Efficacy Of Systemic Therapy Research Articles

Evolution of systemic treatment for advanced hepatocellular carcinoma.

Advanced hepatocellular carcinoma (HCC) was considered an inherently refractory tumor in the chemotherapy era (1950-2000). However, systemic therapy has evolved to molecular targeted therapy and immunotherapy, and nine treatment regimens have been approved worldwide during the past 20 years. The approved regimens target tumor angiogenesis or tumor immunity, the two cancer hallmarks. Recently, the combination of atezolizumab (antiprogrammed cell death ligand 1) and bevacizumab (anti-vascular endothelial growth factor) has improved the efficacy of systemic therapy in treating advanced HCC without excessive toxicities or deterioration of quality of life. This review summarizes the major advances in systemic therapy and provides future perspectives on the next-generation systemic therapy for advanced HCC.

Antitumoral Activity of the MEK Inhibitor Trametinib (TMT212) Alone and in Combination with the CDK4/6 Inhibitor Ribociclib (LEE011) in Neuroendocrine Tumor Cells In Vitro.

Simple SummarySystemic treatment options for advanced neuroendocrine tumors have significantly been improved in the last decade. However efficacy of systemic therapy is limited by tumor resistance and therefore there is a need for further treatment options. Inhibition of the Ras-Raf-Mek-Erk signaling cascade might be a promising new treatment strategy in neuroendocrine neoplasms. In this study we investigated the effects of the MEK inhibitor trametinib, the ERK inhibitor SCH772984 and the CDK4/6 inhibitor ribociclib in human neuroendocrine tumor cell lines BON1, QGP1 and NCI-H727 in vitro. Trametinib alone and in synergism with ribociclib demonstrated antiproliferative effects. Combination therapy of MEK inhibitors and CDK4/6 inhibitors might be a potential strategy to overcome CDK4/6 inhibitor resistance in neuroendocrine tumors.Objectives: This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro. Methods: Human NET cell lines BON1, QGP-1, and NCI-H727 were treated with trametinib or SCH772984, alone and in combination with ribociclib, to assess cell proliferation, cell cycle distribution, and protein signaling using cell proliferation, flow cytometry, and Western blot assays, respectively. Results: Trametinib and SCH772984, alone and in combination with ribociclib, significantly reduced NET cell viability and arrested NET cells at the G1 phase of the cell cycle in all three cell lines tested. In addition, trametinib also caused subG1 events and apoptotic PARP cleavage in QGP1 and NCI-H727 cells. A western blot analysis demonstrated the use of trametinib alone and trametinib in combination with ribociclib to decrease the expression of pERK, cMyc, Chk1, pChk2, pCDK1, CyclinD1, and c-myc in a time-dependent manner in NCI-H727 and QGP-1 cells. Conclusions: MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed.

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively. Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.

Current Status and Future Targeted Therapy in Adrenocortical Cancer.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The current treatment standards include complete surgical resection for localized resectable disease and systemic therapy with mitotane alone or in combination with etoposide, doxorubicin, and cisplatin in patients with advanced ACC. However, the efficacy of systemic therapy in ACC is very limited, with high rates of toxicities. The understanding of altered molecular pathways is critically important to identify effective treatment options that currently do not exist. In this review, we discuss the results of recent advanced in molecular profiling of ACC with the focus on dysregulated pathways from various genomic and epigenetic dysregulation. We discuss the potential translational therapeutic implication of molecular alterations. In addition, we review and summarize the results of recent clinical trials and ongoing trials.

The Role of Radiation Therapy for Symptomatic Desmoid Tumors

Desmoid tumors have a variable clinical course that ranges from indolence or spontaneous regression to an aggressive pattern marked by local invasion. Up to half may remain stable or regress; watchful waiting is the preferred approach in the initial management of desmoid tumors. Symptomatic or progressive tumors or those that may affect adjacent critical structures require surgery, radiotherapy, or systemic therapy. Although radiotherapy effectively controls desmoid tumors in most cases, concerns regarding late toxicity exist. Definitive radiotherapy for macroscopic disease is indicated when a non-morbid complete surgical resection cannot be accomplished and provides similar control rates to surgery plus radiotherapy but avoids toxicity from combined-modality treatment (surgery and radiotherapy). Adjuvant radiotherapy can be considered for microscopically involved margins, particularly for recurrent cases or when a future recurrence may be challenging to treat. Large size, extremity site, and younger age are poor prognostic factors after radiotherapy. In the extremity, radiotherapy may have superior outcomes to surgery. Younger patients, especially children, are challenging to manage as they are at particular risk for late toxicity due to the number of potential years at risk. For patients under 20 years old, for whom a non-morbid complete resection is not possible, we recommend systemic therapy as the first line of treatment. Although the long-term efficacy of systemic therapy is unproven, this strategy allows additional time for growth and development prior to radiotherapy. In younger patients and those with axial desmoid tumors adjacent to critical organs, consideration should be given to using proton therapy as the dosimetric advantages may mitigate some of the toxicity associated with conventional radiotherapy.

Comparison of Efficacy of Systemic Therapies in Advanced Hepatocellular Carcinoma: Updated Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials.

BackgroundSeveral systemic agents have been approved for use in advanced hepatocellular carcinoma (aHCC). However, it is unclear which treatment is superior in either the first- or second-line settings due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings.MethodsRandomized clinical trials evaluating systemic agents in first and second line settings in aHCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and the annual ASCO and ESMO conferences from 2017 to 2020. Studies in English reporting clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. The primary outcomes of interest were pooled hazard ratios (HR) of OS and pooled odds ratios (OR) of ORR in first line studies and pooled HR of PFS and OR of ORR for second line studies. Additionally, OS for second line agents were reported in the qualitative analysis.ResultsOverall, first line studies comprised 8335 patients (13 studies) and second line studies comprised 4612 patients (11 studies). In the first line setting, atezolizumab plus bevacizumab was associated with the highest OS benefit over sorafenib (HR 0.58, 95% CI, 0.42–0.80; P-score 0.993). Additionally, lenvatinib was associated with the greatest ORR benefit (OR 3.34, 95% CI, 2.17–5.14; P-score 0.080) in the first line setting. In the second line setting, cabozantinib was associated with the highest PFS benefit over placebo (HR 0.44, 95% CI, 0.29–0.66; P-score 0.854) as well as the highest ORR benefit (OR 9.40, 95% CI, 1.25–70.83, P-score, 0.266).ConclusionAtezolizumab plus bevacizumab appears to have superior efficacy among first line agents whereas cabozantinib appears to be superior in the second line setting. Further studies are warranted to determine whether the type of prior therapy received affects the efficacy of subsequent second line therapy.

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease.

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the “Murine Ommaya.” As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.

Comparison of systemic therapy efficacy in advanced hepatocellular carcinoma: Systematic review and frequentist network meta-analysis of randomized controlled trials.

293 Background: Several systemic agents are approved for use in the first line and second line treatment settings for advanced hepatocellular carcinoma (aHCC). However, choosing among available options in both first and second line settings remain difficult due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. Methods: Published clinical trials that have evaluated systemic agents in the first line and second line settings in advanced HCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and abstracts presented in the main annual ASCO and ESMO conferences from 2017 to 2020. Studies published in English providing clinical outcomes data including overall survival (OS), progression free survival (PFS) and objective response rate (ORR) were included in the analysis. The primary outcomes of interest were pooled hazard ratios (HR) of OS and OR of ORR in first line studies and HR of PFS and OR of ORR for second line studies. OS for second line agents were synthesized in a qualitative analysis. Results: Overall, 8,335 patients (13 studies) and 4,612 patients (11 studies) were analyzed in phase II/III trials for first line and second line settings respectively. In the first line setting, atezolizumab plus bevacizumab and lenvatinib were ranked highest as the regimens associated with the greatest OS (A+B, HR 0.58, 95% CI, 0.42-0.80; P-score 0.993) and ORR (lenva, OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) respectively. In the second line setting, cabozantinib showed the highest probability of greatest PFS benefit (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest probability of greatest ORR benefit (cabo, OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). Conclusions: In the first line setting, atezolizumab plus bevacizumab may be the superior regimen whereas lenvatinib may be considered as the initial option when robust tumor responses are preferred. In the second line setting, cabozantinib may be the preferred option including in cases when robust tumor responses are favored.

Pursuing efficacious systemic therapy for hepatocellular carcinoma.

In 2020, combination treatments have pushed the efficacy of systemic therapy for hepatocellular carcinoma (HCC) to an unprecedented high, providing a solid base for the future pursuit of further improved, highly efficacious systemic therapies for HCC.

Therapy in Advanced Hepatocellular Carcinoma.

Treatment of advanced hepatocellular carcinoma (HCC) is challenging. Several randomized clinical trials are investigating the efficacy of systemic therapy, immunotherapy, and locoregional therapy as monotherapy or combined with other modalities in the treatment of HCC. Systemic therapy is the preferred treatment in advanced disease. To date, multiple first-line and second-line agents received Food and Drug Administration approval. For over a decade, sorafenib was the only first-line agent. In May 2020, combination of atezolizumab and bevacizumab has been approved as a first-line systemic regimen. Lenvatinib is another first-line agent that has multikinase activity. Second-line agents include cabozantinib, regorafenib, ramucirumab, and nivolumab. Adoptive cell transfer therapy is a highly specific immunotherapy that has shown antitumor activity against HCC. Oncolytic viruses are genetically modified viruses that infect cancer cells and induce apoptosis. Locoregional therapies such as transarterial chemoembolization and radioembolization have shown a potential benefit in selected patients with advanced HCC. In this review, we aim to summarize the treatment options available for advanced HCC.

Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ∼800 000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 was significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlate with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestalled tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival.

IMMUNE EFFECTS OF STEREOTACTIC ABLATIVE RADIATION THERAPY IN PATIENTS WITH MALIGNANT TUMORS: LITERATURE REVIEW

The purpose of the study was to conduct a systematic analysis of the data available in the modern literature on the systemic (abscopal) effects in radiation therapy, which are mediated by immunological phenomena.Material and Methods.A structured search for articles published in peer-reviewed journals between January 2000 and February 2019 was conducted using MEDLINE database. The review included data from registered clinical trials at Clinicaltrials.gov, showing the results of the combined use of immunotherapy and radiation therapy.Results. There is an opinion that the systemic effect of radiotherapy is mediated by immunological phenomena. In connection with the recent data, there is a growing interest in the combined use of immunotherapy with radiation therapy in order to increase the efficacy of systemic therapy. However, the incidence of abscopal effects after standard radiation treatment is very low. In this regard, stereotactic ablative radiotherapy, due to its high immunogenic potential, low toxicity and short duration of the treatment, is apparently an attractive partner for immunotherapy in patients with metastatic disease.Conclusion. In view of the variety of the immunological effects of radiotherapy, further studies of the effect of radiation therapy on the immune system of cancer patients are needed, and the use of various combinations of immunotherapy and radiation therapy should be continued. All this, ultimately, will help improve the survival rates of cancer patients.

Metastasis Directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-Resistant Prostate Cancer

Metastasis Directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-Resistant Prostate Cancer

Review: Brain Metastases in Bladder Cancer

Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.

Radiographical efficacy of systemic treatment for bone metastasis from renal cell carcinoma.

Enlarged bone metastasis from renal cell carcinoma (RCC) can cause skeletal-related events, and thus treatment to inhibit the growth of bone metastases is often required. Although radiotherapy for RCC bone metastases can achieve a certain degree of local control, evidence is lacking regarding the effects of systemic therapy to improve bone metastasis. The present study aimed to assess the treatment efficacy of targeted therapy and immune checkpoint inhibitors, and to determine whether systemic therapy without radiotherapy can shrink bone metastases of RCC. The present study retrospectively reviewed 44 patients with RCC with bone metastases treated via systemic therapy, including targeted therapy or immune checkpoint inhibitors. Patients were divided into two groups: Those who underwent systemic therapy with radiotherapy for bone lesions (n=29); and those who underwent systemic therapy without radiotherapy for bone lesions (n=15). The radiographical efficacy of systemic therapy and the time to progression of bone metastases were compared between groups. The overall response rate of systemic therapy with radiotherapy was 44%, and in total, 13 patients demonstrated a partial response. Only one patient (6%) had a partial response among those who were treated via systemic therapy without radiotherapy. The time to progression of bone metastasis was 9.5 and 2.1 months in patients treated with and without radiotherapy, respectively (P<0.0001). Collectively, the present results suggested that targeted therapy or immune checkpoint inhibitors without radiotherapy had only a slight effect on bone metastasis control.

P-190 A retrospective study of regorafenib versus trifluridine/tipiracil efficacy in chemorefractory metastatic colorectal cancer patients: Multi-institution real-life clinical data

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Over the last two decades, median overall survival (OS) for patients with metastatic CRC (mCRC) has increased to roughly 30 months due to the improvements in the number and efficacy of systemic therapies. Recently, two novel drugs have been approved for the treatment of chemorefractory mCRC patients such as regorafenib and trifluridine/tipiracil (TAS-102). However, despite their clinical approval, it still remains unclear which of these two drugs should be used first because of a lack of head-to-head randomized trials.

Metastasis-directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-resistant Prostate Cancer

BackgroundAvailable therapies for castrate-resistant prostate cancer (CRPC) confer minimal survival advantage; thus, there is interest in metastasis-directed therapy (MDT) for oligometastatic or oligoprogressive disease to improve outcomes. Here, we describe outcomes of oligoprogressive CRPC treated with stereotactic ablative radiotherapy (SABR). ObjectiveTo report outcomes of oligoprogressive CRPC treated with MDT using SABR. Design, setting, and participantsPatients with oligoprogressive CRPC were retrospectively evaluated, and outcomes following MDT were reported. Outcomes were additionally compared with oligoprogressive CRPC treated with change in systemic therapy alone. InterventionSABR to oligoprogressive lesions. Outcome measurements and statistical analysisOutcomes of interest were time to prostate-specific antigen (PSA) failure, time to next intervention (TTNI), distant metastasis-free survival (DMFS), and overall survival. Survival analysis was performed using the Kaplan-Meier method, and univariable analysis and multivariable analysis (MVA) were performed. Results and limitationsA total of 68 patients were included. After MDT, median time to PSA recurrence, TTNI, and DMFS were 9.7, 15.6, and 10.8 months, respectively. A total of 112 lesions were treated, and the cumulative incidences of local failure at 12 and 24 months were 2.1% and 13.8%, respectively. Factors associated with the risk of local recurrence on univariable analysis were age (hazard ratio [HR] 1.07, p = 0.03) and Gleason grade group (HR 2.20, p = 0.07). Compared with change in systemic therapy alone (n = 52), MDT (n = 31) was associated with improved median time to PSA failure (9.7 vs 4.2 months, p = 0.066)), TTNI (14.9 vs 8.8 months, p = 0.025), and DMFS (12.7 vs 8.9 months, p = 0.045), and remained associated with improved outcomes on MVA. ConclusionsIn a retrospective cohort of oligoprogressive CRPC patients, MDT was associated with favorable outcomes and improved cancer control as compared with change in systemic treatment alone. Future prospective trials are needed to confirm these findings. Patient summaryIn this report, we retrospectively analyzed outcomes of patients with oligoprogressive castrate-resistant prostate cancer treated with radiation therapy to progressing lesions. Our results suggest that treatment of these lesions with radiation therapy can result in sustained periods of disease-free survival and might add benefit in addition to systemic therapy at the time of progression. These results need to be verified in a prospective trial to identify the optimal integration of radiation therapy into metastatic castrate-resistant prostate cancer.

Comprehensive analysis of long noncoding RNA expression in circulation of breast cancer patients on neoadjuvant therapy.

e12644 Background: Though long considered “nonfunctional”, recent evidence is growing that non-coding RNAs, including long non-coding RNAs (lncRNAs), have an active role in tumor biology, mainly as gene expression regulators. Breast cancer is heterogeneous in nature and locally advanced cases are distinct entity in terms of curability. Being borderline between early and metastatic disease, long-term outcome here strongly depends on the efficacy of systemic therapy. To the best of our knowledge, no study has yet investigated global changes of circulating lncRNAs in this patient population during preoperative (neoadjuvant) treatment. Methods: We conducted a small transcriptomic trial on 10 locally advanced breast cancer patients, assessing lncRNA and messenger RNA (mRNA) expression in plasma samples before (S1) and after (S2) initiation of neoadjuvant therapy. Next-generation sequencing was performed with differential gene expression analysis between S1 and S2 groups. We assessed co-expression between lncRNAs and mRNAs, identifying mRNAs whose transcription was potentially regulated by lncRNAs, i.e. “lncRNA target genes”. In order to elucidate biological roles of these target mRNAs, we performed gene ontology (GO) and pathway analysis (Kyoto Encyclopedia of Genes and Genomes, KEGG). Results: 394 lncRNAs and 1085 mRNAs demonstrated statistically significant difference in expression between pretreatment and posttreatment samples. Co-expression analysis revealed positive correlation between 25 lncRNAs and 25 mRNAs located in cis, while potential trans interactions exceeded 105. GO evaluation of lncRNA target genes was significant for 44 terms: 28 for biological process (BP), 9 for cellular component (CC) and 7 for molecular function (MF). The most annotated terms for BP, MF and CC were respectively biosynthetic process, DNA-binding transcription factor activity and nucleus. KEGG analysis showed that 105 of 201 analyzed pathways were statistically significant with most prominent being pathways in cancer and transcriptional misregulation in cancer. Conclusions: Despite limited in size, present study provides broad view on transcriptional landscape in blood circulation, interrogating in vivo dynamics of systemic gene expression during neoadjuvant breast cancer treatment. It demonstrates that substantial number of circulating lncRNAs could be up- or downregulated in the course of therapy and this has the potential to control protein-coding genes that are tightly implicated in cancer biology.

Predictors of first line systemic therapy for metastatic renal cell carcinoma in IMDC favorable risk patients.

e17086 Background: With the induction of molecular targeted agents, which interfere with proteins that play critical roles in tumor growth and progression, and immune checkpoint inhibitors (ICI), the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) have dramatically been changed with improved survival. Prognostic risk assessment is essential for choosing the most appropriate first line treatment option, with selection based on International Metastatic RCC Database Consortium (IMDC) Risk Category. This study was designed to evaluate the actual efficacy of systemic therapy in the IMDC favorable risk group patients with mRCC. Methods: A total of 218 patients with mRCC who received systemic therapy were retrospectively reviewed (Institutional review board approval No 2013-0425). Among them, 55 (25%) patients were classified as favorable risk group based on the IMDC Risk Category. These mRCC patients in the favorable risk were divided into 2 groups by following factors; gender (male or female), age (≥70, or not), baseline serum CRP levels (≥0.6, and &lt; 0.6 mg/dl), metastatic sites (exclusive lung, or lung and others), BMI (≥22, or &lt; 22), respectively. The overall survival (OS) of patients in the favorable risk group were compared between the two cohorts. Results: The median PFS for first line treatment and OS of patients in favorable risk group were 31.6 (95% CI 19.9–33.7)) and 85.8 (56.8-NE) months, respectively. The median OS in patients with BMI≥22 and &lt; 22 was 65.6 (95% CI 56.8–NE) and 56.8 (95% CI 30.8–NE) months, respectively (p = 0.0497). The median OS in patients with exclusive lung metastasis, and lung and other metastases were 115.1 (95% CI NE) and 65.6 (95% CI 43.9–NE) months, respectively (p = 0.0073). No significant difference was found in OS between male and female, age≥70 and &lt; 70, and baseline serum CRP levels ≥0.6 mg/dl and &lt; 0.6, respectively. Conclusions: The first line systemic treatment for mRCC patients in IMDC favorable risk group was feasible and effective in patients with BMI≥22 or exclusive lung metastasis.

An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non–small-cell lung cancer

BackgroundDissemination of non–small-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts. MethodsWe identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter® PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software. ResultsWe compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours. ConclusionsWe identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.