Intermediate Prognostic Groups Research Articles

Identification of prognostic and driver gene mutations in acute myeloid leukemia by a bioinformatics analysis.

The representative gene mutation in the prognostic groups of acute myeloid leukemia (AML) patients is not yet known. The purpose of this study is to identify representative mutations that can help physicians better predict patient prognosis and thus develop better treatment plans. The Cancer Genome Atlas (TCGA) database was queried for clinical and genetic information, and individuals with AML were classified into 3 groups based on their AML Cancer and Leukemia Group B (CALGB) cytogenetic risk category. Each group's differentially mutated genes (DMGs) were evaluated. Simultaneously, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to assess the function of DMGs within the 3 distinct groups. We used the driver status and protein impact of DMGs as additional filters to narrow down the list of significant genes. Cox regression analysis was used to examine the survival features of gene mutations in these genes. A cohort of 197 AML patients were divided into 3 groups according to their prognostic subtype: favorable (n=38), intermediate (n=116) and poor (n=43). There were significant differences in age and tumor metastasis rates among the three groups of patients. Patients in the favorable group had the highest rate of tumor metastasis. Different prognosis groups' DMGs were detected. The DMGs were examined for the driver and harmful mutations. We considered the DMGs that had driver and harmful mutations and that affected the survival outcomes in the prognostic groups as the key gene mutations. The group with a favorable prognosis carried specific gene mutations for KIT and WT1. The intermediate prognostic group contained mutations in the genes IDH2, NRAS, NPM1, FLT3, RUNX1, DNMT1A, and MUC16. In the group with a poor prognosis, the representative genes were KRAS, TP53, IDH1, IDH2, and DNMT3A, with TP53 mutations substantially correlated with overall patient survival. We performed the systemic analysis of the gene mutation in patients with AML and identified representative and driver mutations between the prognostic group. identification of representative and driver mutations between the prognostic group can help predict the prognosis of patients with AML and guide treatment decisions.

Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

Simple SummaryEndometrial cancer is the most common gynaecological malignancy in developed countries. Most cases are diagnosed at a localized stage, overall with a good prognosis, although approximately 15% of them will recur. The identification of patients with an increased risk of relapse remains a challenge for clinicians. There are well-defined clinicopathological characteristics associated with prognosis. These variables have been integrated in multiple classifiers to stratify the prognosis, and more recently, molecular features have also been considered. The aim of our retrospective study was to compare the three available prognostic stratification tools for endometrial cancer and determine if additional biomarkers could improve their accuracy. We confirmed that the incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which was improved even further with the addition of CTNNB1 mutational evaluation.There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers could be used to improve the prognosis stratification in early-stage endometrial cancer. Relapse-free and overall survival of each classifier were analyzed, and the c-index was employed to assess accuracy. Other biomarkers were explored to improve the precision of risk classifiers. We analyzed 293 patients. A comparison between the three classifiers showed an improved accuracy in ESGO-ESTRO-ESP 2020 when RFS was evaluated (c-index = 0.78), although we did not find broad differences between intermediate prognostic groups. Prognosis of these patients was better stratified with the incorporation of CTNNB1 status to the 2020 classifier (c-index 0.81), with statistically significant and clinically relevant differences in 5-year RFS: 93.9% for low risk, 79.1% for intermediate merged group/CTNNB1 wild type, and 42.7% for high risk (including patients with CTNNB1 mutation). The incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which could be improved even further with the addition of CTNNB1 mutational evaluation.

Bayesian variable selection for high-dimensional data with an ordinal response: identifying genes associated with prognostic risk group in acute myeloid leukemia

BackgroundAcute myeloid leukemia (AML) is a heterogeneous cancer of the blood, though specific recurring cytogenetic abnormalities in AML are strongly associated with attaining complete response after induction chemotherapy, remission duration, and survival. Therefore recurring cytogenetic abnormalities have been used to segregate patients into favorable, intermediate, and adverse prognostic risk groups. However, it is unclear how expression of genes is associated with these prognostic risk groups. We postulate that expression of genes monotonically associated with these prognostic risk groups may yield important insights into leukemogenesis. Therefore, in this paper we propose penalized Bayesian ordinal response models to predict prognostic risk group using gene expression data. We consider a double exponential prior, a spike-and-slab normal prior, a spike-and-slab double exponential prior, and a regression-based approach with variable inclusion indicators for modeling our high-dimensional ordinal response, prognostic risk group, and identify genes through hypothesis tests using Bayes factor.ResultsGene expression was ascertained using Affymetrix HG-U133Plus2.0 GeneChips for 97 favorable, 259 intermediate, and 97 adverse risk AML patients. When applying our penalized Bayesian ordinal response models, genes identified for model inclusion were consistent among the four different models. Additionally, the genes included in the models were biologically plausible, as most have been previously associated with either AML or other types of cancer.ConclusionThese findings demonstrate that our proposed penalized Bayesian ordinal response models are useful for performing variable selection for high-dimensional genomic data and have the potential to identify genes relevantly associated with an ordinal phenotype.

Real-world prognostic model for malignant pleural mesothelioma.

e20562 Background: Two mesothelioma prognostic models have been suggested: European Organisation for Research and Treatment of Cancer (EORTC) and Cancer and Leukaemia Group B (CALGB) models. Both were based on clinical trial patients enrolled in the mid-1980s to early-1990s. Several changes to mesothelioma management have been adopted since publication of these models, including improved surgical and palliative interventions and changes to systemic therapy. Methods: With ethics approval, we collected and analyzed the health data of malignant pleural mesothelioma (MPM) patients with histologically confirmed diagnosis treated at our institution between January 1991 and March 2019. The primary endpoint was overall survival (OS). Univariate analysis was used to identify significant predictors of survival, which were then used to construct a multivariate survival tree with complete case-analysis and bootstrapping. Patients were then stratified into three prognostic groups based on their median OS. Results: 337 patients were included in the study; 309 (91.7%) were dead at last follow-up. The median OS was 9.4 (8.1-11.5) months for the entire population. Eastern Cooperative Oncology Group (ECOG) performance status (PS), histology, white blood count, platelets, International Mesothelioma Interest Group stage, age and hemoglobin were independent predictors of survival. The final pruned survival tree was based on 285 patients and incorporated the first five predictors. Good, intermediate and poor prognostic groups had median OS of > 12 months, 6-12 months, and < 6 months, respectively. Factors associated with the prognostic groups were: good prognosis: ECOG 0-1, normal platelets, stage 1, 2 and epithelioid histology; intermediate prognosis: ECOG 0-1 with either stage 3, 4 and/or sarcomatoid or biphasic histology; poor prognosis: ECOG 2-4 regardless of other factors. Conclusions: In contrast to EORTC/CALGB, real world evidence generates these prognostic groups with face validity but will need independent validation. Our data does not account for recent advances including immunotherapy, and thus patients with non-epithelioid histology may have better survival than predicted.[Table: see text]

An FDA-pooled analysis of frontline combination treatment benefits by risk groups in metastatic renal cell carcinoma (mRCC).

4559 Background: The International Metastatic RCC Database Consortium (IMDC) risk model was developed for prognosis of patients with mRCC treated with vascular endothelial growth factor (VEGF)-targeted monotherapy in the first-line setting. Efficacy in trials of anti-VEGF therapy has been generally consistent across risk groups, including for overall survival (OS). For trials of immunotherapy combinations, the small numbers of OS events for the favorable risk group in each trial limited reliable conclusions; however, there was a suggestion of possible differential effects on OS between favorable risk and other risk groups. Methods: We pooled individual patient data (n=3447) from four phase III randomized trials of combinations of immunotherapy + immunotherapy (n=1) or immunotherapy + anti-VEGF therapy (n=3) submitted to the US Food and Drug Administration in support of marketing applications. All trials calculated IMDC risk group for each patient and used a control arm of sunitinib. We combined intermediate and poor prognostic groups (“intermediate/poor”) and compared their OS to that of the favorable risk group using Kaplan-Meier and Cox Proportional Hazards methods. Results: In this pooled analysis, treatment with combination immune checkpoint therapy did not demonstrate an improvement in OS compared to sunitinib in the favorable risk group (HR 0.953; 95% CI: 0.72, 1.27). An improvement in OS was observed in the intermediate/poor risk group (HR 0.696; 95% CI: 0.62, 0.78). Conclusions: Our analysis of OS in patients treated with immunotherapy combinations compared to sunitinib suggests possible differential benefit in the favorable risk compared to the intermediate/poor risk group. These results are not conclusive and considered exploratory due to the relative immaturity of OS in the favorable risk group. Follow-up for survival continues in each study to allow for more definitive results.[Table: see text]

Nivolumab as second-line treatment and beyond for metastatic renal cell carcinoma: A real-life experience from Turkish Oncology Group Kidney Cancer Consortium (TKCC) Database.

321 Background: Immune checkpoint inhibitors (ICIs) started a new era in the treatment of metastatic renal cell carcinoma (mRCC). CheckMate-025 and CheckMate-214 trials established the effect of ICIs in the second-line and upfront therapy of mRCC, respectively. This study aimed to share a real-life experience regarding nivolumab in the second-line treatment and beyond in mRCC Methods: We retrospectively searched the Turkish Oncology Group Kidney Cancer Consortium (TKCC) database, which is the multicenter registry system, and extracted patients treated with nivolumab in the second line and beyond. The patients treated with nivolumab plus targeted therapy or ipilimumab were excluded. The primary endpoint was overall survival (OS). The secondary endpoints were response rates and safety. Results: A total of 134 patients were included in this study. The median age at the starting of nivolumab treatment was 61 years (Inter Quartile Range (IQR):55-67). Three out of four patients were male. One hundred four patients (78%) had previous nephrectomy. The majority of patients had clear-cell pathology (83%). Thirteen patients (10%) had sarcomatoid features. According to International Metastatic RCC Database Consortium (IMDC) risk score, seventy patients (52%) were in the intermediate and poor prognostic group. The previous drugs administered in each line before nivolumab are shown in the table below. The number of patients treated with nivolumab was 63(47%), 45(33%), 17(13%), and 9(7%) in the second-, third-, fourth-, and fifth-line setting, respectively. The median OS was 34 months (95% Confidence Interval (CI): 24.1-43.8)) with the 15 months (IQR:5-26) median follow-up. Objective response rate (ORR) and disease control rate (DCR) was 33% and 57%, respectively. The most common grade 3 or higher AEs leading to treatment discontinuation were pneumonitis (%1.4) and colitis (<%1). Conclusions: In compliance with the CheckMate-025 trial results, nivolumab improved OS for mRCC patients treated in the second line and beyond. The median OS was slightly higher in our study than the CheckMate-025 (34 months versus 25.8 months). It may be associated with the patient population in our study. Patients up to the fifth-line setting of mRCC treatment were included in this study. Of note, there was no additional safety concern for nivolumab. [Table: see text]

Low Expression of miR-375 and miR-190b Differentiates Grade 3 Patients with Endometrial Cancer.

Endometrial cancer (EC) is treated according to the stage and prognostic risk factors. Most EC patients are in the early stages and they are treated surgically. However some of them, including those with high grade (grade 3) are in the intermediate and high intermediate prognostic risk groups and may require adjuvant therapy. The goal of the study was to find differences between grades based on an miRNA gene expression profile. Tumor samples from 24 patients with grade 1 (n = 10), 2 (n = 7), and 3 (n = 7) EC were subjected to miRNA profiling using next generation sequencing. The results obtained were validated using the miRNA profile of 407 EC tumors from the external Cancer Genome Atlas (TCGA) cohort. We obtained sets of differentially expressed (DE) miRNAs with the largest amount between G2 to G1 (50 transcripts) and G3 to G1 (40 transcripts) patients. Validation of our results with external data (TCGA) gave us a reasonable gene overlap of which we selected two miRNAs (miR-375 and miR190b) that distinguish the high grade best from the low grade EC. Unsupervised clustering showed a high degree of heterogeneity within grade 2 samples. MiR-375 as well as 190b might be useful to create grading verification test for high grade EC. One of the possible mechanisms that is responsible for the high grade is modulation by virus of host morphology or physiology.

Prognostic impact of tumor budding in endometrial carcinoma within distinct molecular subgroups

Tumor budding is a robust prognostic parameter in several tumor entities but is rarely investigated in endometrial carcinoma. We applied the recently standardized counting method from the International Tumor Budding Consensus Conference for colorectal cancer (ITBCC) on a cohort of 255 endometrial carcinomas with known molecular profiles according to The Cancer Genome Atlas (TCGA) subgroups. Our investigation aims to clarify the potential prognostic role of tumor budding in endometrial carcinoma in contrast to other known prognostic factors, including molecular factors. In addition, the microcystic elongated and fragmented (MELF) pattern and tumor budding were compared with respect to their potential as markers for epithelial–mesenchymal transition (EMT). Tumor budding was found in n = 67 (26.3%) tumors, with a very low mean of 0.7 buds per ×20 HE field. Tumor budding was significantly associated with depth of invasion, nodal status, lymphatic invasion (each p < 0.001), grading (p = 0.004), and vascular invasion (p = 0.01). Tumor budding showed moderate inter-observer-variability with prognostic stratification irrespective of the observer (κ-value = 0.448). In multivariate analysis, tumor budding served as a significant independent prognosticator for worse outcomes in overall and recurrence-free survival (HR 2.376 and 2.736, p < 0.001), but not when the TCGA subgroups entered into the analysis. In consequence, dependency had to be clarified in the subgroup analysis for Polymerase E mutated (POLEmut), mismatch repair deficient (MMRdef), nonspecific mutation profile (NSMP), and P53 aberrant (P53abn) endometrial carcinomas. A particular impact was identified in the intermediate prognostic groups of NSMP and MMRdef carcinomas. Tumor budding outperformed the MELF pattern in single and combined prognostic information. In conclusion, the presence of tumor budding alone is a promising, robust, and easy-to-apply prognostic parameter in endometrial carcinoma. In a morpho-molecular approach, it exerts its prognostic potential in the most clinically relevant subgroups of endometrial carcinoma and serves as a good biomarker for EMT.

Analiza bolesnika s metastatskim rakom bubrega srednje i loše prognostičke skupine liječnih u Kliničkom bolničkom centru Zagreb

Analiza bolesnika s metastatskim rakom bubrega srednje i loše prognostičke skupine liječnih u Kliničkom bolničkom centru Zagreb

Changing paradigm of immunooncology in advanced kidney cancer: nivolumab and ipilimumab combination in the first line therapy

Until now selection of the 1st line therapy for advanced clear-cell renal cell carcinoma was determined by patients distribution into favorable/ intermediate or poor prognosis groups. In the favorable/ intermediate prognostic groups agents of choice included antiangiogenic substances such as bevacizumab (in combination with interferon-alpha), sunitinib, andpazopanib, which had demonstrated only progression-free survival benefit comparing with interferon-alpha in registration studies; in the poor prognosis group the only treatment option was mammalian target of rapamycin inhibitor temsirolimus which had improved overall survival comparing with interferon-alpha. However about 75 % of advanced renal cell carcinoma patients have intermediate or poor prognosis. Only 2 randomized trials investigated systemic therapy in this cohort of patients, CABOSUN and CheckMate 214. The results of the randomized phase III study CheckMate 214 have demonstrated a significant advantage of overall survival and objective response rate in previously untreated patients of intermediate/poor prognostic groups who were randomizedfor combined immunotherapy with nivolumab and ipilimumab comparing with sunitinib independently of PD-L1 expression level. Owing to the achieved data combined immunotherapy became a new standard of the first-line therapy in advanced renal-cell carcinoma patients with intermediate and poor prognosis.

Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer.

Several clinical trials have investigated the prognostic and predictive usefulness of molecular markers. With limited predictive value, molecular markers have mainly been used to identify prognostic subgroups in which the indication for chemotherapy is doubtful and the prognosis is favorable enough for chemotherapy to be avoided. However, limited information is available about which groups of patients may benefit from additional therapy. This study aimed to describe the prognostic effects of Ki-67 in several common subgroups of patients with early breast cancer. This retrospective study analyzed a single-center cohort of 3140 patients with HER2-, hormone receptor-positive breast cancer. Five-year disease-free survival (DFS) rates were calculated for low (< 10%), intermediate (10-19%), and high (≥ 20%) Ki-67 expression levels, as assessed by immunohistochemistry, and for subgroups relative to age, body mass index, disease stage, tumor grade, and (neo-)adjuvant chemotherapy. It was also investigated whether Ki-67 had different effects on DFS in these subgroups. The 5-year DFS rates for patients with low, intermediate, and high levels of Ki-67 expression were 0.90, 0.89, and 0.77, respectively. Ki-67 was able to further differentiate patients with an intermediate prognosis into different prognostic groups relative to common clinical parameters. Patients with stage II breast cancer had 5-year DFS rates of 0.84, 0.88, and 0.79 for low, intermediate, and high levels of Ki-67 expression. Ki-67 had different prognostic effects in subgroups defined by age and tumor grade. Ki-67 may help identify patients in intermediate prognostic groups with an unfavorable prognosis who may benefit from further therapy.

Prognostic Factors for Advanced Pancreatic Cancer Treated with Gemcitabine Plus S-1: Retrospective Analysis and Development of a Prognostic Model.

Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival prediction in patients with APC, treated with GS. Records of 111 patients with newly diagnosed APC who received first-line palliative GS chemotherapy during 2010–2016 in Taiwan were analyzed retrospectively. Univariate and multivariate analyses were performed for the identification of prognostic factors. A prognostic model using prognosticators from the multivariate analysis was developed for survival prediction. The median overall survival (OS) for the cohort was 9.3 months (95% confidence interval [CI], 8.0–10.6). The prognostic model was constructed based on four independent prognosticators: performance status, tumor stage, pre-treatment albumin level, and neutrophil-to-lymphocyte ratio. Patients were categorized by tertiles into good, intermediate, and poor prognostic groups. The median OS values for each of these groups were 21.1 (95% CI, 8.2–33.9), 9.2 (95% CI, 8.3–10.1), and 5.8 months (95% CI, 4.4–7.1; log-rank p < 0.001), respectively. The bootstrapped corrected C-index of this model was 0.80 (95% CI, 0.71–0.89). The developed model was robust and could accurately predict survival in this population, and can assist clinicians and patients in survival discrimination and the determination of appropriate medical care goals. Additional research is needed to externally validate the model’s performance.

Associations d’hormonothérapie et de radiothérapie pour le cancer de prostate

Combination of radiotherapy and androgen deprivation is now considered as the standard of care for patients with a localized prostate cancer but poor prognosis factors. Two groups of randomized trials have led to this recommendation: some have compared radiotherapy alone versus hormonal treatment and radiotherapy: these trials demonstrated, now with a long follow-up, an improvement in 10-year survival for the combined treatment. Three recent trials compared androgen deprivation alone or combined with radiotherapy; a benefit in survival was also demonstrated in favour of the combination. Some questions remained concerning the optimal duration of hormonal treatment, in view of its potential side effects. Patients in the intermediate prognostic groups could receive a short-term androgen deprivation, but those with a high Gleason score must be treated with a long-term hormonal treatment. Modalities of radiotherapy, regarding volumes and dose must also be précised in the next years.

Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification.

PurposeDespite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths.Experimental designThis multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed.ResultsAmong complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group.ConclusionIntegrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.

TARIBO trial: Cytoreductive nephrectomy in metastatic renal cell carcinoma patients treated with targeted agents.

TPS4601 Background: In the cytokine era cytoreductive nephrectomy (CN) has been shown to increase survival in patients (pts) with metastatic renal cell carcinoma (mRCC). Efficacy of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib has been demonstrated. It is unclear if similar survival benefit could be achieved without CN with TKIs since most of pts enrolled into phase III trials had undergone CN. Methods: A total of 270 mRCC pts will be randomized to receiveCN followed by TKIs vs upfront TKIs without CN. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: to compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: i) to compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs; ii) Safety; iii) Exploratory analyses: evaluation of the predictive role of circulating tumor cells count and circulating tumor DNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression. Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; histological diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary tumor in place; up to three different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( &gt; or = 4 metastatic organ sites); disease suitable of metastasectomy ( &lt; 3 lesions confined at one organ site). Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. To date 10/270 pts have been enrolled. Clinical trial information: NCT02535351.

Prognostic Significance of Venous Thromboembolic Events in Disseminated Germ Cell Cancer Patients

Disseminated germ cell cancers are at high risk of developing thromboembolic complications. We evaluated the prognostic value of venous thromboembolic events (VTE) in disseminated germ cell cancer. Patients with germ cell cancer receiving upfront platinum-containing chemotherapy between 2004 and 2014 were pooled from the Spanish Germ Cell Cancer Group (SGCCG) registry and reviewed for the presence of VTE. Results were validated in an independent international group of patients. We used a penalized Cox proportional hazards model including VTE as a time-varying covariate to identify and validate prognostic factors. All statistical tests were two-sided. The SGCCG registry identified 416 patients from 14 referral institutions. With a median follow-up of 49 months, VTEs were observed in 9% of patients (n = 38). Events occurred at diagnosis, during chemotherapy, and after chemotherapy in 2.6%, 5.0%, and 1.4% of patients, respectively. VTE was associated with shorter progression-free survival (PFS; hazard ratio [HR] = 2.29, 95% confidence interval [CI] = 1.18 to 4.47, P = .02) and overall survival (OS; HR = 5.14, 95% CI = 2.22 to 11.88, P < .001). In multivariable analysis, the effect was consistent in the intermediate-risk group, both for PFS (HR = 9.52 95% CI = 2.48 to 36.58, P < .001) and OS (HR = 12.84, 95% CI = 2.01 to 82.02, P = .007). VTE at diagnosis is also an adverse prognostic variable for progression-free survival (HR = 4.64, 95% CI = 2.04 to 10.54, P < .001) and for overall survival (HR = 6.28, 95% CI = 1.68 to 17.10, P= .01). These results were validated in an independent international cohort that included 241 patients from four hospitals. VTE is an independent adverse prognostic factor in disseminated germ cell cancers, in particular for the intermediate prognostic group of the International Germ Cell Cancer Collaborative Group classification. The presence of VTE at diagnosis has also prognostic significance and should be further explored in future prognostic classifications.

Prognostic contribution of mammographic breast density and HER2 overexpression to the Nottingham Prognostic Index in patients with invasive breast cancer

BackgroundTo investigate whether very low mammographic breast density (VLD), HER2, and hormone receptor status holds any prognostic significance within the different prognostic categories of the widely used Nottingham Prognostic Index (NPI). We also aimed to see whether these factors could be incorporated into the NPI in an effort to enhance its performance.MethodsThis study included 270 patients with newly diagnosed invasive breast cancer. Patients with mammographic breast density of <10 % were considered as VLD. In this study, we compared the performance of NPI with and without VLD, HER2, ER and PR. Cox multivariate analysis, time-dependent receiver operating characteristic curve (tdROC), concordance index (c-index) and prediction error (0.632+ bootstrap estimator) were used to derive an updated version of NPI.ResultsBoth mammographic breast density (VLD) (p < 0.001) and HER2 status (p = 0.049) had a clinically significant effect on the disease free survival of patients in the intermediate and high risk groups of the original NPI classification. The incorporation of both factors (VLD and HER2 status) into the NPI provided improved patient outcome stratification by decreasing the percentage of patients in the intermediate prognostic groups, moving a substantial percentage towards the low and high risk prognostic groups.ConclusionsVery low density (VLD) and HER2 positivity were prognostically significant factors independent of the NPI. Furthermore, the incorporation of VLD and HER2 to the NPI served to enhance its accuracy, thus offering a readily available and more accurate method for the evaluation of patient prognosis.

Conditional survival of metastatic renal cell carcinoma patients treated with high-dose interleukin-2.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient’s prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988–2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35–0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10–0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00–9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.

Abstract P5-08-41: Prognostic contribution of mammographic breast density and HER-2 overexpression to the Nottingham prognostic index in patients with invasive breast cancer

Abstract Purpose: To examine the associations between very low mammographic breast density (VLD), HER2, ER and PR status in a more homogenized patient group within matched NPI categories. We also aimed to investigate whether those variables could be added to the NPI to enhance its prognostic and predictive values and better categorize which patients are at higher risk. Materials and methods: A total of 270 patients with invasive breast cancer were included in the final analysis. Patients with mammographic breast density of &amp;lt;10% were considered as VLD. We compared the performance of NPI with and without ER, PR , VLD and/or HER2. Factors first underwent univariate and then multivariate analysis to assess the factors combined until the best fit was obtained. Cox multivariate analysis, time-dependent receiver operating characteristic curve (tdROC), concordance index (c-index) and prediction error (i.e. 0.632+ bootstrap estimator) were used to derive an updated version of NPI. Patients' survival was assessed by the Kaplan-Meier method using a log rank (Mantel-Cox) test. Results: The average NPI value was 4.66 (range 2.12-7.40), the percentage of HER2 positive patients progressively increased from the low to the high prognostic groups of NPI (p&amp;lt;0.001). While MBD, ER and PR status showed no such difference in distribution. Patients showed survival differences in the intermediate and high risk groups of NPI according to VLD and HER2 status (p&amp;lt;0.001 and p=0.02, respectively). Outcome analysis showed that the addition of both factors combined provides improved patient outcome stratification superior to the traditional NPI helping to significantly decrease the percentage of patients in the intermediate patient groups. Conclusion: VLD breasts and HER2 positivity are prognostic factors for breast cancer independent of the NPI. Moreover, their addition to the NPI helps increase its prognostic accuracy and reduces the percentage of patients in the intermediate prognostic group. Citation Format: Masarwah A, Sudah M, Sutela A, Päivi A, Ritva V. Prognostic contribution of mammographic breast density and HER-2 overexpression to the Nottingham prognostic index in patients with invasive breast cancer. [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 P5-08-41.

Conditional survival (CS) of metastatic renal cell carcinoma (mRCC) patients treated with high dose interleukin-2 (HD IL-2).

460 Background: CS is a clinically useful prediction measure that adjusts prognosis of patients on the basis of survival since treatment initiation or therapy duration. CS was recently reported in mRCC patients treated with VEGF targeted therapy in patients stratified by Heng’s criteria. CS has not been reported in mRCC in the context of treatment with HD IL-2. Methods: Patients with histologically confirmed clear cell mRCC treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 were evaluated. Performance status and prognostic risk groups were included. Two-year CS was defined as the probability of surviving an additional 2 years from initiation of HD IL-2 to 18 months after the start of HD IL-2 at 3-month intervals estimated by Kaplan-Meier methodology. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. The median overall survival from HD IL-2 administration was 817 days. Stratification by Heng’s criteria at therapyinitiation resulted in survival estimates for the favorable (n = 13; 15%), intermediate (n = 56; 66%) and poor (n = 16; 19%) prognostic groups of 1616 (p = 0.1993 vs intermediate), 817 (p = 0.0041 vs poor), and 365 (p &lt; 0.0001 vs favorable) days, respectively. Two-year overall CS increased from 56.2% at therapy initiation to 89.5% at 18 months (Table). Two-year CS stratified by Heng’s favorable, intermediate, and poor prognostic risk groups is presented in the Table. Conclusions: CS is a relevant prediction measure in the context of mRCC treated with HD IL-2.A longer survival interval from HD IL-2 treatment was associated with an increased survival probability. CS in this cohort was especially relevant in adjusting prognosis for patients with Heng’s intermediate risk. [Table: see text]