Kaplan-Meier OS Research Articles

1245 Malignant Meningioma Survival, Recurrence and Functional Outcomes in an International Multicenter Cohort

INTRODUCTION: Meningiomas are the most common intracranial tumor. Grade 3 (malignant) meningiomas are the most aggressive subtype and represent 1-3% of all meningiomas cases. METHODS: Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated. RESULTS: We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227) and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). Older age (=65 years old) and male sex were independent predictors of worse OS and PFS in multivariate regression analysis. Postoperative radiotherapy was independently associated with improved OS in all patients and a sensitivity analysis including only patients =65 years old. Functional status, as measured by Karnofsky performance status, was stable between preoperative (median: 80 [IQR: 70, 90]), postoperative (median: 90 [IQR: 70, 98]) and 1-year postoperative (median: 70 [IQR: 50, 80]) timepoints. CONCLUSIONS: This study provides robust survival, recurrence, and functional outcome data for malignant meningiomas in North America and Europe over a 30-year period. We demonstrate that older age and male sex are associated with worse survival and recurrence outcomes. We further affirm that adjuvant radiotherapy confers a survival benefit in the treatment of malignant meningiomas, including in patients older than 65 years. Despite concerns around surgical and radiotherapy treatment complications, functional status remains stable in the first year following treatment of malignant meningiomas.

The Validity of a Synthetic Control Arm Derived from Historical Multiple Myeloma Clinical Trials

Introduction While randomized phase III clinical trials (RCTs) are the gold-standard for establishing drug efficacy in the United States, external control arms (ECAs) may be valuable for both early and late phase drug development. An ECA is a collection of patients with the disease of interest who were treated outside of a clinical trial of interest (ie, target trial) and whose outcomes are compared to those of the target trial patients' to evaluate comparative drug efficacy and/or safety. ECAs created through rigorous statistical non-experimental methods such as matching patient-level characteristics may provide early estimates of comparative efficacy in advance of RCTs and offset prospective enrollment of control patients in randomized studies. We evaluate the validity of using a matched ECA to estimate the comparative efficacy of an experimental drug in relapsed refractory multiple myeloma (r/r MM). Methods From the anonymized Medidata Enterprise Data Store (MEDS), we identified historic RCTs in r/r MM containing patients exposed to an experimental drug as well as an active control drug (ie, a corticosteroid). Arbitrarily, we selected one trial to serve as the “target trial”. For the remaining trials, we collapsed all corticosteroid control patients into a single pool to construct an ECA. Using propensity score (PS) optimal full matching, we identified corticosteroid ECA patients by selecting from the candidate patients those whose baseline demographic and clinical attributes were similar to patients receiving the experimental drug in the target trial. Using the Kaplan-Meier (KM) estimator and a Cox proportional hazards regression, we first compared overall survival time (OS) of patients in the experimental drug arm vs control arm in the target trial. We then compared the OS in the experimental drug arm vs the ECA. Results We found fewer than five historic clinical trials from MEDS which were open-label RCTs conducted from 2010-2017. They enrolled r/r MM patients aged ≥18 years who had received more than two prior lines of therapy, one of which was lenalidomide and bortezomib. The target trial contained 300 patients in the investigational drug arm and 152 patients in the control arm. Using the PS matching, we identified 183 patients from the control arms in pooled trials that were matched with 290 patients in the investigational drug arm in the target trial (i.e., ECA). These ECA patients were then upweighted to be matched with 290 patients in the investigational drug arm in the target trial. Full matching successfully attenuated baseline differences between the investigational drug and ECA arms. Figure 2 shows the KM curves of OS (investigational vs control) in the target trial. Median OS was 13.25 months vs. 8.52 months (log-rank p<0.01) and the investigational drug was associated with a 36% reduction in the hazard of death (HR 0.74, 95% CI: 0.60-0.92). Figure 2 shows the KM curves of OS, after full matching, using the ECA. Median OS was 13.51 months vs. 8.75 months (log-rank p<0.01) and the investigational drug was associated with a 36% reduction in the hazard of death (HR 0.74, 95% CI: 0.58-0.94). Conclusions In this methodologic validation study, we have demonstrated that it is possible to produce an ECA from historical clinical trials data using propensity score methods which replicates the comparative efficacy estimate from a target without introducing bias. That is, the ECA, which was well balanced with the investigational arm with respect to baseline patient attributes, returned nearly identical estimates of comparative efficacy as assessed by OS of both target trial control arm and ECA against the target trial experimental arm. This work illustrates that it is possible to create a valid ECA even when historical data size is limited and to do so without excessive exclusion of non-matched patients. That the treatment effect on OS estimated in comparison to the randomized control was very closely matched by that of the ECA suggests this approach to ECAs may be used to (1) estimate comparative efficacy of therapies that have only been studied in single arm settings and/or (2) augment or replace a randomized control arm in future trials when ethically or practically challenging. Figure 1A. Kaplan-Meier OS estimates of target trial experimental (N=300) vs. control arm (N=152) Figure 1B. Kaplan-Meier OS estimates of target trial experimental (N=290) vs. ECA (N=290)

The Doses of Post-Transplantation Cyclophosphamide in Haploidentical Stem Cell Allografts Can be Reduced

Background Allogeneic hematopoietic cell transplantation (HSCT) remains the most important curative modality for several hematologic malignancies, but an HLA-matched sibling or unrelated donor is not always available, particularly for ethnic minorities and multiethnic families. Haploidentical HSCT (Haplo-HSCT) is a solution and, since it can be safely conducted on an outpatient basis, the costs can be substantially reduced; toxicity, however, remains a major problem. Material and methods All patients given a Haplo-HSCT in the Centro de Hematología y Medicina Interna in Puebla, México and Hospital Universitario de Nuevo León, Nuevo León, México employing the “Mexican” method to conduct Haplo-HSCT on an outpatient basis were included. The employed protocol is as follows: Fludarabine dose of 50 mg/m2 IV daily from Day -6 to Day -4 (total dose received 150 mg/m2), Pre-HSCT Cyclophosphamide dose of 500mg/m2 IV daily from Day -7 to Day -4 (total dose received 2000 mg/m2). Post-HSCT Cyclophosphamide daily from Days +3 to +4, conventional dose: 50 mg/kg IV; reduced dose 25-30mg/kg IV. The employed protocol is registered in www.clinicalTrials.gov, identifier NCT05780554. Between March 2013 and July 2016, the transplants were done using the conventional doses (CD) of PTCy (50 mg/Kg) on d 3 and 4, whereas after July 2016, the allografts were done using reduced doses (RD-PTCy) 25-30 mg/Kg, d 3 and 4. Twenty-one patients received the CD, whereas 14 were given RD. All grafts were started as outpatients and could be completed as outpatients in 71% and 60% of cases respectively, for the groups of CD and RD. Results According to the statistical analysis, the two comparative groups (CD-PTCy versus RD-PTCy) had no significant differences in terms of age, sex and hematological recovery. Cytokine release syndrome and hematological toxicity were less frequent in the group of persons given RD-PTCy, whereas the prevalence of both acute and chronic graft versus host disease was similar in the two groups (Table 1). The median OS for the group CD-PTCy is 5.7 months meanwhile for the RD-PTCy is 15.67 months. The figure 1 depicts the Kaplan-Meier OS plots for the two subsets of patients, which were not statistically different. The RFS were better in the patients grafted with RD-PTCy (2.13 mo vs 5.13 mo). There are no differences between PTCy 25mg/kg and 30mg/kg. The median follow up for entire group is 4.53 months (IQR: 1.1 - 18.9 mo). Conclusion These results indicate that the doses of PTCy can be significantly reduced without compromising the effectiveness of the Haplo-HSCT conducted in an outpatient basis and employing the “Mexican” reduced intensity method. This preliminary observation may be considered as an idea to conduct prospective randomized studies to explore the possibility of significantly reducing the doses of PTCy in the setting of Haplo-HSCT.

Expression and clinical significance of PD-1 in UCEC and its Impact on tumor.

Programmed death 1 (PD-1) plays an important role in the immune escape, occurrence and development of tumors by inhibiting the function of immune cells. However, its prognostic value in uterine corpus endometrial carcinoma (UCEC) and its impact on the tumor microenvironment remain to be further explored. Transcriptional datasets were retrieved from the GEPIA, TIMER and TCGA databases. "edgeR" package was used for the identification of differentially expressed genes (DEGs) between two groups of patients (PD1-high and PD1-low group). Gene set enrichment analysis (GSEA) was performed to identify underlying pathways between betweenPD1-high and PD1-low groups functioning in UCEC. Gene Correlation Analysis was used to further confirm the associations of PD1 expression with T-cell-related genes. Cytoscape software was used to identify hub genes in DEGs. Kaplan-Meier analysis was performed to validate the prognostic value of hub genes. Mutational characteristics of UCEC patients according to PD1 levels were depicted and analyzed. We found that the transcriptional expression of the PD1 gene in UCEC tumor tissues markedly increased in cohorts from the GEPIA and TCGA databases. PD1 expression was negatively correlated with gene signatures associated with the T-cell receptor signaling pathway and primary immunodeficiency. GESA confirmed that PD1 expression was negatively correlated with gene signatures associated with the T-cell receptor signaling pathway. T-cell receptor complex-related genes, ZAP70, TRAC, CD3D, CD3E, CD8A, TRBC2, TRBV28 and CD247, showed significant positive associations with PD1 expression. The results of the Kaplan-Meier OS analysis indicated that PD1, TIGIT, FASLG, ICOS and TNFRSF9 are the protective factor for patients with UCEC. The top 5 genes of mutations in the low expression group, included PTEN (56%), PIK3CA (43%), TP53 (41%), TTN (39%), and ARID1A (37%). The genes with a higher proportion of mutations in the PD1-high group are PTEN (67%), TTN (62%), PIK3CA (53%), ARID1A (52%), and MUC16 (12%). The prognosis of UCEC patients with PD1 overexpression phenotype is worse than that of the PD1 low group, which is due to the involvement of the PD1 gene in the T-cell receptor signaling pathway. This study provides a further theoretical basis and reference for targeted therapy against PD1.

Transcriptome and pan-cancer system analysis identify PM2.5-induced stanniocalcin 2 as a potential prognostic and immunological biomarker for cancers.

Epidemiological studies have shown that air pollution and particulate matter (PM) are closely related to the occurrence of cancer. However, the potential prognostic and immunological biomarkers for air pollution related cancers are lacking. In this study, we proved PM2.5 exposure was correlated with lung cancer through transcriptome analysis. Importantly, we identified STC2 as a key gene regulated by PM2.5, whose expression in epithelial cells was significantly increased after PM2.5 treatment and validated by using RT-qPCR and immunofluorescence. Kaplan-Meier OS curves suggested that high STC2 expression positively correlated with a poor prognosis in lung cancer. Furthermore, we discovered that STC2 was associated with multiple cancers and pathways in cancer. Next, Pan-Cancer Expression Landscape of STC2 showed that STC2 exhibited inconsistent expression across 26 types of human cancer, lower in KIRP in cancer versus adjacent normal tissues, and significantly higher in another cancers. Cox regression results suggested that STC2 expression was positively or negatively associated with prognosis in different cancers. Moreover, STC2 expression was associated with clinical phenotypes including age, gender, stage and grade. Mutation features of STC2 were also analyzed, in which the highest alteration frequency of STC2 was presented in KIRC with amplification. Meanwhile, the effects of copy number variation (CNV) on STC2 expression were investigated across various tumor types, suggesting that STC2 expression was significantly correlated with CNV in tumors. Additionally, STC2 was closely related to tumor heterogeneity, tumor stemness and tumor immune microenvironment like immune cell infiltration. In the meantime, we analyzed methylation modifications and immunological correlation of STC2. The results demonstrated that STC2 expression positively correlated with most RNA methylation genes and immunomodulators across tumors. Taken together, the findings revealed that PM2.5-induced STC2 might be a potential prognostic and immunological biomarker for cancers related to air pollution.

Stereotactic Radiosurgery and Anti-PD-1 + CTLA-4 Therapy, Anti-PD-1 Therapy, Anti-CTLA-4 Therapy, BRAF/MEK Inhibitors, BRAF Inhibitor, or Conventional Chemotherapy for the Management of Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> Immunotherapy and targeted BRAF/MEK inhibition have revolutionized the systemic management of advanced melanoma with sustained intracranial responses noted in prospective clinical trials. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAF inhibitor, or conventional chemotherapy. <h3>Materials/Methods</h3> Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. The assigned regimen was the last course of systemic treatment to avoid the effects of multiple systemic agents influencing clinical end points. The primary endpoint was distant MBM control with secondary endpoints of local MBM control (defined as a sustained less than >20% volume increase on follow-up MRIs) and OS from SRS. <h3>Results</h3> In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 to 2020 were identified: Median SRS dose was 24 Gy (range: 15-24 Gy) all in a single fraction. Median follow-up using the reverse Kaplan-Meier (KM) method was 41.8 months. No significant differences were noted in age (p=0.10), gender (p=0.47), Karnofsky Performance Scale (KPS) (p=0.27), treated gross tumor volume (p=0.07), number of MBM treated per patient (0.08), or Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) (p=0.28) between groups. Twelve-month KM OS rates by DS-GPA were 17%, 33%, 54%, and 69% for scores 0-1, 1.5-2, 2.5-3, 3.5-4, respectively (p=<0.001). Twelve-month KM distant MBM control rates were 42%, 63%, 24%, 44%, 23%, and 16% (p=<0.001) for SRS with anti-PD-1 + CTLA-4, anti-PD-1, anti-CTLA-4, BRAF/MEK inhibitors (i), BRAF-i, or chemotherapy, respectively. The 12-month KM local MBM control rates were 86%, 77%, 79%, 85%, 87%, and 57% (p=<0.001). Twelve-month OS rates from SRS diagnosis were 68%, 59%, 45%, 62%, 21%, and 15% (p=<0.001). On multivariate analysis (MVA), 2-5 MBM (HR 1.72, 95% CI: 1.1-42.7, p=0.02) and >5 MBM being treated (HR 2.65, 95% CI: 1.65-4.25, p=<0.001) was associated with worse distant MBM control. Treatment with anti-PD-1 therapy (HR 0.24, 95% CI:0.14-0.41, p=0.0009) was associated with improved distant MBM control. MVA also showed, treatment with anti-PD-1 (HR 0.27, 95% CI: 0.17-0.41, P=0.0007) and anti-PD-1 + CTLA-4 (HR 0.29, 95% CI: 0.15-0.53, p=0.01) were both associated with increased OS. The rates of symptomatic radiation necrosis were 2%, 2%, 1%, 1%, 2%, and 3% (p=0.93). <h3>Conclusion</h3> To our knowledge, this is the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in distant MBM control as well as OS by systemic therapy.

Glassy cell carcinoma of the cervix (GCCC): a single institution review of treatment patterns and outcomes (184)

Glassy cell carcinoma of the cervix (GCCC): a single institution review of treatment patterns and outcomes (184)

A Risk Score Model Based on Nine Differentially Methylated mRNAs for Predicting Prognosis of Patients with Clear Cell Renal Cell Carcinoma.

Purpose DNA methylation alterations play important roles in initiation and progression of clear cell renal cell carcinoma (ccRCC). In this study, we attempted to identify differentially methylated mRNA signatures with prognostic value for ccRCC. Methods The mRNA methylation and expression profiling data of 306 ccRCC tumors were downloaded from The Cancer Genome Atlas (TCGA) to screen differentially methylated lncRNAs and mRNAs (DMLs and DMMs) between bad and good prognosis patients. Uni- and multivariable Cox regression analyses and LASSO Cox-PH regression analysis were used to select prognostic lncRNAs and mRNAs. Corresponding risk scores were calculated and compared for predictive performance in the training set using Kaplan-Meier OS and ROC curve analyses. The optimal risk score was then identified and validated in the validation set. Function enrichment analysis was conducted. Results This study screened 461 DMMs and 63 DMLs between good prognosis and bad prognosis patients, and furthermore, nine mRNAs and six lncRNAs were identified as potential prognostic molecules. Compared to nine-mRNA status risk score model, six-lncRNA methylation risk score model, and six-lncRNA status risk score model, the nine-mRNA methylation risk score model showed superiority for prognosis stratification of ccRCC patients in the training set. The prognostic ability of the nine-mRNA methylation risk score model was validated in the validation set. The nine prognostic mRNAs were functionally associated with neuroactive ligand receptor interaction and inflammation-related pathways. Conclusion The nine-mRNA methylation signature (DMRTA2, DRGX, FAM167A, FGGY, FOXI2, KRTAP2-1, TCTEX1D1, TTBK1, and UBE2QL1) may be a useful prognostic biomarker and tool for ccRCC patients. The present results would be helpful to elucidate the possible pathogenesis of ccRCC.

Update, validation and comparison of three different clinicopathological scores for patients with resected gastric cancer: A western experience

IntroductionGastric cancer (GC) is a multifactorial disease. Several prognostic scores have been proposed for refining the prognostic information provided by the TNM classification. Our aim is to validate and compare the prognostic performance of different clinicopathological scores in a western cohort of patients (Marubini, Haraguchi and Kologlu scores). Material and methodsRetrospective study of all cases of GC resected in a western tertiary center (N = 377). Clinicopathological features were collected, scores were applied and statistical analyses were performed. Results315 cases were finally included. According to Marubini, Haraguchi and Kologlu scores, patients were stage I (18.5%, 13.3% and 49%), II (29.3%, 47.2% and 29.5%) and III (52.2%, 39.5% and 21.5%, respectively). All classifications were significantly associated with lymphovascular invasion, perineural infiltration, lymph node involvement, patient progression and death due to GC. All scores showed good patient stratification by Kaplan-Meier analyses, but OS and DFS curves depending on Haraguchi score were less evenly spaced. Kologlu classification showed prognostic superiority over Haraguchi and Marubini classifications by ROC analysis. AUC values for OS and DFS were 0.654 and 0.647 (Marubini), 0.626 and 0.618 (Haraguchi) and 0.724 and 0.709 (Kologlu). Kologlu and Marubini classifications were independent factors for both OS and DFS, but Haraguchi classification was independently associated only with DFS. ConclusionsClinicopathological scores can be easily validated and are cost-effective. Kologlu score is the most thorough classification, and it showed the best prognostic performance for both DFS and OS in our study. More studies are needed to validate its value in other populations.

PDL1 expression predicts therapeutic outcome in non metastatic anal squamous cell carcinoma (NMASCC).

4054 Background: NMASCC is a rising incidence disease with up to 30% of treatment failure to achieve complete response (CR) after standard chemoradiotherapy (CRT) leading to severe morbidity and death. Stage III-TNM, p53 mutations, HPV negativity, HIV infection are linked to treatment failure. We investigated the predictive/prognostic role of TNM, CR, HPV, PDL1 positivity and CD3/CD8 densities in NM-ASCC from a single institution. Methods: All 79 eligible consecutive NMASCC pts (available FFPE pre-treatment samples) seen from October-2009 to April-2019 having completed definitive CRT (50.4 Gy Pelvic Radiotherapy with Mitomycin-C 12mg/m2/IV/d1-5 / FU 1000mg/m2/d1-4 d29-32 (28%), Mitomycin-C/Capecitabine 825 mg/m2/bid (38%), Cisplatin 60 mg/m2/IV d1-29 and 5FU (34%) were analyzed. Mean age: 59 (range 26-87), 72% female, Stage III: 59%, HPV positive: 86% (HPV-16: 80%);14% HIV positive. IHC assessed by two pathologist for PD-L1 expression (ClonSP263) and CD3-CD8+ TILS densities (Clone 2GV6, Clone SP57). HPV-DNA assessed by PCR (BSGP5+/6+ multiplexed with beta-globin). Kaplan-Meier survival, CR, DFS, OS and Univariate analyses were performed using Cox proportional hazard model. Results: CR achieved within 6 months of treatment completion was 68%( 53pts). Median follow-up after treatment completion: 35 months (range 6 –149). As of February 2020, 82% (65 pts) are alive, no evidence of disease:(57%) 46 pts, recurrence rate: 26%(22 pts), cancer death: 18% (14 pts). PDL1+ tumors ( &gt; 1% positivity-CPS score): 56%, expression levels: 1-5% (57%,26p), &gt; 10%-100% (43%,19p). PDL1+ had a strong association with CR (p = 0.021); higher PDL1+ levels had 8-fold of CR-likelihood than PDL1 negative.(OR 8.50 vs. 1.12). Significative Spearman correlation between PDL1 tumors with CR and CD3-CD8 TILS density was observed (R = 0.43,p = 0.0017 and R = 0.36,p = 0.00094 respectively), albeit CD3-CD8 failed to reach significance as prognostic factors for either CR, DFS or OS. Only CR and PDL1 positive were strongly significantly associated to DFS (HR 0.10 [IC 95% 0.04-0.28] p &lt; 0.001 and HR 0.28 [IC 95% 0.11-0.73] p = 0.006) and OS (HR 0.12 [IC 95% 0.03-0.45] p &lt; 0.001 and HR 0.15 [IC 95% 0.03-0.68] p &lt; 0.004). Low prevalence of HPV negative, early tumors, HIV positive cases in our series probably impacted in statistical power for prognosis correlation. Conclusions: PDL1 positivity was the strongest predictive/prognostic factor in NM-ASCC. Alternative therapeutics options to standard CRT should be explored on poor-risk patients as HPV-negative, P53-mutated and PDL1 negative patients.

Abstract 5004: A new pattern called Hyperprogression when using Immune checkpoint blockers in real world

Abstract Introduction Although immune checkpoint blockades (ICBs) therapy can lead to favorable and durable results by reinvigorating the anti-tumor immune response in some patients, many other patients experience poor prognosis and even tumor overgrowth can be seen in real practice. So, we performed retrospectively hyperprogression-related studies on patients who underwent immunotherapy to find the predictable clinical factor. We also revealed the difference of immune composition in TME that are associated with HPD by multiplex IHC Method We retrospectively evaluated the medical records of NSCLC patients (n=243) who treated with anti-PD-1/anti-PD-L1 therapy at 5 institutes of St. Mary’s Hospitals between January 2014 to June 2018. Results A total of 231 patients were included in the TGK analysis. Median age was 64.2 years with a majority being male (74.9%) and smokers (70.1%, n=162). Among them, 88.9% were heavy smokers with over 20 pack per years (n=144). Most of the ICB drugs were used in the second and above lines, but the proportion used in the fourth or higher heavy treated patients was 16%(n=37). The rate of over-growth was 33.3% (n=77) among these patients, the rate of hyperprogression was 32.4% (n=25). The proportion of patients harboring oncogenic driver mutation such as EGFR alteration was 18.6%. Univariate analyses indicated that HPD was significantly associated with oncogenic drive mutant status compared with non-HPD (18.6% [8 of 43] vs 9.04% [17 of 188]; P= 0.001). No significant differences were observed according to age, number of previous lines of therapy, or presence of more than 3 metastatic sites before ICBs. Multivariate analyses with a multivariate logistic regression model demonstrated that presence of less than 3 metastatic sites (odds ratio [OR], 4.769; 95% [CI], 1.384-16.433; P &amp;lt; .013) was an independent predictor for HPD. We also analyzed the association of NLR, PLR and CAR with HPD. Serologic markers post 6 weeks, i.e., at the time of first response evaluation, showed prognostic value for the most significant hyperprogression after ICB use. Kaplan-Meier OS estimates showed that there was a clear trend toward worse outcome for the patients with HPD (median OS, 5.6 months;95% CI, 4.5-10.3; P &amp;lt; 0.001) compared with the patients with non-HPD disease progression (median OS, 7.4 months; 95% CI, 15.1-19.6; P = 0.003) The multiplex IHC results showed that the percentage of T-cell marker expression of Tumor and Stroma in each slide was different between good responder and HPD. Conclusion Even though the improved recognition of hyperprogression, the etiology of HPD remains unclear, apart from the pseudoprogression. However, we observed that some clinical factors and some serologic biomarker can be used to predict HPD. Furthermore, we undergo TMB and multiplex IHC to understand mechanism of hyperprogression. Citation Format: Seoree Kim, Sang-Yeob Kim, Jin Hyoung Kang. A new pattern called Hyperprogression when using Immune checkpoint blockers in real world [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 5004.

Elevated miR-20b-5p expression in peripheral blood mononuclear cells: A novel, independent molecular biomarker of favorable prognosis in chronic lymphocytic leukemia

MicroRNA-20b-5p (miR-20b-5p) is part of the miR-106a/363 cluster and a member of the cancer-related miR-17 family. miR-20b-5p regulates important transcription factors, including hypoxia-inducible factor 1 (HIF1) and signal transducer and activator of transcription 3 (STAT3). Recently, the dysregulation of miR-20b-5p expression has been observed in many B-cell lymphomas and T-cell leukemias. In this research study, we examined the putative prognostic value of miR-20b-5p in CLL. Therefore, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients; next, total RNA was polyadenylated and first-strand cDNA was synthesized, using an oligo-dT–adapter primer. miR-20b-5p expression was quantified using an in-house–developed real-time quantitative PCR assay. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-20b-5p expression predicts better OS for CLL patients (p < 0.001). Interestingly, miR-20b-5p overexpression retains its favorable prognostic role in CLL patients of intermediate risk or stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable (IGHV) region]. In conclusion, miR-20b-5p is a potential independent molecular biomarker of favorable prognosis in CLL.

The Impact of a Dedicated Multidisciplinary Care Team on a High-Risk Head and Neck Cancer Population

While the Multidisciplinary Tumor Board (MTB) is the accepted best practice for the management for head and neck cancer, there is a paucity of evidence demonstrating its impact on treatment outcomes. Our goal was to investigate the impact of MTB following the hiring of a fellowship trained head and neck surgeon and implementation of an expanded MTB. As minorities and underinsured patients have consistently had worse outcomes and survival in HNSCC, we hypothesized that these changes would improve survival in our high-risk cohort. A review of head and neck squamous cell carcinomas (HNSCC) treated at our institution between 10/2006 and 5/2015 was performed. The cohort was divided into historical (10/06-2/11) and contemporary (2/11-5/25) cohorts. Prior to 2/2011, the MTB at that time did not consistently include a dedicated surgeon or additional members. In 2/2011 a dedicated fellowship trained head and neck surgeon joined the MTB, and the MTB was expanded with additional members including: speech/swallow therapy, social work, neuroradiology, pathology, and dental. Patients without a HNSCC primary, who were not managed by an otolaryngologist within the institution, had inadequate records, or did not receive any treatment, were excluded. A total of 224 patients were included, with 98 patients in the historical cohort and 126 in the contemporary cohort. 139 (62%) of the patient cohort were black and 91 (40%) were Medicaid or uninsured. Average follow-up time was 2.87 years. Of the overall cohort, 25% were stage I/II and 68% were stage III/IV. OS and DSS in the contemporary cohort were statistically significantly improved over the historical cohort on univariate analysis, and also on multivariate analysis when controlling for age, sex, race, and tobacco use. On Kaplan-Meier evaluation, OS and DSS were significantly different with 5-year DSS of 52% versus 75% (P = .003), respectively. This OS and DSS difference persisted when evaluating only stage III/IV cancers (P = .02). When excluding oropharynx cancers to eliminate potential imbalance from HPV-associated oropharynx cancers, DSS remained statistically significant (P = .02). Average time to treatment was not significantly different. Surgery was more commonly employed for advanced HNSCC treatment in the contemporary group (P = .0067) Implementation of an expanded MTB and dedicated head and neck surgeon had significant impact on OS and DSS for advanced HNSCC. Our study corroborates the belief that treatment of HNSCC by a dedicated multidisciplinary team results in best outcomes for patients. Implementing expanded MTB and specialty surgeon support should be considered to help address HNSCC racial disparity outcomes.

Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer

AimsThe aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC.Patients and MethodsBetween January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy (“early PORT”) or with PORT administered after two cycles of chemotherapy (“late PORT”) at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan–Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS.ResultsOf 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS.ConclusionsEarly PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

Progression after the next line of therapy (PFS2) and updated OS among patients (pts) with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥50% enrolled in KEYNOTE-024.

9000 Background: In KEYNOTE-024 (NCT02142738), pembrolizumab (pembro) was superior to chemotherapy (chemo) as first-line (1L) therapy for advanced NSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR mutations or ALK translocations. After a median follow-up of 11.2 mo, HR was 0.50 for PFS by independent central radiologic review ( P&lt; 0.001) and 0.60 for OS ( P= 0.005). Here we present PFS2 and updated OS. Methods: 305 pts were randomly assigned to pembro 200 mg Q3W (n = 154) or investigator (INV)-choice platinum-doublet chemo with optional pemetrexed maintenance for nonsquamous histology (n = 151). Pts in the chemo arm could cross over to pembro upon PD. Poststudy anticancer therapy and INV-assessed outcomes were collected. Kaplan-Meier PFS2 and OS were calculated in all allocated pts. PFS2 was defined as time from randomization to PD per INV after start of 2L+ therapy or death, whichever occurred first; pts alive and without 2L+ PD were censored at last known survival. Kaplan-Meier OS was defined as time from randomization to death. There was no adjustment for multiplicity (cutoff: Jan 5, 2017). Results: 2L+ therapy was received by 48 (31.2%) pts in the pembro arm and 97 (64.2%) in the chemo arm, including 80 pts who crossed over from chemo to pembro per protocol and 14 pts who received anti–PD-1 therapy outside of crossover. 56 (36%) 1L pembro pts were on 1L pembro therapy or in follow-up as of data cutoff. Updated median OS and PFS2 results are in the Table. Conclusions: Fewer pembro pts received 2L+ therapy vs chemo pts because of the significant improvement in PFS observed for pembro in the 1L setting. Median PFS2 was substantially improved for pembro (not reached [NR]) vs chemo (8.6 mo). Updated OS with median follow-up of 19 mo maintained consistent superiority of 1L pembro, despite increased crossover from 1L chemo. Clinical trial information: NCT02142738. [Table: see text]

MicroRNA-155-5p Overexpression in Peripheral Blood Mononuclear Cells of Chronic Lymphocytic Leukemia Patients Is a Novel, Independent Molecular Biomarker of Poor Prognosis.

MicroRNA-155-5p (miR-155-5p) is a proinflammatory, oncogenic miRNA, involved in various physiological processes, including hematopoiesis, immunity, inflammation, and cell lineage differentiation. It regulates important transcription factors, such as E2F2, hypoxia-inducible factor 1 (HIF1), and FOXO3. Recently, the dysregulation of miR-155-5p expression has been linked to chronic lymphocytic leukemia (CLL) pathogenesis. In this research study, we investigated the potential diagnostic and prognostic value of miR-155-5p in CLL. To achieve our goal, we isolated total RNA from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients and 36 nonleukemic blood donors and performed polyadenylation of total RNA and reverse transcription. Next, we quantified miR-155-5p levels using an in-house-developed real-time quantitative PCR method, before proceeding to extensive biostatistical analysis. Thus, it appears that miR-155-5p is significantly overexpressed in PBMCs of CLL patients and can distinguish them from nonleukemic population. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-155-5p expression predicts inferior OS for CLL patients (p < 0.001). Interestingly, miR-155-5p overexpression retains its unfavorable prognostic role in CLL patients stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable region (IGHV)]. Thus, miR-155-5p appears as a promising, independent molecular biomarker of unfavorable prognosis in CLL.

P17.95 * NOVOTTF-100A ALTERNATING ELECTRIC FIELDS THERAPY FOR RECURRENT GLIOBLASTOMA: AN ANALYSIS OF PATIENT REGISTRY DATA

BACKGROUND: The NovoTTF-100A is a first-of-a-kind anticancer device, approved by the Food and Drug Administration in 2011, for the treatment of recurrent glioblastomas. It emits alternating electric fields, at an intensity of 1 V/cm and a frequency of 200 kHz, that mimic the cytotoxic effect of chemotherapy by disrupting charged cytoplasmic proteins involved in the tightly orchestrated process of mitosis. Past phase III trial demonstrated equivalent efficacy when the device was compared to conventional cytotoxic chemotherapies and bevacizumab, but without their systemic side effects. METHODS: The NovoTTF-100A device has been available by prescription at 91 oncology centers in the United States since November 2011. We retrospectively analyzed the outcome and toxicity data from patients who were prescribed the device from October 2011 to November 2013 as treatment for their recurrent glioblastomas. RESULTS: There were 147 female and 310 male patients (n = 457) who were treated with this device. The median age was 55 (range 18 to 86) years. The Kaplan-Meier median OS was 9.6 (95% confidence interval [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% CI 3.5 to 4.8) months. The most common device-related adverse events include skin reaction (24.3%), neurological disorders(10.4%), heat sensation (8.9%), electric sensation (7.7%) and headache (5.7%). CONCLUSIONS:Treatment with NovoTTF-100A, as prescribed in the general clinical setting to patients with recurrent glioblastomas, offers favorable outcomes compared to historical patient data. The adverse event profile of the device remains benign with no new unexpected toxicities.

Expression of pim-1 in Tumors, Tumor Stroma and Tumor-Adjacent Mucosa Co-Determines the Prognosis of Colon Cancer Patients

Provirus integration site for Moloney murine leukemia virus (pim-1) is a proto-oncogene that is linked to the development and progression of several cancers. In this study, we evaluated pim-1 expression in tumors, tumor stroma and tumor-adjacent mucosa together as an independent prognostic factor for colon cancer patients. The study included 343 colon cancer patients. Immunohistochemical staining was used to detect pim-1. Multivariate cox regression for disease-free survival (DFS) were used to identify independent prognostic factors. Analytic hierarchy process (AHP) was used to calculate the weight of pim-1 in tumors, tumor stroma and tumor-adjacent mucosa in order to obtain a Pim-1 total score (PTS) for recurrence and survival. Kaplan–Meier DFS curves and OS curves for patients with different pim-1 expression levels were compared using the log-rank test. In this study, four independent prognostic factors were identified for colon cancer patients: pim-1 expression in tumors, tumor stroma, tumor-adjacent mucosa, as well as tumor stage. It has been established that clinical stage is an important prognostic factor for colon cancer patients. However, PTS can identify the patients who are likely to recur not only in the whole radical excision group but also within each stage of this group. Based on the results of this study we can conclude that the PTS combined with clinical staging system may be a better predictor of colon cancer patients’ prognosis than using the clinical stage system alone. Clinical Trials Gov. Number: ChiCTR-PRCH-12002842

The Impact of Rituximab Resistance on Overall Survival Rate in Low-Grade Follicular Lymphoma

Background: Recent studies have prospectively established that concurrent or sequential addition of rituximab (R) to conventional therapies improves the overall survival rate (OS) for patients with low-grade follicular lymphoma (FL). However, there is little information regarding the prognosis of patients considered R-resistant.Subjects/Methods: We examined the records of 305 subjects with a diagnosis of FL seen at our institution between 1995 and 2007. To better define the prognosis for R-resistant subjects, we identified 133 subjects (grade 1, N=75; grade 2, N=41; grade 1 or 2, N=17) who completed an R-containing treatment (R alone, N=61; R combination, N=72) and had at least six months of follow-up from start of R-containing therapy. For the purposes of our study, we define R-resistance as progression of lymphoma within 6 months of the first R dose (i.e., the dose defining R-resistance) of the R-containing regimen followed by progression. Overall survival rates were evaluated for all subjects from first dose of R to last follow-up or death and, for R-resistant subjects, from the dose defining R-resistance to last follow-up or death. R-resistant subjects (N=62 [47%]) were subdivided into primary refractory (R-resistant after first R-containing treatment; N=30) or acquired resistant (R-resistant after at least one prior R-containing treatment without progression within 6 months; N=32). Median age at first treatment with R was 55 years (range: 21–87) for all subjects and 54 years (range: 21–87) for R-resistant subjects (for primary refractory, median=54 years [range: 28–87]; for acquired resistant, median=55 years [range 30–81]). The median number of prior non-R-containing treatment regimens was 1 (range: 0–4) for resistant subjects, and 0 (range: 0–3) for non resistant subjects. The median number of R-containing regimens for subjects with acquired resistance was 2 (range: 2–4). The frequency of large cell transformation did not differ between R-resistant and non R-resistant cohorts (N=7/71 [10%] and N=8/62 [13%], respectively).Results: Of 20 deaths observed for all subjects with FL receiving R or R containing regimens, 19 deaths occurred after R-resistance. At a median follow-up of 56 months (range 6–115) for all subjects receiving R, the median OS was not reached with 5-year Kaplan-Meier OS estimate = 81%. For R-resistant subjects, median OS from first dose of R defining R-resistance was 64 months (range: 6–100) with 5-year Kaplan-Meier OS estimate = 58%. Median rates of OS from R dose defining R-resistance were not significantly different between primary refractory and acquired resistant subjects. For subjects with acquired R-resistance, median time from first dose of R to first dose of R defining R-resistance was 10.4 months (range: 9–83).Conclusion: The OS estimate for subjects with R-resistant FL (5-year estimate OS = 58%) appears worse than survival estimates reported for unselected subjects with FL (5 year estimate OS = 80% for grade 1; 76% for grade 2 [SEER Survival Monograph, Non-Hodgkin Lymphoma]). This inferior prognosis seems unrelated to large cell transformation. Survival is similar for subjects with primary refractory and acquired resistance when survival is measured from the R dose used to define R-resistance.

Preoperative uracil/tegafur and concomitant radiotherapy in locally advanced rectal (LAR) cancer: Updated results with a median follow-up of 5 years and analysis of prognostic factors (PF)

3573 Background: Preop chemoradiotherapy (CRT) with CI 5-FU is a standard of care for LAR cancer. Oral fluoropyrimidines, an attractive alternative to intravenous 5-FU, are perceived by patients as more convenient. Methods: We performed a phase II study in patients with potentially resectable tumors, localized in middle or distal rectum, ultrasonographically staged as T3 or T4 or N+ who were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Pts underwent surgery 5 to 6 weeks later followed by four cycles of 5-FU/LV (Mayo Clinic Scheme). Early end points of efficacy (pCR, downstaging, sphincter preserving surgery) and toxicity have already been reported (JCO 2004;22:3016). We now present data on secondary objectives (RFS, DFS and OS) and univariate and multivariate analysis of clinical and pathological PF. Results: 94 patients were included and complete information on 88 (94%) is availablewith a median follow-up of 5 years (60.4 months). Actuarial Kaplan-Meier DFS, RFS and OS are 61%, 66%, and 70 %. Patterns of failure are 7% pelvic and 25% distant. Univariate analysis results are shown in the table . Survival rate was also higher among patients with no or few residual disease after CRT but did not reach statistical significance. In Cox multivariate analysis both ypT and ypN are independent PF for DFS and RFS but only ypT is an independent PF for OS. Conclusions: This approach with preop UFT/RT reproduces the results that have been accomplished with 5-FU. ypT and ypN could be helpful to identify different risk groups and to select adjuvant treatments. [Table: see text] No significant financial relationships to disclose.