNES(P-value, FDR)Leading-edge genesTumor nest size (Mean tumor nest area)TGFB_UP.V1_DNGenes down-regulated by TGFB11.55(p&amp;lt;0.001, FDR=0.036)FGF6; PSG2; CHRNGTumor-stroma interface (non-)complexity (mean solidity of tumor nests)NFE2L2.V2Genes upregulated with knockout of NFE2L2 gene (involved in oxidant stress response and inflammation)-1.51(p&amp;lt;0.001, FDR=0.027)DEFB119; CNTNAP5; SCGB1D1MTOR_UP.V1_DNGenes downregulated by everolimus (an mTOR inhibitor)1.43(p=0.0017, FDR= 0.094)HIGD1CSmall, solitary tumor nestsE2F1_UP.V1_UPGenes up-regulated when E2F1 is over-expressed (cell cycle regulation)1.48(p&amp;lt;0.001, FDR&amp;lt;0.001)PRM1MTOR_UP.V1_DNGenes downregulated by everolimus (an mTOR inhibitor)-1.50(p=0.0027, FDR= 0.079)PDE6H; HIGD1CSmall tumor nests with abundant surrounding immune infiltration (a spatial descriptor meant to capture immune success)E2F1_UP.V1_UPGenes up-regulated when E2F1 is over-expressed.(cell cycle regulation)1.55(p&amp;lt;0.001, FDR= 0.0019)PRM1; KRT72; DBF4 Citation Format: Mohamed Amgad, Uday Kurkure, Habiba Elfandy, Hagar H. Khallaf, David A. Gutman, Carlos S. Moreno, Michael Barnes, Lee A. Cooper. Systematic computational analysis of histologic-genomic associations in triple-negative infiltrating ductal carcinomas of the breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2436.

Abstract 2905: Clinical features in relation to age at diagnosis in luminal breast cancer patients: A hospital-based case series study in Beijing, China

Abstract Background Breast cancer (BC) is a heterogenous disease that can be classified into various molecular subtypes. Patients with younger age at diagnosis are less likely to develop luminal A cancers. However, a large proportion of early-onset luminal BCs are seen among Asian BC patients. While this may be explained by the increasing exposure to Westernized lifestyle, germline genetics, breast density, or immune factors may also give rise to a distinct age-related biology in Asian BC. We investigated several tumor characteristics in luminal BC patients with respect to age, among women in Beijing, China. Methods Subjects in this study were diagnosed with invasive breast cancer and treated at the Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, between 2008-2016. 7,543 luminal cases (ER+ and/or PR+), were further defined as Luminal A: ER+, PR+, HER2-, low grade (1/2); Luminal B/high grade: ER+ and/or PR+, HER2-, high grade (3); Luminal B/HER2+: ER+ and/or PR+, HER2+. Patients were divided into four age groups: &amp;lt;40 (12.1%), 40-50 (34.2%), 50-60 (32.2%), and 60+ (21.5%) years old. We investigated the associations between age and tumor markers (ER, PR, HER2, KI67, P53, CK5/6, and EGFR) and features (tumor size, lymph node involvement, and histologic grade) using unconditional logistic regression. Results The mean age at diagnosis among these cases was 51.5 years (SD=10.8). Compared to older women (60+), patients diagnosed &amp;lt;40 years old were more likely to have lower ER percentage/intensity, to be positive for HER2, P53, and EGFR, to have higher KI67, and luminal B/HER2+ tumors (p-values=&amp;lt;.0001). PR showed a different and interesting pattern among patients in age group 40-50, who had higher values of PR percentage/intensity compared to women 60+ years old. After mutually adjusting for the significant tumor features, the associations for ER [OR&amp;lt;40 vs 60+=0.34 (0.21, 0.55), OR40-50 vs 60+=0.22 (0.15, 0.32), strong vs. weak staining] and PR [OR&amp;lt;40 vs 60+=2.95 (2.00, 4.35), OR40-50 vs 60+=4.22 (3.13, 5.68), strong vs. weak staining], HER2 positivity [OR&amp;lt;40 vs 60+=1.60 (1.15, 2.23)], KI67 [OR&amp;lt;40 vs 60+=1.52 (1.04, 2.21), quartile 4 vs. 1], and lymph nodal involvement [OR&amp;lt;40 vs 60+=1.87 (1.38, 2.51)] remained significant. While younger patients in general were more likely to have luminal B/HER2+ tumors, women in age group 40-50 were less likely to develop luminal B/high grade BC [OR40-50 vs 60+=0.78 (0.63, 0.97)] compared to women 60+ years old. Conclusion We observed the known associations between younger age at diagnosis and more aggressive tumor features. We also found that patients in the age 40-50 group showed interesting associations with PR and the luminal B/high grade subtype. We intend to replicate these results in other Asian datasets and to explore the age associations with etiologic factors. Citation Format: Hela Koka, Changyuan Guo, Mustapha Abubakar, Hyuna Sung, Hyuna Sung, Bin Zhuo, Eric Tang, Joseph Deng, Nan Hu, Ning Lu, Xiaohong R. Yang. Clinical features in relation to age at diagnosis in luminal breast cancer patients: A hospital-based case series study in Beijing, China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2905.

Abstract 3530: Gene expression alterations associated with histologic aggressiveness in stage I lung adenocarcinomas

Abstract RATIONALE: The National Lung Screening and Nelson Trials demonstrated a 20% and 26% (for men) reduction, respectively in lung cancer mortality for patients screened using low-dose CT. However, lung cancer screening has the potential for over-diagnosis of indolent tumors. Therefore, we sought to identify molecular features that could distinguish indolent from aggressive early stage lung tumors based on histologic aggressiveness profiling, with the ultimate goal being to translate these findings into biomarkers that could inform post-biopsy/surgery management. METHODS: 63 FFPE samples of stage I lung adenocarcinomas were included for pathologic annotation and Whole Exome sequencing. An average of 48.2±15.6 million total reads per sample were generated with 78.4%±4.8% reads uniquely mapped. Tumors were categorized into 3 groups based on histologic features previously associated with tumor aggressiveness: Minimally-Aggressive (n=18): containing zero aggressive components (e.g. zero solid/cribriform); Medium-Aggressive (n=19): not yet dominated by aggressive components; Highly-Aggressive (n=26): solid/cribriform predominant. Tumor histology was characterized for percentage of lepidic, acinar, papillary, micro-papillary, solid and cribriform components. Negative binomial models were used to identify genes whose expression was associated with tumor histology. Estimate Algorithm was used to estimate immune cell type infiltration of these tumors. RESULTS: 430 genes (FDR q&amp;lt;0.05) were differentially expressed between the three histologic groups. Genes with elevated expression in the Medium- and Highly-Aggressive subgroups were enriched for genes with roles in cell-cycle regulation and the EMT transition. The genes elevated in the Minimally-Aggressive subgroup were enriched for genes with roles in inflammatory pathways and cytokine production. This gene signature was also associated with tumor invasiveness and mitotic grades (p&amp;lt;0.05). Using the Estimate Algorithm, we compared whether the three histologic groups had differential immune cell infiltrations using hallmark gene sets of lymphocytes and myeloid cells. We identified that Minimally-Aggressive subgroups had significantly higher Th-1, Tfh, Th17 and NK cell infiltration than Medium- and Highly-Aggressive subgroups (adjusted p value&amp;lt;0.05). CONCLUSION: We identified gene expression alterations among stage I adenocarcinomas associated with histologic features of tumor aggressiveness. This gene signature may help identify more indolent tumors and potentially impact their post biopsy/surgery clinical management. Citation Format: Jiarui Zhang, Eric Burks, Jennifer Beane, Travis Sullivan, Gang Liu, Steven Dubinett, Marc Lenburg, Avrum Spira. Gene expression alterations associated with histologic aggressiveness in stage I lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3530.

A Low Geriatric Nutritional Risk Index is Associated with Aggressive Pathologic Characteristics and Poor Survival after Nephrectomy in Clear Renal Cell Carcinoma: A Multicenter Retrospective Study

Purpose: To investigated the prognostic significance of the geriatric nutritional risk index (GNRI) in patients with surgically treated clear cell renal cell carcinoma (ccRCC).Patients and methods: We retrospectively selected 4,591 consecutive patients with surgically treated ccRCC from a multi-institutional Korean collaboration between 1988 and 2015. The clinical significance of the GNRI as a continuous and categorical variable was determined.Results: Preoperative low GNRI was significantly associated with older age, low body mass index, presence of diabetes, poor performance status, and presence of symptoms at diagnosis, as well as pathologic features such as aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, sarcomatous differentiation, and tumor necrosis. A low GNRI was significantly associated with a short recurrence-free survival (RFS) in localized (pT1-2N0M0) ccRCC and cancer-specific survival (CSS) in the entire cohort, and with short RFS and CSS in the subgroup analysis according to age categories (≤65 and >65 years). Multivariate Cox regression analysis showed that preoperative GNRI, as a continuous or categorical variable, was an independent predictor of RFS and CSS.Conclusion: Malnutrition as assessed by the preoperative GNRI is associated with aggressive tumor characteristics and poor survival in patients with surgically treated ccRCC.

Heterogeneity of human pancreatic adenocarcinoma (PDAC) cancer-associated fibroblasts (CAF): subtype-A (periostin-positive) CAF is associated with aggressive tumor features and is an early CAF

Microstrip silicon detectors are one of the key trackers in particle physics experiment like LHC at CERN. There is a continuous need to improve upon various parameters of detectors like breakdown voltage, leakage current, full depletion voltage, post radiation hardness, charge collection efficiency and low thermal budget. We have introduced new doping less silicon microstrip detector for the very first time and investigated the various parameter of the detector. We have studied and compared the results of doped and dopingless charge plasma silicon microstrip detector. Our study shows improvement in Preradiation breakdown voltage of 2200 V with leakage current of 5.2 pA/um in dopingless charge plasma microstrip detector as compared to 1500 V of breakdown voltage with leakage current of 6.5pA/um as in the case of doped silicon microstrip detector.

B7-H3 Expression in Merkel Cell Carcinoma-Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density.

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease.Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3-positive cell centroid. Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.

Comparative study of breast cancer with or without concomitant Paget disease: An analysis of the SEER database.

BackgroundMost mammary Paget disease (MPD) is associated with underlying in situ or invasive breast cancer. The objective of this study was to compare the clinicopathological characteristics and survival outcomes between breast cancer with Paget disease (PD) and breast cancer alone.MethodsFrom the Surveillance, Epidemiology, and End Results (SEER) database, 2000‐2015, of the US National Cancer Institute, we identified 1569 women who had PD with invasive ductal carcinoma (PD‐IDC) and 1489 women who had PD with ductal carcinoma in situ (PD‐DCIS). Independent demographic and clinicopathological variables as well as survival outcomes of these patients were compared to patients with the corresponding breast cancer without concomitant PD.ResultsPD‐IDC and PD‐DCIS both had worse survival outcomes and poorer tumor characteristics than the corresponding disease without PD. Contrary to in the breast cancer alone groups, in the breast cancer with PD groups, the HR status (P = 0.182 in PD‐IDC and P = 0.371 in PD‐DCIS), HER2 status (P = 0.788 in PD‐IDC and P = 0.643 in PD‐DCIS), and combined molecular subtype (P = 0.196 in PD‐IDC and P = 0.853 in PD‐DCIS) were not found to affect disease prognosis. After matching tumor characteristics and treatment approaches, PD‐IDC as well as PD‐DCIS exhibited no significant difference in disease prognosis with corresponding IDC and DCIS. Finally, by comparative analysis, a kind of PD‐DCIS (ICD‐O‐3 code 8543/3) showed many invasive behaviors (31.8% of 8543/3 patients had stage I‐III cancer) and was associated with worse survival outcomes than the other type of PD‐DCIS.ConclusionsBreast cancer with concomitant PD was associated with more aggressive tumor characteristics and worse survival outcomes. The HR status, HER2 status, and combined molecular subtype could not affect the prognosis of breast cancer with PD. Moreover, a portion of the PD‐DCIS cases were invasive breast cancer cases that required special treatment.