Independent Prognostic Factor In Terms Research Articles

Prognostic factors and survival of breast cancer in patients over 40 years of age

Aims: Breast cancer is the cancer with the highest incidence and mortality in women. There are differences in prognosis and survival between women over and under the age of 40. In this article, we aimed to examine breast cancer prognostic factors and survival results in people over the age of 40. Methods: 1187 patients aged 40 and over who underwent surgery at the Ondokuz Mayıs University Department of General Surgery between August 2005 and April 2019 and whose data were accessible were retrospectively examined. Data were obtained from the hospital automation system, the Ministry of Health’s online database, hospital archives, patients, and/or their relatives. They were classified separately in terms of type of surgery, axillary metastasis status (according to radiological status if axilla surgery is not performed), type of axilla surgery performed, pathological tumor size, number of pathological lymph nodes, pathological stage, lymphovascular and perineural invasion status, hormone receptor positivity, C-erb B2 and Ki-67 status, neoadjuvant treatment status, and molecular subgroup. Variables were analyzed individually for recurrence, mortality, and survival. Results found to be significant were subjected to multivariate analysis testing. Statistical significance was accepted as p<0.05. Results: As a result of multivariate analysis performed by excluding data that disrupted homogeneous distribution, perineural invasion, lymphovascular invasion, grade, and progesterone receptor status were determined to be independent prognostic factors in terms of recurrence. Lymphovascular invasion and progesterone receptor status were found to be independent prognostic factors for mortality. Conclusion: A lot of studies have been conducted, and criteria have been determined for breast cancer prognosis and survival. In our results, lymphovascular invasion and progesterone receptor status were found to be independent prognostic markers for both recurrence and mortality. More reliable results can be obtained with prospective study analyses.

Mismatch Repair Deficiency in Biliary Tract Cancer: Prognostic Implications and Correlation with Histology

Introduction: Mismatch repair (MMR) deficiency represents a biomarker and therapeutic target in various neoplasms, but its role in biliary tract cancers (BTCs) remains misunderstood. Methods: MMR status was retrospectively assessed using immunohistochemistry in 163-BTCs patients. We identified MMR proficiency (pMMR)/deficiency (dMMR) according to the loss of MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary objective of the study was to assess the incidence of dMMR in BTCs; the secondary purpose was to explore its association with prognosis and clinical features. Results: dMMR was recorded in 9 patients, and it was strongly associated with mucinous histology (p < 0.01). Regarding the prognostic effect, in 122-radically resected patients, disease-free survival (DFS) resulted significantly shorter in dMMR patients compared to pMMR patients (10.7 vs. 31.3 months, p = 0.025) and so did nodal status (48.2 vs. 15.3 months in N0 vs. N+) (p < 0.01). Moreover, dMMR confirmed its prognostic role in terms of DFS at multivariate analysis (p = 0.03), together with nodal status (p = 0.01), and resection margin (p = 0.03). In 103 M+ patients (encompassing 41 metastatic de novo and 62 recurred after surgery patients) there were not differences between dMMR and pMMR regarding survival analyses. Conclusions: dMMR status is strongly correlated with mucinous histology and represents an independent prognostic factor in terms of disease relapse in patients with resected BTC. Implications for Practice: MMR may play an independent role in promoting an aggressive behaviour in patients with radically resected BTC. These results could be useful in improving the selection of patients after resection and, above all, should justify the evaluation of MMR status as a therapeutic target in BTC, especially in patients with atypical histology.

Impact of perioperative red blood cell transfusion, anemia of cancer and global health status on the prognosis of elderly patients with endometrial and ovarian cancer.

IntroductionPerioperative red blood cell (RBC) transfusions have been associated with increased morbidity and worse oncological outcome in some solid neoplasms. In order to elucidate whether RBC transfusions themselves, the preoperative anemia of cancer (AOC), or the impaired global health status might explain this impact on patients with endometrial cancer (EC) or ovarian cancer (OC), we performed a retrospective, single-institution cohort study.Materials and methodsWomen older than 60 years with EC or OC were included. The influence of RBC transfusions, AOC, and frailty status determined by the G8 geriatric screening tool (G8 score), as well as the clinical-pathological cancer characteristics on progression-free survival (PFS) and overall survival (OS), was determined by using the Kaplan-Meier method and the Cox regression analyses.ResultsIn total, 263 patients with EC (n = 152) and OC (n = 111) were included in the study. Patients with EC receiving RBC transfusions were faced with a significantly shorter 5-year PFS (79.8% vs. 26.0%; p < 0.001) and 5-year OS (82.6% vs. 25.7%; p < 0.001). In multivariable analyses, besides established clinical-pathological cancer characteristics, the RBC transfusions remained the only significant prognostic parameter for PFS (HR: 1.76; 95%-CI [1.01–3.07]) and OS (HR: 2.38; 95%-CI [1.50–3.78]). In OC, the G8 score stratified the cohort in terms of PFS rates (G8-non-frail 53.4% vs. G8-frail 16.7%; p = 0.010) and AOC stratified the cohort for 5-year OS estimates (non-anemic: 36.7% vs. anemic: 10.6%; p = 0.008). Multivariable Cox regression analyses determined the G8 score and FIGO stage as independent prognostic factors in terms of PFS (HR: 2.23; 95%-CI [1.16–4.32] and HR: 6.52; 95%-CI [1.51–28.07], respectively). For OS, only the TNM tumor stage retained independent significance (HR: 3.75; 95%-CI [1.87–7.53]).DiscussionThe results of this trial demonstrate the negative impact of RBC transfusions on the prognosis of patients with EC. Contrastingly, the prognosis of OC is altered by the preoperative global health status rather than AOC or RBC transfusions. In summary, we suggested a cumulatively restrictive transfusion management in G8-non-frail EC patients and postulated a more moderate transfusion management based on the treatment of symptomatic anemia without survival deficits in OC patients.

Tumor-Infiltrating Lymphocytes (TIL), Tertiary Lymphoid Structures (TLS), and Expression of PD-1, TIM-3, LAG-3 on TIL in Invasive and In Situ Ductal Breast Carcinomas and Their Relationship with Prognostic Factors

IntroductionImmunotherapy has been determined as an important choice in breast carcinomas, especially in tumors with markedly inflammatory response. About this promising subject, tumor-infiltrating lymphocytes (TIL) and the expression of immune control point receptors on TIL have gained importance. Materials and MethodsIn this study, stromal TIL and tertiary lymphoid structures (TLS) were determined in tumor tissues of 312 invasive and 68 in situ breast cancer patients. Expression rates of PD-1, LAG-3, and TIM-3 on intratumoral and stromal TIL were immunohistochemically evaluated. ResultsIn invasive breast carcinomas, stromal TIL was found to be significantly associated with lymph node metastasis, HR and HER2 expression, and basal-like phenotype, as the presence of TLS with neoadjuvant therapy, recurrence, death, and expression of HR and HER2. PD-1, LAG-3, and TIM-3 expressions were found to be associated with HR and HER2 status, stromal TIL rates, and TLS. In multivariate analysis, high stromal TIL and PD-1 expression in intratumoral TIL were found to be independent prognostic factors in terms of overall survival and disease-free survival. ConclusionEvaluation of TIL and immune control point receptor expressions in breast cancer is particularly important in terms of planning the therapeutic approaches based on immunotherapy protocols.

Abstract PD6-08: Exploring the interplay among ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype of metastatic breast cancer (MBC) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS)

Abstract Background: High throughput genomic technologies such as NGS are enhancing the ability to dynamically characterize MBC but their role in describing biological evolution of multiple mutations together remains unclear. ESR1 and PIK3CA are central mutations related to the biology and druggability of hormone-receptor positive, HER2 negative (luminal-like) MBC. The aim of this study was to explore the interplay between oncogenic pathway alterations and ESR1 and PIK3CA codon variants on the impact and clinical phenotype of luminal-like MBC. Methods: The study retrospectively analyzed a multi-institutional cohort comprising 1047 MBC patients (pts) characterized for ctDNA through NGS before treatment start at Northwestern University (Chicago, IL), Massachusetts General Hospital (Boston, MA) and Washington University in St. Louis between 2015-2020. The analysis was then focused on luminal-like MBC. Pathway classification was defined based on previous work (Sanchez-Vega F et al, Cell. 2018) (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB and ClinVar. Only pathogenic variants were included in the models. Associations among, pathway classification, and ESR1/PIK3CA codon variants were explored through stepwise logistic regression. Overall survival (OS) was tested through Cox regression. Results: The luminal-like cohort comprised 702 pts. ESR1 mutations were detected in 166 pts (24%) and PIK3CA in 214 pts (31%). The most common ESR1 gene mutations were found in codons 537 (31%), 538 (21%), 536 (8%) and 380 (7%), while alterations in codons 1047 (38%), 545 (25%), and 542 (20%) were the most common for PIK3CA. Other pathogenic SNVs were observed in 33% and 17% of pts for ESR1 and PIK3CA, respectively with the former being polyclonal. SNVs alterations were mainly observed in the PI3K (35%), P53 (32%), ER (28%), RAS (8%), RTK (8%) and cell cycle (5%) pathways, while copy number variations (CNVs) were detected in the RTK (15%), cell cycle (11%), MYC (7%) PI3K (6%) and RAF (5%) pathways. ESR1 537 variants were associated with alterations in the ER and WNT pathways, 538 with cell cycle, 380 with P53 and ER, 536 with RTK. PIK3CA 1047 variants were associated with alterations in the RTK and P53 pathways, 542 with RTK, RAS and RAF, E545 with PI3K, RAS, cell cycle and P53. 1047 and 542 were also associated with CNVs in the PI3K pathway. Independent prognostic factors in terms of OS were ESR1 537/380 codon variants (HR 1.94 P = 0.001 and HR 2.29 P = 0.047), SNVs in the RAS, cell cycle, and P53 pathways (HR 1.74 P = 0.003 HR 1.84 P = 0.009 and HR 1.56 P &amp;lt; 0.001) and CNVs in the cell cycle pathway (HR 1.96 P &amp;lt; 0.001). Conclusions: This study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDs) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making. Odds Ratio95% Confidence IntervalPESR1 Y537ER SNVs3.341.487.530.004WNT SNVs6.251.4127.740.016ESR1 D538cell cycle SNVs5.221.7915.230.003ESR1 E380P53 SNVs4.801.4116.310.012ER SNVs5.331.3321.400.018ESR1 L536RTK CNVs4.511.1517.690.031PIK3CA H1047RTK SNVs3.751.708.290.001P53 SNVs2.611.584.34&amp;lt; 0.001PI3K CNVs6.082.4515.08&amp;lt; 0.001PIK3CA E542RTK SNVs5.001.9412.880.001RAS SNVs3.651.369.770.01RAF SNVs6.011.0733.870.042PI3K CNVs6.302.2917.36&amp;lt; 0.001PIK3CA E545PI3K SNVs2.881.276.530.011RAS SNVs2.871.186.980.02cell cycle SNVs3.071.088.740.035NRF2 SNVs21.431.29356.520.033P53 SNVs3.752.046.89&amp;lt; 0.001 Citation Format: Lorenzo Gerratana, Andrew A Davis, Marko Velimirovic, Katherine Clifton, Whitney L Hensing, Ami N Shah, Charles S Dai, Carolina Reduzzi, Paolo D’Amico, Qiang Zhang, Firas Wehbe, Seth Wander, William J Gradishar, Amir Behdad, Fabio Puglisi, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Exploring the interplay among ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype of metastatic breast cancer (MBC) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-08.

Epidemiological, Clinical, and Oncological Outcomes of non-Alcohol Drinking and non-Smoking Laryngeal Squamous Cell Carcinoma Patients: A Distinct Entity.

Purpose: To explore the discrepancy in clinicopathological and prognostic features between smoking and alcohol drinking (SA) and non-smoking and non-alcohol drinking (NSNA) patients with laryngeal squamous cell carcinoma (LSCC). Methods: This retrospective study including 1735 patients with LSCC was conducted from January 2005 to December 2010, which were categorized into 4 groups, NSNA group, smoking only group, alcohol-drinking only group, and SA group. We compared overall survival (OS) and disease-free survival (DFS) using the Kaplan–Meier method and indicated clinicopathological features by Cox proportional hazards regression models before and after propensity score matching (PSM). Results: A total of 415 patients (23.92%) were identified as NSNA. The SA group was predominantly patients ≤60 years old (46.63%) while the NSNA group was more older (58.07%). NSNA group was more likely to present at earlier disease stage and more female. No significant difference in OS (P = .685) and DFS (P = .976) was found between the 2 groups. In addition to age and recurrence and metastasis being common independent prognostic factors in terms of OS in both groups of patients, NSNA group also exhibited other factors, namely tumor area >3.7 cm2 and positive resection margin. For DFS, N + stage, tumor size >3.7 cm2, and positive resection margin were prognostic features specific to NSNA group. Conclusion: The outcome is similar in LSCC patients with and without SA. NSNA group shows a distinct profile from that found in SA group. Clinicopathological features from NSNA group should be considered for LSCC management.

Expression pattern and prognostic impact of glycoprotein non-metastatic B (GPNMB) in triple-negative breast cancer

Glycoprotein non-metastatic B (GPNMB) is a transmembrane protein overexpressed in numerous cancers including triple-negative breast cancers (TNBC). It has been linked to promote cancer aggressiveness and implicated as a novel target for GPNMB-expressing cancers. In current study, we aimed to explore the clinical significance of GPNMB in TNBC. Among 759 specimens, immunohistochemistry (IHC) exhibited GPNMB expressions were variable in different subtypes and significantly higher in TNBC. Kaplan–Meier analysis revealed GPNMB overexpression in TNBC was associated with worse prognosis especially distant metastasis (P = 0.020, HR = 2.515, CI 1.154–5.480). Multivariate analysis showed GPNMB expression was an independent prognostic factor in terms of recurrence and distant metastasis (P = 0.008, HR = 3.22, CI 1.36–7.61; P = 0.017, HR = 3.08, CI 1.22–7.74). In silico analysis showed high mRNA expression of GPNMB was associated with distant metastasis and GPNMB was overexpressed in TNBC. Furthermore, GPNMB positively correlated with epithelial–mesenchymal transition (EMT) regulators, mesenchymal marker vimentin, MMP and integrins. The protein levels of Twist and MMP2 were upregulated by GPNMB overexpression in TNBC cells. GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC.

A Low Albumin-to-Globulin Ratio Predicts a Poor Prognosis in Patients With Metastatic Non-small-cell Lung Cancer.

Objective: The serum albumin-to-globulin ratio (AGR) may be a useful prognostic factor for various cancers. This study aimed to evaluate the prognostic value of the AGR in patients with metastatic non-small-cell lung cancer (NSCLC).Methods: A retrospective study was conducted on patients with stage IV NSCLC diagnosed in Hubei Cancer Hospital from July 2012 to December 2013. The formula for calculating the AGR was serum albumin/total protein-serum albumin. The chi-square test or Fisher's exact test was used to analyze the classified variables. The Kaplan-Meier method was used to analyze the overall survival (OS) rate, which was plotted with the R language. The impact of the AGR on OS and progression-free survival (PFS) was analyzed by a multivariate Cox proportional hazard model.Results: A total of 308 patients were included in the study population. The optimal cutoff values for the AGR in terms of OS and PFS were 1.12 and 1.09, respectively, as determined by X-Tile software. Kaplan-Meier curve analysis showed that the difference in survival rate between patients with different AGR levels was statistically significant (p = 0.04). The OS of patients with a high AGR (≥1.12) was longer than that of patients with a low AGR (<1.12). PFS in the high AGR group were better than those in the low AGR group (16.90 vs. 32.07months, p = 0.008). The univariate and multivariate models proved that the AGR was an independent prognostic factor in metastatic NSCLC patients in terms of both OS (p = 0.009, hazard ratio [HR] = 0.55, 95% confidence interval [95% CI] = 0.35–0.86) and PFS (p = 0.004, HR = 0.55, 95% CI = 0.37–0.83).Conclusion: The AGR, which is measured in routine clinical practice, is an independent prognostic factor in terms of OS and PFS in metastatic NSCLC and can serve as a prognostic tool for metastatic NSCLC.

Is Albumin-Bilirubin Grade an Effective Factor in Terms of Recurrence Following Resection in HCC Patients?

Introduction: Recent studies have revealed the fact that albumin-bilirubin (ALBI) grade can be an independent prognostic factor in terms of liver failure, long-term survival and recurrence. Material-Method: Patients who had undergone resection with pathologic diagnosis of HCC were examined retrospectively. Age, gender, etiologic factor, preoperative and postoperative 5th day ALBI grade, type of hepatic resection, length of hospital stay, tumor size, lymph node involvement and resection margin of tumor were examined. Recurrence and survival therefore in the long-term results were investigated. Patients who underwent non-HCC liver resection, those who died in early postoperative period, patients who went out of follow-up and patients who underwent R1-R2 resection were excluded from the study. Results: Thirty-one patients were included in the study. The mean age was 65.52±10.87 years. The median tumor size was 5 cm (2-17). The median hospital stay was 4 (1-25) days. Kaplan-Meier mean recurrence time was 32.17 (standard error = 4.67) months. In the univariate analysis, surgical margin of < 1 mm was the only factor affecting recurrence (p = 0.001). Resection margin (p = 0.002) and lymph node involvement (p = 0.019) were found to be significant for overall survival. Preoperative ALBI grade was found to be significant in terms of recurrence (p = 0.026) (HR = 3.414 (95% confidence interval: 1.154-10.097)). Conclusion: Preoperative ALBI grade is more significant compared to postoperative ALBI grade in postoperative recurrence. At the same time, surgical margin's being < 1 mm is the only negative prognostic factor in terms of recurrence and overall survival.Table 1Characteristics of patientsCharacteristicsNGender (M / F)27 / 4Tumor Size < 5 cm ≥ 5 cm14 / 17Etiology HBV / HCV / Other15 /4 /12Surgery Major resection / minor resection11/ 20Preoperative ALBI grade Grade 1/Grade 2 /Grade 318/12 /1Postoperative ALBI grade Grade 1/Grade 2 /Grade 32/ 21 / 7Resection margin < 1 mm, ≥ 1- 5 mm, > 5- 10mm, > 10 mm8/ 15/ 5 /3 Open table in a new tab

Prognostic Correlation of an Autophagy-Related Gene Signature in Patients with Head and Neck Squamous Cell Carcinoma.

Considerable evidence indicates that autophagy plays a vital role in the biological processes of various cancers. The aim of this study is to evaluate the prognostic value of autophagy-related genes in patients with head and neck squamous cell carcinoma (HNSCC). Transcriptome expression profiles and clinical data acquired from The Cancer Genome Atlas (TCGA) database were analyzed by Cox proportional hazards model and Kaplan–Meier survival analysis to screen autophagy-related prognostic genes that were significantly correlated with HNSCC patients' overall survival. Functional enrichment analyses were performed to explore biological functions of differentially expressed autophagy-related genes (ARGs) identified in HNSCC patients. Six ARGs (EGFR, HSPB8, PRKN, CDKN2A, FADD, and ITGA3) identified with significantly prognostic values for HNSCC were used to construct a risk signature that could stratify patients into the high-risk and low-risk groups. This signature demonstrated great value in predicting prognosis for HNSCC patients and was indicated as an independent prognostic factor in terms of clinicopathological characteristics (sex, age, clinical stage, histological grade, anatomic subdivision, alcohol history, smoking status, HPV status, and mutational status of the samples). The prognostic signature was also validated by data from the Gene Expression Omnibus (GEO) database and International Cancer Genome Consortium (ICGC). In conclusion, this study provides a novel autophagy-related gene signature for predicting prognosis of HNSCC patients and gives molecular insights of autophagy in HNSCC.

The Prognostic Power of Gene Expression Profiling with Cytogentics and Routinely Acquired Serum Markers: SKY92 Combined with Revised ISS

Background Updating prognostic models for multiple myeloma is important in the context of changing treatment options. Previously we have described the value of the prognostic marker SKY92, which identifies high-risk multiple myeloma patients, as well as the value of the combined SKY92-ISS marker. With the introduction of revised ISS, it is of interest to evaluate the value of the updated combination of SKY92 with R-ISS. Within the HOVON87/NMSG18 trial, stratification into 3 groups was described: high-risk: 11% SKY92 high-risk (HR) + R-ISS II-III, low-risk: 15% SKY92 standard risk (SR) + R-ISS I and intermediate risk (74%, other). The 3-year PFS rates were 54% (95%CI: 38-77%), 27% (95%CI: 21-37%) and 7% (95%CI: 1-46%) for SKY-RISS I, II and III, respectively (p &amp;lt; 0.001). The 3-yr OS rates for SKY-RISS I to III were 88%, 66% and 26% (p=6×10-7). Here we describe the validation of SKY92-RISS in the CoMMpass dataset. Methods SKY92 was determined using RNA-seq data available from the CoMMpass dataset. Briefly, the SKY92 score was obtained as a weighted summation of the expression given by the available Ensembl gene IDs, corresponding to the probe sets of the SKY92 classifier. Renormalization of the original SKY92 discovery data (HOVON65/GMMG-HD4) allowing a direct remodeling between the Affymetrix probe-set expressions (i.e. SKY92) and RNAseq Ensembl gene IDs. Only Ensembl gene IDs with an average log2 expression &amp;gt;8 were used. Revised ISS status was determined as described. For optimal comparison to the discovery cohort of the HOVON87/NMSG18 trial, the analysis was limited to 93 patients older than 65 years in the CoMMpass data set, that did not receive transplant, and for whom RNA-Seq at diagnosis, R-ISS and follow-up data were available. Results The median follow-up is 41 months. SKY92 identified 24 high-risk patients (24/93: 26%). The 3-yr PFS and OS rates of standard-risk patients were 49% and 80% respectively, compared to 23% and 44% for high-risk, resulting in a significant log rank test (p &amp;lt; 0.005). The R-ISS classified patients into the low-risk R-ISS I (24% of patients), intermediate-risk R-ISS II (63%) and high-risk R-ISS III (13%). The 3-yr PFS rates were 76% (RISS I), 33% (RISS II) and 33% (RISS III); for OS: 100% (RISS I), 68% (RISS II) and 33% (RISS III; PFS, p = 0.07; OS, p &amp;lt; 0.001). SKY92 and R-ISS were independent prognostic factors in terms of OS and PFS. The SKY-RISS classification resulted in 20% low-, 61% intermediate- and 18% high-risk patients (Figure 1). The 3-yr PFS rates were 81% (95%CI: 64-100%), 42% (95%CI: 30-59%) and 12% (95%CI: 3-44%; p &amp;lt; 0.001) and 3-yr OS rates were 100% (95%CI: 100-100%), 77% (95%CI: 66-89%) and 32% (95%CI: 16-61%; p &amp;lt;0.001). Out of 69 patients classed as standard risk using the SKY92 classifier (80% 3-yr OS rate), 17 and 52 were classified as SKY-RISS I and II, respectively, resulting in a 3-yr survival rate of 100% and 74%, respectively. In contrast, out of 24 SKY92 HR patients (44% 3 yr OS rate), 5 were classified as SKY-RISS II (100% alive at 3 years) with the remainder true high-risk patients (32% alive at 3 years). Out of 12 RISS III patients (3-yr OS, 33%), 5 were classified as SKY-RISS II (3-yr OS: 60%) and 7 as SKY-RISS III (3-yr OS: 14%). Conclusion This study demonstrates the value of gene expression profiling - SKY92 - alongside revised ISS. They form a solid combination, improving on either marker separately. Both models combined clearly identified more high-risk patients correctly, whilst also placing low risk patients into a more appropriate risk category. This was shown in the discovery set and was subsequently applied to an independent set, confirming the validity and usability of the SKY-RISS. Disclosures Kuiper: SkylineDx: Current Employment, Current equity holder in private company. Van Vliet:SkylineDx: Current Employment, Current equity holder in private company. Van Beers:SkylineDx: Ended employment in the past 24 months. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

NF-kappa B Signaling-Related Signatures Are Connected with the Mesenchymal Phenotype of Circulating Tumor Cells in Non-Metastatic Breast Cancer.

The role of circulating tumor cells (CTCs), tumor microenvironment (TME), and the immune system in the formation of metastasis is evident, yet the details of their interactions remain unknown. This study aimed at exploring the immunotranscriptome of primary tumors associated with the status of CTCs in breast cancer (BCa) patients. The expression of 730 immune-related genes in formalin-fixed paraffin-embedded samples was analyzed using the multigenomic NanoString technology and correlated with the presence and the phenotype of CTCs. Upregulation of 37 genes and downregulation of 1 gene were observed in patients characterized by a mesenchymal phenotype of CTCs when compared to patients with epithelial CTCs. The upregulated genes were involved in NF-kappa B signaling and in the production of type I interferons. The clinical significance of the differentially expressed genes was evaluated using The Cancer Genome Atlas (TCGA) data of a breast invasive carcinoma (BRCA) cohort. Five of the upregulated genes—PSMD7, C2, IFNAR1, CD84, and CYLD—were independent prognostic factors in terms of overall and disease-free survival. To conclude, our data identify a group of genes that are upregulated in BCa patients with mesenchymal CTCs and reveal their prognostic potential, thus indicating that they merit further investigation.

Impact of Early Immune Reconstitution after Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction:Immune reconstitution (IR) has a significant impact in HSCT outcome with a role against opportunistic infections and in disease control. In the setting of unmanipulated haploidentical transplantation (Haplo-HSCT), some groups have identified the absolute leukocyte count on day +30 (ALC30) as an independent prognostic factor in terms of overall survival (OS), disease free survival (DFS) and infection related mortality (IM).The aim of this study was to evaluate the impact of early IR on different HSCT outcomes in patients who underwent Haplo-HSCT with postransplant cyclophosphamide (PTCy) at our institution.Patients and methods:Eighty-eight patients received a Haplo-HSCT from 2011 to 2016. Thirty-six percent of the patients received myeloablative conditioning regimen and 64% received reduced intensity regimen. Graft-versus-host disease (GVHD) prophylaxis was based on PTCy, cyclosporine and mycophenolate mofetil. Early IR was assessed through the analysis of different lymphocyte subpopulations at days +30 and +90 after transplantation, including ALC30 (cellular analyzer DXH, Beckman Coulter®); CD3+ lymphocyte count and their different subpopulations (CD4+ and CD8+ lymphocytes, naive and memory T cells) and NK cells count. Lymphocytes subpopulations were determined by multiparametric flow cytometry (FC500 and Navios, Beckman Coulter®). ROC curves were used to determine the optimal cut-off values for each of the studied variables.Results:Eighty-one patients were studied, excluding 7 who died before day +30. Median follow-up was 26 months (10-43). Patient´s characteristics are shown in Table 1.CMV reactivation was documented in 76% (62) of the patients, 4% (3) developed a proven invasive fungal infection, and 31% (25) presented hemorrhagic cystitis. Median OS and DFS were 26 months (10-43) and 24 months (9-39), respectively. IM rate and NRM rate were 10% and 24%, respectively, at the end of follow up.Median lymphocyte populations counts at day +30 are shown in Table2.ALC30 below 100 cells/uL (p= 0.027) and CD4+ naïve lymphocytes below 12 cells/uL (p=0.033) (both corresponding to the 25 percentile) were associated with lower OS compared to patients with higher counts at day +30 (Figure 1).Patients with ALC30 lower than 300 cells/uL (p=0.026) showed significantly higher NRM; CD8+ count lower than 20 cells/uL (p=0.022) also showed higher NRM.NK cells counts at day +30 lower than 14 cells/uL (p=0.014), near to percentile 25, predicted higher IM (62.5% vs 37.5%).We did not identify any lymphocyte subpopulation that could predict DFS. Patients with acute GVHD grades II-IV showed values of ALC30 lower than 200 cells/uL (p=0.051), although non-statistically significant. No relationship was found between lymphocytes subpopulations at day +90 and HaploSCT outcomes.Conclusions:Our study supports the prognostic significance of early IR after unmanipulated haploidentical transplantation with PTCy, as previously described by other groups. ALC30, CD4+ naïve lymphocytes, and CD8+ lymphocyte count at day +30 may be good early predictors for OS and NRM in this setting. On the other hand, low NK cells counts (lower than percentile 25) predicted higher IM. Patients with very low lymphocyte counts should be monitored closely as they are at high risk for infectious complications, NRM and OS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Circulatory YKL-40 & NLR: Underestimated Prognostic Indicators in Diffuse Glioma.

In addition to histopathological parameters, evaluation of associated hematological factors is essential for devising a sensitive prognostic scale in glioma. Increased neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammatory response, has recently been associated with worse outcome in various cancers. Given that glioma progression is characterized by inflammation, aggressive angiogenesis, and invasion, increased levels of systemic human-chitinase-3-like-one protein (YKL-40) have also been linked to poor prognosis. The aim of the present study was to assess the plausible association of YKL-40, NLR, and platelet count with increasing tumor grade, and evaluate their status as independent prognostic factors in terms of overall survival (OS) in treatment naive patients with diffuse glioma. Plasma levels of both biochemical markers in 72 diffuse gliomas, median age 42 years, were compared with 36 controls. Comparison of YKL-40, NLR, and PC with respect to tumor grade was found to be significant for each of the markers (P <0.0001) while an inverse significant correlation was seen for YKL-40 and NLR with OS (r = -0.4619, P <0.0001, and r = -0.5561, P < 0.0001, respectively). NLR was the best performing marker with AUC 0.9417 at 97% specificity. In addition, YKL-40 had a positive correlation with NLR (r = 0.4902, P <0.0001), indicating that expression of both markers was linked to inflammation and tumor progression as they were significantly correlated with tumor grade. Expression of YKL-40 and NLR was independently associated with worse survival (HR 1.0062, P = 0.039, and HR 1.1787, P = 0.0003, respectively), thus establishing their clinical utility as prognosticators for diffuse gliomas.

Identification of a prognostic molecular signature composed of 3 genes involved in immunity in muscle-invasive bladder cancer.

e16029 Background: Immunotherapy in bladder cancer appears to be promising. The aim of this study was to evaluate the involvement of 33 genes of anti-tumor immunity in a wide range of muscle-invasive bladder cancers (MIBC) and to identify new prognostic markers. Methods: The levels of expression of 33 genes involved in anti-tumor immunity were analyzed by real-time quantitative RT-PCR on a consecutive series of 83 TVIM and 15 normal bladder samples. Tissue samples were taken on a cystectomy patch in patients operated between 2002 and 2006. All patients have signed informed consent. The results of the transcriptomic analysis were confirmed by immunohistochemistry and coupled with survival analysis. Results: Of the 33 genes studied, 24 (72.7%) were significantly overexpressed compared to normal bladder tissue. In univariate analysis, overexpression of OX40L was significantly associated with a pejorative prognosis in terms of recurrence-free survival and overall survival (p = 0.0027 and p = 0.014 respectively) while overexpression of CD8 was associated with a better prognosis (p = 0.024 and p = 0.029 respectively). A clustering analysis allowed us to identify a molecular signature composed of 3 genes ( OX40L, CD8 and TIGIT) allowing to separate the tumors into 3 distinct prognostic subgroups. In a multivariate analysis including all clinico-pathological and molecular factors significant in univariate, molecular signature was an independent prognostic factor in terms of recurrence-free survival and overall survival (p = 0.0007 and p = 0.007 respectively). Conclusions: We identified several genes involved in the immune response during bladder urothelial carcinogenesis, as well as a molecular signature composed of 3 genes ( OX40L, CD8 and TIGIT) associated with MIBC prognosis, suggesting a potential interest in Individual step.

Impact of preoperative thrombocytosis on prognosis after surgical treatment in pathological T1 and T2 renal cell carcinoma: results of a multi-institutional comprehensive study.

BackgroundThe prognostic significance of preoperative thrombocytosis (TC) in renal cell carcinoma (RCC) is not without some debate. The aim of the present multi-institutional study was to determine the association of preoperative TC with the clinicopathological features and prognosis of localized RCC patients who underwent surgery in a large cohort.MethodsA study involving 8 institutions, and 4,376 patients with pT1 and pT2 RCC from the Korean renal cell carcinoma (KORCC) database, was conducted. TC was defined as a platelet count ≥400,000/μL. Patients were divided into 2 groups based on the presence of preoperative TC. Clinicopathological variables and survival rates were compared between the 2 groups.ResultsOut of the 4,376 patients in the study, 106 (2.4%) had preoperative TC. Compared to patients without TC, these patients had a lower body mass index. Additionally, these patients had more advanced stage tumors with a higher Fuhrman grade, and higher incidence of symptoms at the time of diagnosis. Kaplan-Meier curves revealed that patients with TC had a significantly lower rate of recurrence-free survival (RFS). Furthermore, a lower rate of overall survival (OS) was exhibited amongst patients with TC. Multivariate analysis revealed that TC was an independent prognostic factor in terms of the RFS and OS.ConclusionsTC appeared to be an important prognostic determinant in localized RCC. Furthermore, preoperative platelet count may be clinically useful for risk stratification of patients with surgically treated localized RCC.

Immune Reconstitution Impact on Overall Survival after Hematopoietic Haploidentical Stem Cell Transplantation

Introduction:Early immune reconstitution (EIR) is clinically relevant for the outcome of allogeneic hematopoietic stem cell transplantation. In the setting of unmanipulated haploidentical transplantation (Haplo-HSCT), some groups have identified the absolute leukocyte count on day +30 (ALC30) as an independent prognostic factor in terms of overall survival (OS), disease free survival (DFS) and infectious mortality (IM).The aim of this study was to evaluate the impact of EIR on OS, DFS and IM among patients who underwent Haplo-HSCT with postransplant cyclophosphamide (PTCy) at our institution.Patients and methods:Sixty-six patients received a Haplo-HSCT at our institution from July 2011 to February 2016. Conditioning regimen consisted of fludarabine, cyclophosphamide and busulfan. Forty-five percent of the patients received a myeloablative regimen, including busulfan for 3 or 4 days, while 55% were conditioned using a reduced intensity regimen with 1 or 2 days of busulfan. Graft-versus-host disease (GVHD) prophylaxis was based on PTCy, cyclosporine and mycophenolate mofetil.EIR was assessed by means of ALC30 (cellular analyzer DXH, Beckman Coulter®), CD3+ lymphocyte count on day +30 (CD3-30) and NK-lymphocyte count on day +30 (NK30), both determined by multiparametric flow cytometry (FC500 and Navios, Beckman Coulter®).The Kaplan-Meier method was used to evaluate OS rate and DFS rate. Differences in survival rate were assessed using the log-rank test. P values <0.05 were considered statistically significant.Results:We analyzed 66 patients, with a median follow-up of 17 months (8-31). The median age of the patients was 43 years (range 30-57), 77% were men. The diagnosis were: acute myeloid leukemia 33%, acute lymphoid leukemia 8%, chronic myeloid leukemia 6%, Hodgkin lymphoma 21%, non-Hodgkin lymphoma 17%, myelodysplastic syndrome 8%, myelofibrosis (MF) 4%, others 3%. Most patients were in complete remission at the time of the transplant (56%), while 21% were in partial remission and 23% with overt disease.CMV reactivation was documented in 74% of the patients, 8% developed a proven invasive fungal infection and 36% suffered from hemorrhagic cystitis. Median OS and DFS were 17 (8-31) and 13 months (7-26), respectively. IM rate was 27% at the end of follow up.ROC curves were used to determine the optimal cut-off values for each of the studied variables: 300 cells/µL for ALC30, 120 cells/µL for CD3-30 and 40 cells/µL for NK30 were chosen.Those patients with an ALC30 ≥ 300/µL had longer OS (p=0.001) and DFS (p=0.005). Median OS and DFS were 25 months vs. not reached (NR) and 13 months vs. NR respectively.Patients with CD3-30 ≥120/µL had better OS (p=0.07, non-significant) and similar DFS than those with CD3-30 <120/µL. No differences were observed for the NK30 in terms of OS and DFS. Cumulative incidence of IM was significantly lower in patients with an ALC30≥300 (p=0.001). Cumulative incidence of relapse was not affected by ALC30. Patients with CD3-30>120/µL had a lower incidence of relapse than patients with CD3-30<120/µL (p=0.06, non-significant).Conclusions:Our study supports the independent prognostic significance of early immune reconstitution after unmanipulated haploidentical transplantation with postransplant cyclophosphamide, previously described by other groups. Patients with an ALC30 count over 300 cells/µL have a statistically significant better overall survival, disease free survival and a lower cumulative incidence of infectious mortality. However, ALC30 seems to have no correlation with relapse rate. CD3+ and NK-cell total counts on day 30 seem to have less prognostic impact, according to our study. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical outcome and prognostic factors of patients with early-stage epithelial ovarian cancer.

Some subsets of early stage ovarian cancer patients experience more recurrences than others. Studies on prognostics factors gave conflicting results. We investigated consecutive 221 patients with stage I/II ovarian cancer at our institution from 1999 to 2010. Univariate and multivariate analysis of progression free survival (PFS) and overall survival (OS) were performed. After a median follow-up of 79 months, the 5-year/10-year PFS and 5-year/10-year OS were 78% /76% and 90% /87% respectively. Multivariate analysis revealed that stage as the most prominent independent prognostic factor in terms of PFS (stage I vs stage IIA vs stage IIB, Hazard Ratio (HR): 1 vs 4 vs 6.1, P < 0.05) and OS (stage I vs stage II, HR: 1 vs 2.1, P < 0.05). Peritoneal biopsy reduced the risk of recurrence by 29% (95% CI: 0.15-0.58, P < 0.05). Ascites (HR = 2.8, 95% CI: 1.2-6.6, P < 0.05) and not the first-line chemotherapy (HR = 2.6, 95% CI: 1.1-6.5, P < 0.05) contributed to decreased OS. Overall, early-stage ovarian cancer had a favorable outcome, stage was the most powerful prognostic factor.

Abstract P4-09-01: FGFR1 protein expression is associated with prognosis in primary breast cancer: A comprehensive analysis of gene copy number, mRNA and protein expression

Abstract Background: The Cancer Genome Atlas (TCGA) showed that copy number gain/amplification of FGFR1 was around 10% in primary breast cancer. FGFR1 gene amplification in breast cancer has been reported in some studies, more likely seen in ER-positive subtype. Several preclinical and clinical studies demonstrated that FGFR1 was one of novel targets of therapy for metastatic breast cancer. Previous studies suggested that aberrant FGFR1 expression was associated with poor prognosis, while there was no report that compared copy number aberration, mRNA and protein expression. The aim of this study is to analyze FGFR1 gene copy number, expression levels of FGFR1 mRNA and FGFR1 protein in ER-positive/HER2-negative primary breast cancer, and to examine the relationship between FGFR1 status and clinicopathological parameters including prognosis. Methods: The cohort of this study included 307 ER-positive/HER2-negative primary invasive breast cancer patients treated with standard care at Kumamoto University Hospital between June 2000 and January 2011. We performed a comprehensive analysis of FGFR1 at the levels of gene copy number, mRNA and FGFR1 protein expression analyzed by qPCR, qRT-PCR and immunohistochemistry, respectively. Results: FGFR1 gain/amplification was identified in 43 (14.0%) out of 307 patients. FGFR1 gain/amplification had significantly associated with higher nuclear grade (p=0.010). No correlations between FGFR1 mRNA expression levels and any clinicopathological factors were found. Expression levels of FGFR1 protein was positively associated with invasive tumor size (p=0.039). Modest positive correlations between these three (FGFR1 gene gain/amplification, expression levels of FGFR1 mRNA and FGFR1 protein) were found. The univariate analysis revealed that high FGFR1 protein expression was significantly related to poor prognosis (p=0.0019, HR: 2.63, 95%CI: 1.17-5.98) in terms of relapse-free survival (RFS) but not breast cancer-specific survival. The univariate analysis did not show that any factors except FGFR1 protein expression were significantly associated with RFS in this cohort. Conclusion: Expression levels of FGFR1 protein may be an independent prognostic factor in terms of RFS for ER-positive/HER2-negative breast cancer patients receiving standard care. Citation Format: Tomiguchi M, Yamamoto Y, Yamamoto-Ibusuki M, Yamaguchi R, Fujiki Y, Fujiwara S, Sueta A, Takeshita T, Inao T, Iwase H. FGFR1 protein expression is associated with prognosis in primary breast cancer: A comprehensive analysis of gene copy number, mRNA and protein expression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-01.

Clinical Significance of CA125 Level after the First Cycle of Chemotherapy on Survival of Patients with Advanced Ovarian Cancer.

PurposeTo determine the most powerful cancer antigen 125 (CA125)-related prognostic factor for advanced epithelial ovarian cancer (EOC) and to identify cut-off values that distinguish patients with a poor prognosis from those with a good prognosis.Materials and MethodsWe included 223 patients who received staging laparotomy and were diagnosed with stage IIC–IV serous EOC. Cox regression analysis was used to determine the most significant prognostic factor among the following variables: serum CA125 before surgery and after the first, second, and sixth cycles of chemotherapy; the nadir CA125 value; the relative percentage change in CA125 levels after the first and second cycles of chemotherapy compared to baseline CA125; CA125 half-life; time to nadir; and time to normalization of the CA125 level.ResultsThe CA125 level after the first chemotherapy cycle was the most significant independent prognostic factor for overall survival (OS). Time to normalization (p=0.028) and relative percentage change between CA125 levels at baseline and after the first chemotherapy cycle (p=0.021) were additional independent prognostic factors in terms of OS. The CA125 level after the first chemotherapy cycle (p=0.001) and time to normalization (p<0.001) were identified as independent prognostic factors for progression free survival (PFS).ConclusionAmong well-established CA125-related prognostic factors, serum CA125 levels after the first cycle of chemotherapy and time to normalization were the most significant prognostic factors for both OS and PFS.