Significant Prolongation Of Overall Survival Research Articles

The Role of CLDN18.2 in Gastric Cancer Prognosis: A Systematic Review and Meta-Analysis

Background Gastric cancer (GC) is a major global cause of cancer mortality, with a median overall survival of just 12 months. CLDN18.2, a specific isoform of Claudin18 normally expressed in the gastric mucosa, has emerged as a potential therapeutic target and prognostic biomarker due to its exposure on the surface of tumor cells following malignant transformation. This exposure allows CLDN18.2's extracellular loops to bind monoclonal antibodies, presenting new opportunities for targeted therapy and improved prognostic assessment. Methods A comprehensive search of PubMed, EMBASE, Cochrane Library and Web of Science databases was conducted for studies that addressed the correlation of CLDN18.2 with: (1) Progression-free survival (PFS), and (2) Overall Survival (OS). Hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. Heterogeneity was examined with I2 statistics. P values of ≤ 0.05 were considered statistically significant. Statistical analyses were performed using RStudio, version 4.2.3. Results A total of 15 studies encompassing a total of 4,085 patients were included. There were 2,691 (65.8%) male, and 1,394 (34.2%) female patients. In the histologic GC analysis, there were 1,582 (38.7%) patients that had intestinal type and 1,280 (31.3%) with diffuse type. Patients with CLDN18.2 negative status exhibited a non-significant trend towards prolonged PFS (HR: 1.25; 95% CI: 0.98-1.61; p = 0.07; I2=18%) and a significant prolonged OS (HR: 1.20; 95% CI: 1.07-1.34; p < 0.01; I2=37%) when compared to CLDN18.2-positive patients. Conclusion Our findings establish CLDN18.2 as a robust negative prognostic indicator for overall survival in GC patients. While its impact on PFS was not statistically significant, the association with OS suggests CLDN18.2 may serve as a marker for complex biological processes underlying tumor advancement.

Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer

BackgroundCD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear.MethodsThe expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry.ResultsIn this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents.ConclusionsOur preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.

Therapie peritonealer Metastasen

BackgroundPeritoneal carcinomatosis arising from gastrointestinal malignancies represents a major therapeutic challenge for oncological surgeons, oncologists and radiotherapists. The development of so-called multimodal therapy consisting of perioperative systemic chemotherapy, radical cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy (HIPEC) has resulted in significant prolongation of overall survival in these patients.AimSurvival data from prospective, randomized trials and register studies in recent years have established multimodal therapy as a treatment option for peritoneal metastatic colorectal as well as gastric cancer in the German guidelines. The current work on this complex topic ensures insight into the background of this topic.Materials and methodsThis paper is based on a selective literature search in the medical database PubMed on the keywords hyperthermic intraperitoneal chemotherapy, colorectal cancer, gastric cancer, multimodal therapy as well as on internal data from a reference center for the therapy of peritoneal malignancies from Germany.ResultsMultimodal therapy consisting of perioperative systemic chemotherapy, radical cytoreductive surgery, and HIPEC leads to better oncologic outcome in well-selected patients with peritoneal metastatic gastric and colorectal cancer in high-volume centers.

The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center

Elderly patients > 70 years of age with esophageal cancer (EC) represent a challenging group as frailty and comorbidities need to be considered. The aim of this retrospective study was to evaluate the efficacy and side effects of curative chemoradiation therapy (CRT) with regard to basic geriatric screening in elderly patients in order to elucidate prognostic factors. Thirty-four elderly patients > 70 years with EC treated at our cancer center between May 2014 and October 2018 fulfilled the selection criteria for this retrospective analysis. Treatment consisted of intravenous infusion of carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. Clinicopathological data including performance status (ECOG), (age-adjusted) Charlson comorbidity index (CCI), Frailty-scale by Fried, Mini Nutritional Assessment Short Form, body mass index, C-reactive protein to albumin ratio, and treatment-related toxicity (CTCAE) were assessed. Data were analyzed as predictors of overall survival (OS) and progression-free survival (PFS). All patients (ten female, 24 male) received combined CRT (22 patients in neoadjuvant, 12 patients in definite intent). Median age was 75 years and the ECOG index between 0 and 1 (52.9% vs. 35.3%); four patients were rated as ECOG 3 (11.8%). Median follow-up was 24 months. Tumors were mainly located in the lower esophagus or esophagogastric-junction with an T3 stage (n = 25; 75.8%) and N1 stage (n = 28; 90.3%). 15 patients (44.1%) had SCC, 19 patients (55.9%) AC. 26 of the patients (76.5%) were scored as prefrail and 50% were in risk for malnutrition (n = 17). In relation to the BMI, ten patients (29.4%) were ranked as overweight, and 15 patients were presented in a healthy state of weight (44.1%). Grade 3 acute toxicity (or higher) occured in nine cases (26.5%). Most of the patients did not show any late toxicities (66.7%). Trimodal therapy provides a significant prolonged OS (p = 0.049) regardless of age, but without impact on PFS. Our analysis suggests that chemoradiation therapy is feasible for elderly patients (>70 years) with tolerable toxicity. Trimodal therapy of EC shows a positive effect on OS and PFS. Further studies are needed to elucidate benefitting subgroups within the elderly. In addition to age, treatment decisions should be based on performance status, nutritional condition and multidisciplinary validated geriatric screening tools.

Current Status of Racial and Ethnic Disparities for Follicular Lymphoma: A Surveillance, Epidemiology, and End Results (SEER) Database Analysis with Emphasis on Hispanics

Background Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in the Western hemisphere (Blood PMID: 26989204). In prior studies, better progression-free survival has been noted in Hispanics (HI), however, further characterization of this ethnic difference needs to be addressed. This result is consistent with previous research explaining the development of NHL as an heterogeneous process where unique outcomes for races have been noted. There is a need for further understanding of HI diagnosed with FL. METHODS: Data were analyzed on follicular FL patients in the United States (US) reported to the Surveillance, Epidemiology, and End Results (SEER) 18 database between 2000 and 2018. SEER 18 contains the most comprehensive population-based cancer information in the US, covering approximately 27% of the total US population, and up to 36% of HI alone. Racial groups analyzed included NH whites, HI whites, blacks, and Asians/PIs (Pacific Islanders). Patient characteristics, age-adjusted incidence rate, and survival rate were compared across ethnic groups, HI vs NH. Stratification by age, gender, and stage at diagnosis was considered. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. RESULTS Of 59250 FL patients, 11% were HI, and 89% NH. 48% of HI were male, compared to 50% of NH. The majority of HI (42%) were diagnosed in the age bracket of (40-60) vs majority of NH (50%) who were diagnosed in the age bracket of (60-80) (p<0.001). HI were diagnosed at a median younger age, 59 y.o vs 65 y.o, compared to NH (p<0.001). Regarding race, most of HI and NH were whites (96% vs 88%), followed by blacks (1% vs 5%). When examining stage, most of HI (22%) as well as NH (22%) were stage IV (p<0.001). In terms of radiation, 13% of HI received it, compared to 14% of NH (p<0.001). On survival analysis, the survival probability at 2, 5 and 10 years of HI vs NH were (87%vs 86%),(77% vs 74%), and (64% vs 86%), respectively. The median survival time was 17.1 years for HI, vs 13.2 years for NH; and there was OS difference favoring HI/NH with (p<0.001). On multivariate analysis, when adjusted for age, those patients who were older than 80 y.o and between 60 to 80 y.o, had worse OS compared to those younger than 60 y.o, with hazard ratio (HR) 9.4 (95% CI: 8.7 - 10 ) and HR 3 (95% CI: 2.8-3.2) respectively. Regarding stage, those who were at stage III and IV, had worse OS than those at early stage (I/II) with HR 1.3 (95% CI: 1.26 - 1.45) and HR 1.7 (95% CI: 1.6 - 1.8), respectively. CONCLUSION In this data analysis from the SEER 18 database, HI with FL lymphoma, had a statistically significant prolonged OS compared to NH. There were also, statistically significant differences in median survival at 2, 5, and 10 years among the HI cohorts. Unique characteristics from HI may explain why there is an increase in OS after a FL diagnosis in this data set. Biological differences in the background of HI with FL are needed to better understand improved outcomes on this cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Different treatment regimens in breast cancer visceral crisis: A retrospective cohort study.

Breast cancer visceral crisis (VC) is caused by excessive tumor burden leading to severe organ dysfunction with poor prognosis. Traditional chemotherapy reduces the quality of life of patients without significantly improving survival. The aim of this study was to investigate the clinical characteristics of patients with VC and the prognosis by using different treatment options. According to the 5th European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) international consensus guidelines for advanced breast cancer guidelines (ABC 5), patients who were treated in the First Hospital of Jilin University from 2018 to 2022 and diagnosed with breast cancer VC were retrospectively analyzed. The analysis focused on the characteristics of the patients, the treatment regimens, and prognosis. A total of 133 patients were included in this study. As for metastasis breast cancer subtype, 92 (69.18%) were hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER-2) negative, 20 (15.04%) had HER-2 overexpression, and 21 (15.78%) were triple negative. All patients had an mOS of 11.2 months (range, 1.1-107.8 months). In different types of VC, the median overall survival (mOS) of bone marrow metastasis (BMM) was 18.0 months (range, 2.0-107.8 months), that of diffuse liver metastasis (DLM) was 8.1 months (range, 1.3-30.2 months), and that of meningeal metastasis (MM) was 9.0 months (range, 1.2-53.8 months). In 92 HR+, Her-2- patients using different treatment regimens, mOS was 6.2 months (range, 1.2-29.8 months) in the chemotherapy group while it was 24.3 months (range, 3.1-107.8 months) in the endocrine therapy (ET) group. Multivariate Cox regression analysis suggested that Eastern Cooperative Oncology Group (ECOG) scores and type of VC were associated with survival. Prognosis varied in different types of VC. Patients with BMM had the best prognosis, and DLM had the worst. As treatment options continue to progress, our retrospective study showed a significant prolongation of overall survival (OS) in patients with VC compared to previous studies.

Abstract 95: In vitro, in vivo and molecular effects of triptolide and minnelide in renal cell carcinoma

Abstract Background: The worldwide incidence of Renal Cell Carcinoma (RCC) is increasing. Although new therapies have improved outcomes in advanced RCC, most patients eventually fail treatment and succumb to this devastating disease. Systemic therapy strategies have focused on TKI and immunotherapy, alone or in combination. Triptolide, a diterpenoid epoxide extracted from Tripterygium wilfordii Hook f (TWHf), has potent antitumor activity in multiple cancer models. Few studies have focused on the potential of triptolide as a novel therapeutic option in RCC. Objective: the objectives of this study are to characterize the in vitro and in vivo effects of Triptolide (T) and its water-soluble form, Minnelide (M), in models of renal cell carcinoma. Methods: The in vitro effects of triptolide (T) on human and murine RCC (786-0, A498, Caki-1, ACHN, and RENCA) cell proliferation was assessed using cell count and xCelligence assays at 24, 48, 72 and 96h. Molecular and mechanistic characterization of triptolide’s effects in 786-0 cells were analyzed by the (Reverse Phase Protein Array) and validated by western blot analysis. The in vivo effects (tumor progression and survival) of M were assessed in nude mice bearing 786-0 tumors (8x106 cells per mouse). M was administered to tumor-bearing mice at two different doses (0.21mg/kg and 0.42mg/kg daily), intraperitoneally, for 21 days. Correlative studies to explain the in vivo effect of M and the correlation with the molecular changes in vitro seen are being performed and will be shown in the poster. Results: T significantly inhibited, in a dose-response manner, cell proliferation in all human and murine renal cancer cell lines, with IC50 ranging between 12.5 and 25 nM). T was associated with significant negative modulation of proliferation, cell cycle, survival, increased apoptosis, and ER stress pathways in 786-0 cells, as demonstrated by RPPA analysis and validated by western Blot of selected pathway proteins, such as apoptosis (PARP cleavage and Caspase 3 activation), ER stress induction (pEIF2a, CHOP), and down-regulation of survival and proliferation pathways (pAKT). In vivo, M was associated with significant antitumor effects in 786-0 xenografts, with complete responses in the majority of mice while on treatment. These effects were associated with significant prolongation in overall survival in M treated vs. control mice. No significant toxicity or treatment-related deaths were observed. Conclusion: Our results have shown for the first time the potent in vitro and in vivo antitumor effects of T in RCC and the molecular changes associated with these effects. The profound antitumor effects in the aggressive 786-0 RCC xenograft model are highly encouraging and warrant further preclinical studies and potential clinical trials of M this devastating disease. Correlative tumor studies to understand the mechanisms of M in vivo antitumor effects are underway and will be presented at the meeting. Citation Format: Valery A. Chavez, Floritza Bustamante, Abner Murray, Ashok Saluja, Jaime Merchan. In vitro, in vivo and molecular effects of triptolide and minnelide in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 95.

Efficacy and Safety of Immune Checkpoint Inhibitors for Advanced Malignant Melanoma: A Meta-Analysis on Monotherapy Vs Combination Therapy.

Background: Immune checkpoint inhibitors (ICIs) are approved as cancer immunotherapeutic agents for advanced malignant melanoma (MM) in recent years, and nivolumab and ipilimumab are the most widely used ICIs either alone or in combination. However, their efficacy and safety between single and combined ICIs are not clear. This meta-analysis (MA) is aimed to update the efficacy and safety of ICIs by comparing monotherapy and combination therapy in the treatment of advanced MM.Method: We searched PubMed, Embase, EbscoHost and ClinicalTrials.gov for the eligible randomized controlled trials (RCTs) which compared the efficacy and safety of ICIs between a single ICI and combined ICIs. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on the study heterogeneity.Results: A total of nine RCTs were included in this MA. Regarding the efficacy, combined nivolumab and ipilimumab therapy showed statistically significant prolonged OS and PFS with HR 0.65, 95% CI [0.53, 0.79], p <0.0001 and HR 0.48, 95% CI [0.38, 0.60], p<0.0001 respectively. Combination therapy with nivolumab and ipilimumab also showed statistically significant longer ORR than monotherapy; with RR 2.15, 95% CI [1.63, 2.84], p <0.00001. In terms of safety, the incidence of all AEs which include any AEs, high-grade, haematological, gastrointestinal, dermatological, pulmonary, liver and endocrine AEs were significantly lower with monotherapy (either nivolumab or ipilimumab) of ICI compared to combination ICI therapy with a p-value <0.00001 to 0.03.Conclusion: Efficacy of the combined nivolumab and ipilimumab was better than a single ICI, especially in the treatment of advanced MM. Although combination therapy showed better efficacy than monotherapy, monotherapy (either nivolumab or ipilimumab) was safer than combination therapy as it tended to decrease the incidence of most of the treatment-related AEs.

IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma

Inactivated Sendai virus particle, hemagglutinating virus of Japan-envelope (HVJ-E), is a non-replicating virus-derived vector, in which the genomic RNA of Sendai virus (HVJ) has been destroyed. HVJ-E is a promising vector that enables the highly efficient and safe introduction of enclosed molecules such as RNA into target cells. Moreover, HVJ-E provokes robust antitumoral immunity by activating natural killer (NK) cells and CD8+ T lymphocytes and their induction into the tumor periphery, and by suppressing regulatory T lymphocytes (Treg) locally in the tumor. In the present study, we investigated a novel combination of antitumor immunotherapy by the antitumor immune-activating effect of HVJ-E itself with the inhibition of tumor PD-L1 molecule expression. We confirmed that intratumoral injection of HVJ-E containing siRNA targeting PD-L1 (siPDL1/HVJ-E) inhibited tumor PD-L1 protein expression in a mouse subcutaneous tumor model using TS, a mouse glioma stem-like cell. We conducted treatment experiments in the mouse brain tumor model in three groups: control group (PBS), siNC/HVJ-E group (negative control siRNA + HVJ-E), and siPDL1/HVJ-E group. We obtained a significant prolongation of overall survival in the siPDL1/HVJ-E group. Flow cytometric analyses of brain tumor models showed that the proportions of brain-infiltrating CD8+ T lymphocytes and NK cells were significantly increased after giving siPDL1/HVJ-E; in contrast, the rate of Treg/CD4+ lymphocytes was significantly decreased in HVJ-E-treated tumors (siNC/HVJ-E and siPDL1/HVJ-E). No difference was observed in the proportions of macrophages or M2 macrophages. CD8 depletion abrogated the therapeutic effect of siPDL1/HVJ-E, indicating that CD8+ T lymphocytes mainly mediated this therapeutic effect. We believe that this non-replicating immunovirotherapy may be a novel therapeutic alternative to treat patients with glioblastoma. The full article has been published (Cancer Science. 2021 Jan;112(1):81–90).

DDRE-25. WSD0628: A BRAIN PENETRABLE ATM INHIBITOR AS A RADIOSENSITIZER FOR THE TREATMENT OF GBM AND METASTATIC CNS TUMOR

Abstract ATM (ataxia telangiectasia mutated) kinase, activated by DNA double-strand breaks, promotes DNA repair as well as activates DNA damage checkpoint and plays a key role for resistance to radiotherapy and chemotherapy. ATM function loss confers hypersensitivity to ionizing radiation evidenced by ataxia-telangiectasia (A-T) cells. Thus, pharmacological inhibition of ATM kinase is expected to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiotherapy and other DNA double-strand breaks-inducing chemotherapy. Herein, we report a discovery of a potent, selective, orally bioavailable, and brain penetrable ATM inhibitor WSD0628, as a radiosensitizer for GBM and metastatic CNS tumors with IC50 against ATM &amp;lt; 1nM with high selectivity ( &amp;gt;400 folds) for ATR and DNA-PK. WSD0628 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays have shown that WSD0628 is highly permeable and not a substrate of P-gp or BCRP, two main efflux transporters expressed on human BBB. Preclinical CNS PK studies in rat and mouse confirmed good brain penetration of WSD0628 with Kp,uu,brain and Kp,uu,csf &amp;gt; 0.3. Significant prolongation of overall survival for mice bearing GBM PDX intracranial model was achieved by treatment with WSD0628 (5mpk, QD) combo with radiation. Moreover, WSD0628 shows low PK variation liability without aldehyde oxidase (AO) metabolism, low hERG liability ( &amp;gt;30 uM), and good safety window based on DRF studies. Taken together, our data provide a good rationale for WSD0628 to be developed toward clinic combo with radiation for the treatment of patients with GBM and cancers with CNS metastasis.

Multimodal, interdisciplinary therapeutic concepts for liver metastasized colorectal cancer

About half of all patients with colorectal carcinoma (CRC) develop metastases mainly in the liver during the course of their disease. Metastatic disease is associated with a low 5-year overall survival rate of only 5-7 %, particularly when there is no possibility of local treatment. However, if there is an opportunity to resect the metastases, especially isolated liver metastases, the chance of long-term survival is approximately 15-27 % after both primary resection or secondary resection after neoadjuvant pretreatment. Overall, long-term survival of patients with metastatic CRC has improved significantly in recent years due to a combination of modern systemic therapies, advanced liver surgery and local ablative procedures.Of note, for the vast majority of patients, metastatic resection does not mean cure, but a significant prolongation of overall survival with a good quality of life. Chemotherapy-free intervals after metastasis resection maintain quality of life and can help to reduce toxicity.In this review, we would like to present the "toolbox" for the multidisciplinary treatment of metastatic CRC and give recommendations how the individual modalities should be optimally used, considering tumor-specific characteristics and patient preferences.

High Visceral Adipose Tissue Density Correlates With Unfavorable Outcomes in Patients With Intermediate-Stage Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Objectives: This study aimed to evaluate the association between different body composition features with prognostic outcomes of intermediate stage hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE).Methods: The areas and density of skeletal muscle area (SM) and adipose tissue [subcutaneous (SAT); visceral (VAT)] were calculated on the pre-TACE CT scans. Overall survival (OS) and progression-free survival (PFS) curves were calculated using the Kaplan–Meier method and compared with log-rank test. The discrimination and performance of body composition features were measured by area under time-dependent receiver operating characteristic (ROC) curve. Univariate and multivariate Cox proportional hazard analyses were applied to identify the association between body composition parameters and outcomes.Results: A significant prolonged OS and PFS was displayed by Kaplan–Meier curve analysis for HCC patients with VAT HU below −89.1 (25.1 months, 95% CI: 18.1–32.1 vs. 17.6 months, 95% CI: 16.3–18.8, p < 0.0001, 15.4 months, 95% CI: 10.6–20.2 vs. 6.6 months, 95% CI: 4.9–8.3, p < 0.0001, respectively). The 1-, 2-, 3-, and 5-year OS area under the curve (AUC) values of the VAT HU were higher than the other body composition parameters. Meanwhile, it is also found that 3-, 6-, 9-, and 12-month PFS AUC values of VAT HU were the highest among all the parameters. Univariate and multivariate Cox-regression analysis suggested a significant association between VAT density and outcomes (OS, HR: 1.015, 95% CI: 1.004–1.025, p = 0.005, PFS, HR: 1.026, 95% CI: 1.016–1.036, p < 0.0001, respectively).Conclusion: The VAT density could provide prognostic prediction value and may be helpful to stratify the intermediate stage HCC patients.

Aberrant Hedgehog Signaling in Myelodysplastic Syndrome Accelerates Leukemic Transformation Via Smoothened-Dependent and Smoothened-Independent Gli1 Activation

Introduction: Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders with increased risk of transformation to secondary acute myeloid leukemia (sAML) that carries uniformly dismal prognosis. The exact mechanisms driving this process remain obscure. Aberrant Hedgehog (Hh) signaling has been demonstrated in a number of solid tumors and hematologic malignancies. An emerging body of literature suggests the importance of Hh signaling in leukemic transformation of MDS. Moreover, a recent Phase II clinical trial using Smoothened (SMO) inhibitor with low-dose chemotherapy resulted in significant prolongation of overall survival (Lancet et al. Blood 2016). Thus, we sought to examine the clinical impact of aberrant Hh activation in MDS and further explore the mechanism of Hh-driven leukemic transformation.Methods/Results:To determine the pathway activity, we quantified the level of GLI1 in CD34+ cells from patients with MDS and healthy controls in published databases (N=17 and N=159, respectively; GSE58831) and while absent in controls, GLI1 was significantly upregulated in MDS patients (p<0.05). Analysis of serial samples revealed Hh activation at disease progression in 67% of patients (4/6). In addition, GLI1 levels were significantly higher in poor-risk AML with complex cytogenetics comparing to favorable risk disease (p<0.001, TCGA).To further evaluate the impact of of Hh activation in MDS progression, we crossed Nup98-HoxD13 (NHD13) mice with mice conditionally expressing the constitutively active mutant of Smoothened (SmoM2). Double transgenic NHD13/SmoM2 mice succumbed to aggressive myeloid leukemia (median survival of NHD13/SmoM2 and NHD13 controls, 3 months vs. 13 months, respectively, p<0.0001) characterized by leukocytosis (p<0.05), splenomegaly (p<0.0001) and significant expansion of immature myeloid progenitors in peripheral blood (p<0.0001) and bone marrow (p<0.0001). Analysis of hematopoietic stem/progenitor (HSPC) compartment revealed expansion of phenotypic granulocyte macrophage progenitors (GMP) (6244 vs. 131487 mean GMPs/femur , in NHD13 v. NHD13/SmoM2 respectively, p<0.05). To determine whether Hh activation resulted in aberrant self-renewal in GMP compartment, we carried out an in vivo repopulation assay. While NHD13 GMPs showed only transient engraftment, characteristic of non-self-renewing progenitors, NHD13/SmoM2 GMPs robustly engrafted and significantly expanded over time, and all recipient animals developed aggressive leukemia within 2-3 months. The engraftment was sustained through secondary transplantation. Our results suggest that Hh activation resulted in abnormal self-renewal in normally non-self-renewing progenitors.To delineate the mechanism leading to aberrant activation of self-renewal we compared the transcriptome of GMPs isolated from NHD13/SmoM2 and NHD13 controls. In addition to expected Hh activation, Gene Set Enrichment Analysis (GSEA) showed enrichment in gene signatures associated with other developmental pathways such as Wnt or TGF-β signaling as well as EWS/FLI1-protooncogen signature. Interestingly, these pathways have been found to act via direct activation of GLI1 .Using human AML (TF-1) and MDS (MDS-L) cell lines we confirmed that GLI1 may be activated in the absence of SMO. GLI1 knock-down and/or inhibition with GANT61 resulted in growth arrest (p<0.05, both) and significantly lower clonogenic potential in vitro (p<0.05, both) more so than upstream SMO inhibition.Conclusions: Our data suggest that aberrant Hh/GLI1 signaling is frequent in MDS and marks disease progression and leukemic transformation. In some cases, GLI1 can be activated in a SMO-independent manner and therapeutic strategies focused on targeting downstream Gli transcription factors may be more effective than currently used Smo inhibitors. DisclosuresNo relevant conflicts of interest to declare.

Abstract PS10-16: Real-world efficacy of ribociclib + aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Third interim analysis from the RIBANNA study

Abstract Background: In MONALEESA-3 and MONALEESA-7 trials, ribociclib (RIB, a selective CDK4/6 inhibitor) in combination with endocrine therapy (aromatase inhibitor [AI] or fulvestrant [FUL]) demonstrated a significant prolongation of overall survival among patients with breast cancer (BC), regardless of menopausal status and treatment-line. In the premenopausal or perimenopausal women, RIB + AI/FUL should be combined with a luteinizing hormone-releasing hormone agonist. The real-world evidence for the effectiveness, safety, and tolerability of RIB + AI/FUL in the routine clinical practice is needed to support the use of this combination. Methods: RIBANNA is a prospective, non-interventional study ongoing in Germany since October 2017. Pre-, peri- and postmenopausal women (planned, n = 3020) treated with RIB + AI/FUL, or endocrine monotherapy (ET), or chemotherapy (CT) as the first-line treatment for HR+/HER2- aBC in accordance with German guidelines were included. Data from routine clinical practice in all 3 cohorts, including further lines of sequential therapy, were collected. Updated data on baseline demographics and safety analysis will be presented. Additionally, first experience with CANKADO, an innovative digital and patient-friendly application for electrocardiogram (ECG) measurement, are described. By combining this app to Kardia mobile (AliveCor’s single lead device), single-lead ECG can be recorded and sent via the CANKADO app for a cardiologist to read over. The cardiologist reviews the measurements, and reports the corrected QT interval by Fredericia (QTcF) results towards the trial site. Impact of the use of CANKADO onto the clinical routine will be analyzed. Results: For the second interim analysis, 1141 patients were enrolled until July 12th, 2019, while the full analysis set comprised 813 patients (Table 1). Median duration of RIB exposure in patients on RIB + AI/FUL vs total population was 151 vs 150 days respectively. At cut-off date, patients received first-line (89%, n = 1016), second-line (7%, n = 82), and third-line treatments (1%, n = 11). A starting dose of 600 mg per day for RIB in the first-line setting was seen in most of the patients (85%); data of second-line patients will be reported later. The first-line mean daily dose of RIB was 451.6 mg/day RIB was prescribed mainly in combination with letrozole (75%), fulvestrant (12%), anastrozole (7%), and exemestane (6%). A total of 62% of patients in the study were documented as therapy-naïve for ET. Of 424 patients with early breast cancer, 129 (30%) had documented prior CT without ET. The most common all-grade adverse events frequently noted in RIB + AI/FUL cohort in comparison with other cohorts were nausea (RIB [19%] vs ET [9%] vs CT [11%]), neutropenia (19% vs 1% vs 10%), fatigue (17% vs 9% vs 14%), and leukopenia (14% vs 4% vs 12%). The usage of CANKADO application to assess QTcF was initiated in the year 2019 and first data will be presented. Conclusion: RIBANNA study showed diverse population characteristics among the patients who received RIB treatment in a real-world setting. The third interim analysis is planned in October 2020, and the updated baseline data, information on safety, digital ECG measurement using CANKADO application will be presented. Baseline Demographic Characteristics as of Second Interim AnalysisDemographic VariableRIB + AI/FUL (n = 658)Endocrine Therapy (n = 78)Chemotherapy (n = 77)Mean age, years (SD)67 (11)72 (12)62 (10)Mean time since initial diagnosis, years6.17.23.6T stage at baseline*, n (%)TX204 (31)28 (36)18 (23)T0+T1132 (20)12 (15)11 (14)T2-T4302 (46)35 (45)42 (54)N stage at baseline*, n (%)NX212 (32)29 (37)28 (36)N0+N1317 (48)36 (46)35 (46)N2+N3108 (16)10 (13)8 (10)M stage at baseline*, n (%)MX6 (1)0 (0)0 (0)M018 (3)1 (1)1 (1)M1616 (94)75 (96)71 (92)Metastatic location at baseline*, n (%)CNS, liver, lungs258 (39)14 (18)42 (54)Bone only181 (28)42 (54)11 (14)Skin, lymph nodes, other149 (23)16 (20)14 (18)*Remaining cases are missing.CNS, central nervous system. Citation Format: Achim Wöckel, Cosima Brucker, Thomas Decker, Jörg Falbrede, Helmut Forstbauer, Thomas Göhler, Oliver Hoffmann, Christian Jackisch, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Frederik Marmé, Arnd Nusch, Toralf Reimer, Christian Roos, Marcus Schmidt, Rudolf Weide, Peter Fasching. Real-world efficacy of ribociclib + aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Third interim analysis from the RIBANNA study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-16.

PC04.02 CON: ICI Is Enough

PC04.02 CON: ICI Is Enough

EGFR-TKI plus brain radiotherapy versus EGFR-TKI alone in the management of EGFR-mutated NSCLC patients with brain metastases.

It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) presented better efficacy than brain radiotherapy (brain RT) in the treatment of brain metastasis (BM) in EGFR mutated NSCLC patients. However, whether the combination of EGFR-TKIs and brain RT is better than EGFR-TKIs alone remains unclear. We aim to compare the outcomes of adding brain RT to EGFR-TKIs and to screen for the beneficial population by a meta-analysis of currently available data. A systematic search for relevant articles was conducted in six databases. The outcomes were overall survival (OS) and intracranial progression-free survival (iPFS) between groups, both were measured as hazard ratios (HRs). Meta-regression and dominant subgroup analysis were used to explore advantageous subgroups. A total of 12 retrospective studies involving 1,553 EGFR mutated patients with BM at the first diagnosis were included. EGFR-TKIs plus brain RT showed a significant prolonged OS (HR =0.64, 95% CI: 0.52-0.78; P<0.001) and iPFS (HR =0.62, 95% CI: 0.50-0.78; P<0.001) compared to EGFR-TKIs alone. Meta-regression analyses showed that potential factors contributed to the heterogeneity were the proportion of ECOG performance score (2+ vs. 0-1, P=0.070) and brain symptomatic patients (no vs. yes, P=0.077) regarding iPFS and was age (younger vs. older, P=0.075) for OS. Dominant subgroup analyses suggested that symptomatic patients (HR 0.46 vs. 0.74, interaction P=0.01) for iPFS, and older patients (HR 0.55 vs. 0.75, interaction P=0.03) and 19Del mutation (HR 0.55 vs. 0.74, interaction P=0.04) for OS, seemed to benefit more from the combination therapy than their counterparts. However, direct subgroup results based on only two studies did not show significant difference in iPFS benefit between age, mutation type and sex subgroup. EGFR-TKIs plus brain RT is superior to EGFR-TKIs alone in the management of EGFR-mutated NSCLC patients with BM, of which the benefits might be influenced by age, BM-related symptoms and mutation type.

Timing of docetaxel chemotherapy and impact on outcomes in metastatic castrate-resistant prostate cancer (MCRPC).

298 Background: Docetaxel use has led to a significant prolongation in overall survival (OS) in metastatic prostate cancer after castrate resistance, with a more substantial OS gain when used in combination with initial androgen deprivation therapy (ADT). There is however limited information on outcomes in patients who initially do not receive chemotherapy, perhaps through patient choice or impaired performance status, who become suitable for docetaxel, comparing earlier with later docetaxel treatment. Methods: We retrospectively reviewed patients’ electronic clinical and prescribing records diagnosed with MCRPC and treated with docetaxel from 01/01/2006 to 24/11/2016 in a single centre in the UK. Data was reviewed for number of individual treatments received pre and post chemotherapy, including initial ADT, enzalutamide, abiraterone, docetaxel, cabazitaxel, mitoxantrone, radium 223, single agent steroids and diethylstilboestrol. Prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and OS were also reviewed. Results: 168 consecutive patients with MCRPC receiving docetaxel were reviewed. Median Gleason grade across the three groups was 8. 48 patients (29%) received docetaxel after 1 or 2 previous treatments, 105 (63%) after 3 or 4 previous treatments and 15 (9%) after 5 or 6. PSA response rates were superior in the earlier treated group (61%, p=0.003), compared with 30% and 31% respectively in the later groups. Median number of cycles was 5.5 overall, with a mean weighted dose received of 396mg/m2, 373mg/m2 and 301mg/m2 in the after 1 or 2 treatments, after 3 or 4 treatments and after 5 or 6 treatment groups. Median OS from castrate resistance for the earlier group was 29 months, not significantly less (p=0.1) than the 35 months for an intermediate number of prior treatments and 42 months for the later treated group. Conclusions: In this group of patients in routine clinical practice who do not receive docetaxel with initial ADT, PSA response rates are significantly improved and overall dose received is higher with subsequent earlier use. However, overall survival is not significantly different between the early and later docetaxel treated patients.

Docetaxel in older patients for metastatic prostate cancer.

187 Background: Docetaxel use has led to a significant prolongation in overall survival in metastatic prostate cancer (MPC). There is however limited information on treatment tolerance and outcomes in patients 80 years old and over in routine clinical practice. With the ever aging population it is becoming more important to assess outcomes in this age group. Methods: Patients diagnosed with MPC and treated with docetaxel from 2006 to 2016 were identified and their records retrospectively reviewed via electronic clinical and prescribing systems in a single centre in the UK. Data was assessed for prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and castrate resistant overall survival (OS). Results: 209 consecutive patients with MPC receiving docetaxel were reviewed. Three patient groups were identified; younger than 75 years old (n = 150, 37 early (as part of initial therapy) docetaxel), 75-79 years (n = 40, 2 early docetaxel) and 80 years or over (n = 19, no early docetaxel). When comparing mean OS excluding early docetaxel treatment, respective mean survival times for each of the three age groups, younger to older were 1001, 1045 and 1294 days, with between class difference being insignificant. The PSA response rates to docetaxel excluding first line use were compared between the age groups and did not show a significant difference at 39% in the youngest group, 38% in the intermediate age group and 42% for the oldest patients. There was a trend that the older the patient, the more likely docetaxel was the final systemic treatment given at 42% (80 years or over), 32% (75-79 years) and 23% (younger than 75 years). The 80 years or over group received fewer docetaxel cycles (3.8, p = 0.006) and less dose per course (226mg/m2, p = 0.004) than the group less than 75 years (5.8 cycles, 409mg/m2) and 75-79 years (5.1 cycles, 341mg/m2). Conclusions: In this group of patients, in routine clinical practice, the 80 years and over age group received fewer cycles of docetaxel in MPC and less dose per course, but nevertheless achieved similar PSA response rates and castrate resistant OS. Given these results, docetaxel should be considered as a treatment option in suitable patients of 80 years and over.

Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives.

Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.

Functional Cure, Defined As PFS of More Than 7 Years, Is Achieved in 9% of Myeloma Patients in the Era of Conventional Chemotherapy and of First-Generation Novel Anti-Myeloma Agents; A Single-Center Experience over 20-Year Period

Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period after first-line therapy. The aim of this analysis was to evaluate the characteristics of patients who achieved at least 7-year of PFS after frontline therapy and compare them with those of all other patients who were treated in a single center during the same time period. Between January 1994 and December 2010, 406 consecutive newly diagnosed MM patients received first line therapy in the Department of Clinical Therapeutics (Athens, Greece). All patients had symptomatic disease, based on the IMWG criteria of that period (at least one CRAB symptom to start anti-myeloma therapy). Thirty-six (8.8%; 23M/13F) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. The median PFS of these 36 patients is 10 years, while the other patients had a median PFS of 22 months. Long PFS patients were younger (median age 56 vs 68 years; p All patients received either conventional chemotherapy (CC) or first-generation novel anti-myeloma agent (bortezomib (B), thalidomide (T) or lenalidomide (R)-based regimens as frontline therapy. There was no difference between the two groups regarding CC versus novel agent-based induction treatment. Out of 36 long-term PFS patients, 11 (30%) received CC, 8 (22%) B-based, 8 (22%) RD, 6 (17%) T-based, and 3 (8%) VTD; 10 (28%) patients received first-line therapy participating in a clinical trial. Long PFS patients had received more often autologous stem cell transplantation (ASCT, 61% vs 23%; p=0.001) as part of first line therapy; therefore, more long PFS patients had also received consolidation and/or maintenance (50% vs 15%; p=0.001). Higher proportion of patients achieved at least VGPR (74% vs 41%) or at least CR (32% vs 18%) in the long PFS group. We performed next generation flow cytometry in 23 patients of the long PFS group to evaluate minimal residual disease (MRD) and 14 (61%) of them were MRD (-) at the level of the 10-6. The probability of achieving long PFS (≥7 years) for patients who managed to be progression-free at 2, 3 and 4 years was 11.6%, 13.2% and 15.3%, respectively. In the multivariate analysis, only younger age was associated with probability for long PFS (p In conclusion, our study in an unselected group of patients, the majority of whom did not participate in clinical trials, showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years (median: 10 years) even in the era of CC or first-generation novel agents. These patients have low risk disease, mainly of ISS-1 or -2, no high-risk cytogenetics, no or mild renal impairment, and achieve deep responses after ASCT. These patients may be considered as "functionally" cured. The incorporation of novel treatment approaches may lead to a significant improvement in the probability of achievement of this "functionally" cured status. Disclosures Terpos:Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding. Kastritis:Prothena: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Dimopoulos:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria.