bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of bioinformatics approach to identify indications for PFKFB3-mediated glycolysis inhibition as potential anticancer treatment.
Authors: Khodova Kristina , Pyatnitskiy Mikhail , Eremeeva Tatiana , Fedichev Peter
Published: September 2018

e23158

Background: Glycolysis is one of the mechanisms which enables cancer cells to adapt to intermittent oxygen deprivation and obtain the best available metabolic strategy in the lack of resources. Therefore, inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) enzyme, one of the glycolysis pathway regulators, may result in decreased tumor metabolism, as well as suppressed cell growth. Additionally it has been shown that PFKFB3 is involved in angiogenesis regulation, which contributes to tumor growth, and in immune cells activation, which mediates anti-tumor immune response. Methods: We performed the analysis of available data on the role of PFKFB3 gene expression in various cancer types, i.e. patients’ stratification to identify tumors in which PFKFB3 inhibition improved survival. We exploited TCGA expression data and applied cluster analysis and Cox-regression analysis. The objective was to detect the relation between the increased level of PFKFB3 gene expression and patients’ survival. We also compared the clusters we identified with TCGA metadata to define whether any of them fall down into well-established tumor subtypes. Results: As a result we selected four clusters among solid tumor types, in which increased expression of the target was related to significant decrease in overall survival rate. These include breast cancer, renal cell carcinoma, cervical carcinoma, and leiomyosarcoma. We managed to cross-validate the obtained results on independent datasets. The results show potential indications for PFKFB3 inhibitors. Using our proprietary molecular modelling tool, we designed a series of novel small molecule PFKFB3 inhibitors to target the fructose binding pocket rather than occupying the ATP-pocket which leads to the highly selective inhibition and strong reduction of potential off-target binding. We proved target coverage by performing in vitro biochemical assays. Conclusions: Our current data provide strong rationale for further preclinical and clinical development of PFKFB3 inhibitors as novel anticancer treatment with the potential to overcome resistance to chemo- or radiotherapy.
The role of procollagen alpha 1 type 1 (Col1A1) on invasion and cellular signaling in glioma cells.
Authors: Savaraj Niramol , Chen Shumei , Wu Chunjing , Li Ying-Ying , Wangpaichitr Medhi , Benveniste Ronald , Feun Lynn G.
Published: September 2018

e23165

Background: We have previously shown that Procollagen alpha 1 type 1 (Col1A1) is found more in low and intermediate grade glioma and less often in glioblastoma(GBM) (Cancer Invest. 23:577, 2005). We now investigate their role in cellular function. Methods: 4 glioma cell lines: Glioma 1 and U118 express high amount of Col1A1 ( Col1A1+) ; A172 and SW1783 express insignificant amount of Col1A1 ( Col1A1 - ) as the model . All four cell lines express SPARC. Scratch, transwell, and metrigel assay were used to study migration and invasion. Cell cycles were analyzed by flowcytometry. Results: U118 has the highest amount of SPARC followed by A172, SW1783 and Glioma 1. Thus it does not appear to have any relationship between these two proteins which are known as binding partner. Glioma 1 showed the least invasion and migration followed by U118, SW1783 and A172. Thus, Col1A1 expression appear to correlate with invasiveness. To further confirm this, we have silence Col1A1 in Glioma 1 and U118 using both siRNA and shRNA. All clones exhibit more migration and invasion. However, it does not affect both intracellular and extracellular levels of SPARC. Silencing Col1A1 results in increasing G2M arrest; 11% in U118 and 6% in Glioma 1. However it does not affect cellular proliferation. To further verify this, we have overexpressed Col1A1 in A172 and SW1783 using plasmid containing Col1A1 and DDK tag. These Col1A1 (+) A172 and SW1783 transfectants exhibit less migration and invasion. However, there is no effect on SPARC levels. These Col1A1 positive cells exhibit 12% increase in Go/G1 arrest and decrease in proliferation. A limited protein array also showed that silencing Col1A1 increase in STAT3, 5 and 6 and AKT levels. Interestingly, a difference in sensitivity to STAT3/5 inhibitors also noted in parental and their Col1A1 knock down transfectants. Conclusions: our results support the role of Col1A1 in glioma cell invasiveness, and hence confirm our previous data which showed that Col1A1 is found more in low grade and intermediate grade glioma. Thus, Col1A1 could be an additional useful marker to assess the aggressiveness of GBM beside histopathological grading. Col1A1 may also play a role in cellular signaling pathway.
Concordance of PD-L1 expression detection in non-small cell lung cancer (NSCLC) tissue biopsies between OncoTect iO single cell PD-L1 quantification assay and immunohistochemistry (IHC).
Authors: Chargin Amanda , Morgan Rian Janine , Patterson Bruce Kendrick
Published: September 2018

e23172

Background: PD-1/PD-L1 therapy has been shown to be effective in patients with NSCLC, specifically those with 50% PD-L1 expression or greater by IHC. Response rates for those with lower PD-L1 expression do not consistently correlate with PD-L1 amount. The OncoTect iO Lung PD-L1 Assay was designed to provide non-subjective quantification of PD-L1 expression on tumor cells and immune cells from a multitude of tumor types. The objective of this study was to compare OncoTect iO and the current method of PD-L1 testing by immunohistochemistry (IHC) in NSCLC biopsies. Methods: Eleven NSCLC tissues were obtained from two IRB approved sites. Fresh tissues were processed into single cell suspensions using the IVD IncellPREP Kit (IncellDx, Inc). Normal lung tissue adjacent to tumor sites was obtained for 9 of the samples. Cell suspensions were tested with the OncoTect iO Lung Assay which contains antibodies directed against PD-L1 (28-8), CD45, CD3, and CD8. Suspensions are fixed and permeabilized, labeled with the antibodies, and then stained with DAPI to identify intact, single cells, and to analyze cell cycle including aneuploidy.Matched FFPE sections were taken from the tissue biopsies and were tested at BioReference Laboratories with the Dako PD-L1 IHC 28-8 PharmDx Kit. Results: A cut-off of 4% was used for the OncoTect iO Assay and a positive result for the Dako assay is ≥ 5% of the tumor cells (equivalent to 5 cells out of 100). PD-L1 expression ranged from 0% to 75% in the tumor samples which is consistent with reported ranges. Seven samples were positive by OncoTect iO Lung and 6 were positive by IHC. Twelve samples were negative by OncoTect iO Lung and 13 were negative by IHC demonstrating a concordance of 95%. Of note, one tumor that was negative by OncoTect iO and IHC demonstrated 5% of aneuploidy tumor cells that were positive and most likely very rare to be detected in the assays. Conclusions: In this study, the concordance between Oncotect iO and IHC was 95%, however, the Oncotect iO Single Cell PD-L1 Quantification Assay was fast ( < 3 hours), non-subjective, and provided addition expression information for aneuploid tumor cells.
A combination of anti-PD-L1 mAb plus Lm-LLO-E6 vaccine to suppress tumor growth and metastasis in HPV-infected cancers.
Authors: Lin Po Lin , Yen Yun , Lee Huei
Published: September 2018

e23175

Background: PD-1/PD-L1 immunotherapy is viewed as having clinical benefits in advanced cancers but is effective in only a few patients, suggesting that an efficient combination approach is needed to improve efficacy for certain non-small cell lung cancer (NSCLC) patients. Methods: PD-L1 and E6 oncoprotein expressions in lung tumors from 122 NSCLC patients were examined by immunohistochemistry and their prognostic value was evaluated by Kaplain-Meier and Cox regression analysis. HPV16-postive and negative TL-1 and TL-4 lung cancer and SiHa and C33A cervical cancer cells were used to test whether PD-L1 expression could be regulated by E6, not by E7 oncoprotein. Immune deficiency nude mice were used to test the possibility that combining anti-PD-L1 mAb with Lm-LLO-E6 vaccine could have a higher antitumor activity compared with anti-PD-L1 mAb or Lm-LLO-E6 vaccine alone. Results: Immunohistochemistry analysis indicated that PD-L1 expression was correlated with the E6 expression in tumors from 122 lung cancer patients. The poorest survival occurred in PD-L1-positive/E6-positive tumor. PD-L1 expression was increased by the expression of E6, but not the E7, oncoprotein in lung and cervical cancer cells. PD-L1 expression was responsible for E6-mediated colony formation and soft agar growth. Therefore, PD-L1 secreted from tumor cells may directly promote tumor progression, particularly in E6-positive tumors. A greater antitumor activity was obtained with anti-PD-L1 mAb+Lm-LLO-E6 vaccine than with anti-PD-L1 mAb or Lm-LLO-E6 alone in subcutaneous and metastatic tumors induced by TL-1 and SiHa cells. The longest survival time for nude mice was observed in the anti-PD-L1 mAb+Lm-LLO-E6 vaccine group. Conclusions: An anti-PD-L1 mAb+Lm-LLO-E6 vaccine may be an efficient treatment for suppression of tumor growth and metastasis induced by HPV-infected cells.
Conversion of nontumorigenic dormant MOLT3 by lactate into a glycolytic cancer via epigenetic changes and lymphangiognesis.
Authors: Haaga John , Coller Hilary , Kao Hung-Ying , Lee Richard T.
Published: September 2018

e23176

Background: Lactate considered a "waste product" lactate is a multifunctional modulator. Processes modulated by lactate are: 1. initiation of the transformation of the microenvironment 2.production of hyaluronan which interacts with RHAMM to cause cell motility, stabilize mitotic spindle, and supports stem cells. With these many processes, we hypothesized that lactate might interrupt the dormant state of the MOLT3 dormant cell line. Previous authors Indraccola et al, PNAS, 2006 reported that the dormant MOLT3 cell line implanted in SCID mice could be interrupted to become tumorigenic by co-implantation with VEGF,FGF, or irradiated (dead) Kaposi Sarcoma. We used this model to determine if lactate could stimulate tumorigenesis in a similar manner. Methods: In multiple cohorts of SCID mice, lactate was coimplanted with MOLT3 cells. In approximately 40 days, tumors grew rapidly in an exponential manner. Arterial perfusion was measured by contrast enhanced dual energy CT and MRI perfusion. Immunohistochemistry was performed for vascular stains CD21,VEGFR3, Notch 1, Ephrin B, VEGFA,VEGFD, Macrophages, VEGFD. Rna sequencing was performed on six samples, 3 Molt3 cell plugs, 3 MOLT3/lactate tumors (sequencing done at UCLA, data processed at Broad Street Institute MIT). Results: The data confirmed lactates's modulator role. Perfusion studies showed no arterial flow. The IHC showed many cancer cell with many mitotic figures and apoptosis.IHC confirmed presence of numerous macrophages, increased VEGFD, lymphatics and no arteries. Indraccola's reported their tumors showed no mitotic figures. 1114 genes were up/down regulated. In general rna showed: 1.mitochondrial dysfunction 2.Down regulated tumor suppressors 3) Up regulated oncogenes 4)Increased Stem cell markers 5) increased NFK-b and other pathways. Conclusions: Lactate induced an avascular "cancer" with features similar to natural pancreatic ductal and triple negative breast cancer. Results question the universality of the angiogenic switch. We hypothesize Lactate from marophages may be the cause of inflammation induced cancer.
The prognostic significance of infiltrating immune cells subtypes in invasive ductal carcinoma of the breast.
Authors: Zheng Qiuhong
Published: September 2018

e23177

Background: To explore the correlation between tumour infiltrating immune cell subsets and breast cancer prognosis. Methods: Specimens of 102 patients with invasive breast ductal carcinoma were analyzed for immune -related markers (CD8, CD20, FoxP3 and CD68). The number of positive cells in 3 most highly-stained intratumoural stroma areas of the primary tumour was counted. The mean number of each marker was calculated and used to divide patients into two groups respectively (CD8high/CD8low group, CD20high/CD20low group, FOXP3high/ FOXP3 low group and CD68high/CD68 low group). Results: Kaplan–Meier survival analysis showed : (A) For all patients, high tumour-infiltrating CD8+ and CD20+ B lymphocytes , low tumour-infiltrating FoxP3+ Treg and CD68+ macrophages all increased the OS and DFS (P < 0.05); (B) For both the 35 ER negative and the 45 lymphonode negative patients, high CD8+ CTLs increased the OS and DFS(P < 0.05). Multivariate analysis of OS and DFS showed for all patients, high CD8+ CTLs and low FoxP3+ Treg were related to good OS and DFS(P < 0.05). Conclusions: high number of tumour-infiltrating CD8 and low FoxP3 T lymphocytes both could function as potential independent prognostic markers for invasive ductal breast carcinoma .
Molecular classification of cancers with an uncertain diagnosis as candidates for immunotherapy.
Authors: Barzi Afsaneh , Soifer Harris S , Israel Mason , Schnabel Catherine A.
Published: September 2018

e23183

Background: FDA approvals of immunotherapy checkpoint inhibitors (CPIs) are based on organ site and thus cancers of unknown primary or with uncertain tumor type diagnoses have limited access to these revolutionary treatments. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor type/subtypes for metastatic patients, six of which (lung adenocarcinoma, lung squamous cell, head & neck squamous cell, urinary bladder, kidney, and melanoma) have FDA-approved indications for CPIs. Study objectives were to analyze the distribution of the 6 tumor types with available CPIs in a large dataset of clinical cases and report patient and disease characteristics for this subset. Methods: A de-identified database was created under an IRB approved protocol that contains pathology and molecular information from consecutive cases submitted for clinical testing with the 92-gene assay. The distribution of molecular diagnoses was analyzed based on biopsy site, age, and gender. Chi-squared tests were used to compare between subgroups. Results: A total of 24,484 patients were available for analysis. Median age was 66y and 46% were male. The assay rendered a molecular diagnosis with an approved CPI in 27% (N = 6536) of cases. The most common biopsy sites were lymph node (23%), lung (15%) and liver (12%). Lung adenocarcinoma (31%) was the most common molecular diagnoses, followed by urinary bladder (20%), and head & neck squamous (16%). The proportion of melanoma molecular diagnoses decreased with age (11% in < 40y vs 4-6% across other age groups, p < 0.001), whereas the proportion of urinary bladder molecular diagnoses increased from 15% in < 40y to 23% in patients > 65y (p < 0.001). Women had a higher proportion of lung adenocarcinoma molecular diagnoses (36% vs 28% in men; p < 0.001), while kidney molecular diagnoses were more common in men (14% vs 8% in women; p < 0.001). Conclusions: These findings highlight the utility of molecular classification to identify metastatic cancers with unknown or uncertain tumor type diagnoses that are eligible for CPI. In addition, there was a significant difference in the distribution of 92-gene molecular diagnoses by age and gender among cancers susceptible to CPI.
Elucidation of the molecular and clinical impact of microsatellite instability in Brazilian colorectal cancer patients at Barretos Cancer Hospital.
Authors: Berardinelli Gustavo Noriz , Duraes Ronilson Oliveira , de Oliveira Marco Antonio , Scapulatempo Cristovam , Peixoto-Guimarães Denise , Pereira Rui , Reis Rui Manuel
Published: September 2018

e23185

Background: Colorectal cancer (CRC) has a high incidence and mortality in the world and in Brazil. The microsatellite instability (MSI) pathway is associated with a distinct mutational profile, which affects MSI target genes contributing to a different clinical impact. Reports have suggested that CRC aspects may be influenced by patients’ ancestry. This study aims to elucidate the molecular and clinical impact of MSI, and to determine Brazilian patients’ genetic ancestry. Methods: We enrolled 1013 patients. MSI was evaluated by molecular analysis, and MSI-H cases were further analyzed for alterations in 24 MSI-target genes, BRAF V600E, and MLH1 methylation. Genetic ancestry was evaluated by an AIMs panel. Results: MSI-H was observed in 10.5% of the cases. MSI-H cases were significantly associated with: right colon localization, staging II, absence of metastasis, mucinous histological type, III/undifferentiated histological grade, presence of synchronic tumor, no disease recurrence, and complete cure response. The most altered MSI target genes was HSP110, followed by ATM and EGFR. The frequency of BRAF V600E mutation was 26.4% and of MLH1 methylation was 72.3% in MSI-H cases. No significant overall survival (OS) differences were observed among the MSI statuses, neither when stratified by 5-FU treatments, nor by HSP110 mutational status. The average ancestry proportion was 74% of European, 12% of African, 7% of Native Americans, and 7% of East Asian. We observed that African ancestry is associated with increased chance of being MSI-H, and that in MSI-H cases, the lower the Asian ancestral component the greater the probability of patient survival. Conclusions: The MSI frequency of 10% identified in Brazilian CRC is in agreement with literature. MSI-H status was found correlated with clinic-pathological features associated with less aggressive tumors, although we did not find significant differences in patient’s OS. The European ancestral component was the most representative one, confirming population genetic studies. In conclusion, this study constituted the deepest and most extensive analyses of the MSI impact in the CRC Brazilian patients.
Profiling analysis reveals potential prognostic biomarkers for esophageal cancer patients treated with radiotherapy.
Authors: Fan Yu , Li Tao , Wang Qifeng , Lv Jiahua , Li Qi , Wang Yi , Wang Junchao
Published: September 2018

e23190

Background: Survival time among esophageal cancer patients undergoing radiotherapy varies considerably. Treatment failure resulting from local recurrence and metastasis reflects varying biological features such as radiosensitivity, invasion, and metastasis. This study aims to explore the genetic characterizations that are associated with prognosis of esophageal cancer patients who have undergone radiotherapy. Methods: We retrospectively reviewed specimens of 21 patients who were treated with radiotherapy. Based on the progression-free-survival (PFS), these patients were divided in to two groups: short PFS group with an average PFS of 6.9 months and long PFS group with an average PFS of 31.9 months. We extracted DNA from paraffin specimens for next generation sequencing. Mutation burden (the sum of mutation frequencies of targeted genes) and copy number aberrance were analyzed by targeted sequencing that covers 1086 genes. Results: We excluded six samples in the mutation burden analysis because of the shortage of coverage of the targeted genes. The mutation burden of 15 genes panel, which included ARID1A, BCL2, BRAF, CDH1, ERBB2, FAT1, LRP1B, MET, MTOR, NOTCH1,NOTCH2, PDGFRA, PTCH1, RB1, STK11, showed a statistically significant difference between the long PFS group and the short PFS group (p value = 0.001408). We then used copy number variation (CNV) kit to detect genes copy number variation between these two groups. The CNV of 9 genes panel, which include ASH1L, CD55, CDK4, CREBBP, FGFR1, MYC, TP53 , TYMS, XRCC3, showed a statistically significant difference between the long PFS group and the short PFS group (p value = 0.03147). Conclusions: Our results suggested that the gene mutation burden and CNV detected by targeted sequencing have a relationship with the prognosis of esophageal cancer patients who had undergone radiotherapy. In this exploratory study, we involved patients with extreme PFS ( < 1 year and > 2 years), which can be expanded in the future. To construct a predictive genetic model of prognosis in esophageal cancer patients, one may also consider analyzing circulating tumor DNA (ctDNA) in serum.
Case-control study of PD-1, PD-L1, and B7-H3 expression in human immunodeficiency virus infected (HIV+) and uninfected patients with head and neck cancers.
Authors: Mainor Candace Barette , Scilla Katherine Ann , Heath Jonathon , Ioffe Olga B. , Cellini Ashley L , Riedel David , Bentzen Soren , Feliciano Josephine Louella , Zandberg Dan Paul
Published: September 2018

e23194

Background: HIV+patients are typically excluded from immunotherapy trials but there are limited data on co-signaling molecule expression in these patients, including in head and neck squamous cell carcinoma (HNSCC). Methods: A case control study was conducted to evaluate tumor tissue sections for PD-L1, PD-1, and B7-H3 expression in HIV+HNSCC patients (n = 12) and HNSCC controls (n = 12). Cases and controls were matched for age at diagnosis, race, gender, TNM stage, and primary site. Smoking status, HIV RNA viral load (VL), and CD4 count were also recorded. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (PD-L1%) and B7-H3(B7-H3%) (Abcam), and percent of tumor infiltrating lymphocytes (TIL) expressing PD-1 (TIL-PD-1%) and PD-L1 (TIL-PD-L1%) (Abcam). Statistical analysis used the non-parametric Mann-Whitney test, chi-square test and Spearman’s rank correlation, Rs. Results: The 12 HIV+ HNSCC cases were predominantly male (67%), black race (67%) and cigarette smokers (100%), with a median age of 50.4 years, median viral load (VL) of 52399 copies/mL, median CD4 count (CD4) of 236cells/uL, predominantly locally advanced (75% Stage III/IVa/IVb), and oropharyngeal primary site (42%). Defining positive expression as > 5%, 42% of HIV+ HNSCC patients tumors were positive for PD-L1, 100% for B7-H3, and 92% had TILs that expressed PD-1 and PD-L1. HIV+ patients had significantly higher B7-H3% (Median 60% vs. 20%, p = 0.03) and TIL-PD-L1% (Median 15% vs. 10%, p = 0.045) compared to controls. There were no differences in PD-L1% or TIL-PD-1%. In HIV+ cases, increased VL correlated with increased TIL-PD-1% (Rs = 0.73, p = 0.011) and increased CD4 count correlated with increased tumor PD-L1% (Rs = 0.62, p = 0.04). There were no other significant correlations between CD4 count or VL and co-signaling molecule expression. Conclusions: HIV+ HNSCC patients had significantly higher tumor B7-H3 and TIL PD-L1 expression, with similar tumor PD-L1 and TIL PD-1 expression, compared to HIV negative HNSCC control patients. These findings support inclusion of HIV+ HNSCC patients in immunotherapy trials with checkpoint inhibitors.
Novel mechanisms-guided treatments for betel-nuts related head and neck squamous cell carcinoma in Taiwan.
Authors: Chen Jo-Pai , Chang Jui-Ying , Kuo Sung Hsin
Published: September 2018

e23217

Background: Betel-nuts related HNSCCs in Taiwan will cause (1)strong inflammation, invasion, and angiogenesis; (2)poor response to chemotherapy, radiation, and epidermal growth factor receptor inhibitors. Methods: HNSCC cell lines(SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, and TW2.6, betel-nuts related) were used to evaluate (1)the in vitro drug sensitivity; (2)synergistic effects of different treatment combinations with MTT assay, colony formation, flow cytometry, and western blotting; (3)invasion capacity by wound healing. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2. Results: TW2.6 was resistant to chemotherapies, radiation, & EGFR inhibition; but sensitive to PI3K/mTOR dual inhibition(BEZ235), CDK4/6 inhibitor(palbociclib), Bcl2 inhibitor(ABT-199), WEE1 inhibitor(AZD1775), FGFR inhibitor(BGJ398), ALK/IGF-1R inhibitor(ceritinib), & eribulin. Polo-like kinase inhibitor(volasertib) with radiation, resulting in G2/M arrest in flow-cytometry and increased cyclin B levels in western blotting, caused TW2.6 apoptosis. Nintedanib & regorafenib(VEGFR/PDGFR/FGFR inhibitor) and foretinib (VEGFR/c-MET/Axl inhibitor) would suppress HUVEC, block invasion capacity of TW2.6, inhibit TW2.6 growth, and resensitize TW2.6 to docetaxel, afatinib, and volasertib. Western blotting showed (1)mesenchymal markers(Slug, Snail, Axl, Twist, Vimentin, Claudin-1), PI3K/Akt/mTOR signaling(p-Akt & p70S6K), and BMI-1 dropped after nintedanib, regorafenib, and foretinib; (2)PDL1 drop after foretinib use. BYL719, ABT-199, and ceritinib also sensitize TW2,6 to docetaxel. Astragalus polysaccharides, minimally cytotoxic on TW2.6, could inhibit tumor migration, suppress epithelial-mesenchymal transformation & PI3K/AKT/mTOR pathway, and induce PDL1 drop. APS re-sensitizes TW2.6 to afatinib & volasertib. Olaparib(PARP inhibitor) also had poor effect on TW2.6; but volasertib, AZD1775, and foretinib could reverse olaparib resistance. Conclusions: TW2.6 might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan. Several novel-mechanisms-guided treatment combinations could be developed in the future.
Long-term results of a phase II randomized controlled trial (RCT) of a psychological intervention (Conquer Fear) to reduce clinical levels of fear of cancer recurrence in breast, colorectal, and melanoma cancer survivors.
Authors: Beith Jane McNeil , Thewes Belinda , Turner Jane , Gilchrist Jemma , Sharpe Louise , Girgis Afaf , Smith Allan 'Ben' , Fardell Joanna , Tesson Stephanie , O'Connell Rachel , Asher Rebecca , Butow Phyllis ,   Members of the Conquer Fear Authorship Group
Published: September 2018

LBA10000

The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Adverse health outcomes in relationship to hypogonadism (HG) after platinum-based chemotherapy: A multicenter study of North American testicular cancer survivors (TCS).
Authors: Abu Zaid Mohammad Issam , Menendez Alvaro G. , El Charif Omar , Fung Chunkit , Monahan Patrick O. , Feldman Darren R. , Hamilton Robert James , Vaughn David J. , Beard Clair , Cook Ryan , Althouse Sandra K. , Sesso Howard D. , Ardeshirrouhanifard Shirin , Dinh Paul C , Einhorn Lawrence , Fosså Sophie , Travis Lois B. ,   For the Platinum Study Group
Published: September 2018

LBA10012

The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.
Authors: Basch Ethan M. , Deal Allison Mary , Dueck Amylou C. , Bennett Antonia Vickery , Atkinson Thomas Michael , Scher Howard I. , Kris Mark G. , Hudis Clifford A. , Sabbatini Paul , Dulko Dorothy , Rogak Lauren J. , Barz Allison Emily , Schrag Deborah
Published: September 2018

LBA2

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.
Authors: Fizazi Karim , Tran Namphuong , Fein Luis Enrique , Matsubara Nobuaki , Rodríguez Antolín Alfredo , Alekseev Boris Y. , Ozguroglu Mustafa , Ye Dingwei , Feyerabend Susan , Protheroe Andrew , De Porre Peter , Kheoh Thian , Park Youn C. , Todd Mary Beth , Chi Kim N. ,   On Behalf of the LATITUDE Investigators
Published: September 2018

LBA3

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial.
Authors: Scherpereel Arnaud , Mazieres Julien , Greillier Laurent , Dô Pascal , Bylicki Olivier , Monnet Isabelle , Corre Romain , Audigier-Valette Clarisse , Locatelli-Sanchez Myriam , Molinier Olivier , Thiberville Luc , Urban Thierry , Ligeza-poisson Catherine , Planchard David , Amour Elodie , Morin Franck , Moro-Sibilot Denis , Zalcman Gerard ,   French Cooperative Thoracic Intergroup (IFCT)
Published: September 2018

LBA8507

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Monday, June 5, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase III trial.
Authors: Mok Tony , Cheng Ying , Zhou Xiangdong , Lee Ki Hyeong , Nakagawa Kazuhiko , Niho Seiji , Tsuji Fumito , Rosell Rafael , Corral Jaime Jesus , Migliorino Maria Rita , Pluzanski Adam , Linke Rolf Gerhard , Sbar Eric , Wang Tao , Wu Yi-Long
Published: September 2018

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Monday, June 5, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/- nab-paclitaxel in elderly pancreatic cancer patients (GrantPax).
Authors: Betge Johannes , Haertel Nicolai , Chi-Kern Jing , Belle Sebastian , Schulte Nadine , Maenz Martin , Wedding Ulrich , Ebert Matthias Philip
Published: September 2018

TPS10124

Background: Nab-paclitaxel/gemcitabine ( nab-P/gem) is an effective 1st line regimen for metastatic pancreatic ductal adenocarcinoma (mPDAC). Elderly mPDAC patients (pts) may as well benefit from nab-P/gem. Geriatric assessments to evaluate the functional reserve of these pts may allow individualization of treatment. Therefore, the aim of this study is to determine whether comprehensive geriatric assessments (CGAs) can predict the benefit from combined nab-P/gem therapy for elderly mPDAC pts in 1st line. A stratified treatment approach shall result in patient groups with a stable or improving CGA performance during the 1st cycle of treatment. Methods: GrantPax (NCT02812992) is a multicenter, open label phase 4 interventional trial with stratified parallel treatment groups (n = 45 per arm). The hypothesis is that individualized assessment directed treatment algorithms identify elderly pts (≥70 yrs), who benefit from combined nab-P/gem therapy. The study uses a CGA to stratify pts as GOGO, SLOWGO or FRAIL. Depending on test outcome, pts receive chemotherapy (GOGO: nab-P/gem; SLOWGO: gem mono) or best supportive care (FRAIL). After 1st cycle of chemotherapy (4 wks) a CGA and safety assessment will be performed to assign pts to their definite treatment arm. The primary objective is that CGA-stratified pts do not decline in their CGA performance in response to chemotherapy, measured as a loss of 5 points or less in Barthels activities of daily living (ADL1 vs. ADL2 during CGA core assessment). The expected proportion of pts with ADL decline in each treatment group is 6%. Under this assumption it shall be shown with 80% power at one-sided significance level alpha of 0.05 that the proportion of pts with functional decline is less than 20% (n = 43 per group; ADL decline: n = 2 per group). Secondary endpoints are CGA scores during the course of therapy (CGA1-4), response rates, safety, survival rates, duration of treatment, cumulative dose, quality of life and discrepancy between CGA strata estimation by the investigator and true CGA assessment. GrantPax is the first trial realizing a CGA-driven treatment to individualize cancer therapy for elderly pts. Clinical trial information: NCT02812992.
A phase II-III, multicenter, randomized, open study evaluating the feasibility and efficacy of a supervised home-based standard physical exercise program for metastatic cancer patients receiving oral targeted therapy: The UNICANCER SdS 01 QUALIOR study (ID-RCB: 2015-A01922-47).
Authors: Joly Lobbedez Florence , Vanlemmens Laurence , Descotes Jean-Marc , Abadie-Lacourtoisie Sophie , Boiron Claude , Garnier-Tixidre Claire , Girre Veronique , Helissey Carole , Houede Nadine , Lefeuvre-Plesse Claudia , Mastroianni Benedicte , Meneveau Nathalie , Oudard Stephane , Plence Valérie , Priou Frank , Salas S Bastien , Stefani Laetitia , Zannetti Alain , Bonnetain Franck , Krakowski Ivan
Published: September 2018

TPS10126

Background: Fatigue is a frequent side effect with oral targeted therapies (OTT). Physical activity has been reported to improve fatigue and quality of life (QoL). However, few studies focused on metastatic cancer patients and mainly among patients treated with chemotherapy. Furthermore, recent guidelines recommend evaluation and optimization of standardized exercise programs. The aim of our study is to evaluate home-based standard physical exercise program (SPEP) for metastatic cancer patients treated with OTT. Methods: This phase II-III study will randomize (2:1) patients starting first-line OTT for metastatic cancer between an individualized SPEP supervised by a personal coach, and recommended physical exercises via a booklet. Eligible patients will have received ≤2 lines of metastatic chemotherapy, ECOG PS ≤2, controlled pain (VAS < 3/10), and life expectancy ≥3 months. The phase II part (120 patients) will evaluate the feasibility of a 3-month SPEP using the rate of patients performing ≥50% of SPEP (2-stage Fleming: one-sided α = 5%; β = 85%). An interim analysis is planned after the phase II. The phase III will compare the efficacy of an SPEP as opposed to recommendations to reduce fatigue and/or improve physical well-being (PWB) dimensions of QoL (evaluated with FACT-G and FACT-F questionnaires). To show a difference of ≥5 points in PWB and 2.5 for fatigue (α = 2.5%; β = 80%), 312 patients are required in the phase III trial. . Secondary objectives include: PFS, OS, other dimensions of QoL, tolerability and observance of OTT, change in body composition, physical benefits, and a medico-economic study. The SPEP was developed by specialized coaches involved in physical activity and cancer. The study has Ethic committee approval and accrual is planned in 18 French centers in April 2017, for 30 months. This is the first randomized trial dedicated to patients with metastatic cancer treated with OTT evaluating the feasibility and the efficacy of a well design home based SPEP on fatigue and physical well-being.
A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (mBC) (HER2CLIMB).
Authors: Anders Carey K. , Murthy Rashmi Krishna , Hamilton Erika Paige , Borges Virginia F. , Cameron David A. , Carey Lisa A. , Müller Volkmar , Curigliano Giuseppe , Gelmon Karen A. , Hortobagyi Gabriel N. , Krop Ian E. , Loibl Sibylle , Pivot Xavier B. , Pegram Mark D. , Slamon Dennis J. , Hurvitz Sara A. , Tsai Michaela L. , Winer Eric P.
Published: September 2018

TPS1107

Background: Tucatinib (ONT-380) is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, tucatinib demonstrated synergistic activity with Tz, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, tucatinib was combined with C and Tz in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) and Tz. Objective responses were seen, including in pts with brain mets. The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Based on these data, tucatinib is now being evaluated in a study in combination with C and Tz (HER2CLIMB). Methods: The primary study objective is to assess the effect of tucatinib vs. placebo given with C + Tz on progression-free survival (PFS) based on independent central review. Additional objectives include PFS in patients with brain mets, overall survival, ORR, duration of response, clinical benefit rate, and safety. The study population includes adult patients with progressive HER2+ locally advanced or MBC who have had prior treatment with a taxane, Tz, pertuzumab and T-DM1. Patients with brain mets, including untreated or progressive brain mets, may be enrolled. 480 patients will be enrolled in North America, Europe, Israel, and Australia. Patients are receiving C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and Tz (6 mg/kg IV once every 21 days), and are being randomized in a 2:1 ratio to tucatinib 300 mg PO BID or placebo. Patients with isolated CNS progression may continue on study treatment after undergoing local CNS therapy. An independent Data Monitoring Committee is monitoring patient safety. Clinical trial information: NCT02614794.
Phase 2 trial of the novel multi-receptor tyrosine kinase inhibitor sitravatinib in well-differentiated/dedifferentiated liposarcoma.
Authors: Ingham Matthew , Lee Shing Mirn , Patwardhan Parag , Choy Edwin , Chen Isan , Singh-Kandah Shahnaz , Taiclet Lauren , Schwartz Gary K.
Published: September 2018

TPS11082

Background: Well-differentiated/dedifferentiated liposarcoma (WD/DD LPS) is a sarcoma subtype of adipocytic origin characterized by amplification of cyclin dependent kinase 4 (CDK4) and MDM2. WD/DD LPS is resistant to chemotherapy and success with CDK4 inhibitors is limited. We recently characterized the landscape of activated receptor tyrosine kinases (RTKs) and intracellular signaling pathways finding marked heterogeneity by sarcoma subtype [Patwardhan et al. Oncotarget 2016;7(4)]. In WD/DD LPS cell lines, phosphorylated (p) IGF1-R, MET and PDGFRb are strongly expressed. Selective siRNA knockdown of expression of 1 or more of these RTKs inhibited growth of WD/DD LPS cell lines. Sitravatinib (S) is a novel inhibitor of a broad panel of related RTKs. We showed that S abrogates expression of p-RTKs, including IGF1-R, MET and PDGFRb, at low nanomolar concentrations and potently inhibits proliferation of WD/DD LPS cell lines, where anti-proliferative effects of S were superior to other RTK inhibitors including imatinib, crizotinib and pazopanib. S suppressed tumor growth in vivo in WD/DD LPS . A phase 1 trial of S in solid tumors showed clinical activity in WD/DD LPS. Recommended phase 2 dose was 150 mg/day. As there are no approved RTK inhibitors for adipocytic sarcomas, and based on these findings, we initiated a phase 2 trial of S in WD/DD LPS. Methods: This is a single-arm open-label multi-center Simon 2 stage phase II trial of S in 29 patients (pts) with advanced WD/DD LPS who failed 1 prior therapy and show disease progression before enrollment. Pts receive S 150 mg orally daily continuously. Primary endpoint is the progression free rate at 12 weeks (PFR12) versus historical controls. The design has power of 85% to show improvement in PFR12 from 20% (inactive) to 40% (active) with α = 0.10. Secondary endpoints are ORR, PFS and safety. A subset of pts undergo baseline and on-treatment biopsies and reverse phase protein array used to measure changes in expression of p-RTKs and signaling pathway proteins with confirmation by immunoblot. Genomic landscape of these tumors will be analyzed by next generation sequencing. The study opened in 1/2017. Clinical trial information: NCT02978859.
A phase 3 study of alpelisib (ALP) plus fulvestrant (FUL) in men and postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) ABC progressing on or after aromatase inhibitor (AI) therapy: SOLAR-1.
Authors: Rugo Hope S. , Andre Fabrice , Rubovszky Gabor , Kaufman Bella , Inoue Kenichi , Takahashi Masato , Shimizu Satoru , Ciruelos Eva M. , Campone Mario , Conte Pier Franco , Iwata Hiroji , Loibl Sibylle , Mayer Ingrid A. , Juric Dejan , Longin Anne-Sophie , Mills David , Wilke Celine , Sellami Dalila B.
Published: September 2018

TPS1111

Background: Patients (pts) with HR+ breast cancer (BC) often havedysregulatedphosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, which further leads to resistance to endocrine therapy (ET). In a phase 1 study, alpelisib (BYL719), a PI3Kα-specific inhibitor in combination with fulvestrant (FUL) has demonstrated antitumor activity in pts with estrogen receptor-positive, HER2– advanced BC (ABC) with PIK3CA-altered tumors. SOLAR-1 (NCT02437318) aims to assess the efficacy of ALP + FUL in PIK3CA-mutant and non-mutant tumors in HR+, HER2– ABC setting. Methods: SOLAR-1 is a phase 3, randomized, double-blind study conducted in men and postmenopausal women with HR+, HER2– ABC. Pts are randomly (1:1) allocated to oral alpelisib/placebo (300 mg qd) and intramuscular FUL (500 mg) until disease progression or treatment (tx) discontinuation. Stratification factors are presence of liver and/or lung metastases and prior use of CDK4/6 inhibitors. The eligibility criteria for the targeted BC patient population are shown in the Table. The primary endpoint is progression-free survival (PFS; RECIST v1.1; local assessment), while overall survival (OS) is a key secondary endpoint in the PIK3CA-mutant cohort. Other secondary endpoints are PFS and OS in the PIK3CA non-mutant cohort, the association between PFS and baseline PIK3CAstatus in ctDNA, overall response rate, clinical benefit rate, and safety. Recruitment of the planned 560 pts is currently ongoing. Clinical trial information: NCT02437318. [Table: see text]
A phase 2 study of investigational TORC1/2 inhibitor TAK-228 with fulvestrant in women with ER+/HER2–advanced or metastatic breast cancer (mBC) that has progressed during or after aromatase inhibitor (AI) therapy.
Authors: Garcia Saenz Jose Angel , Ramos Vazquez Manuel , Martin Miguel , Ruiz Amparo , Morales Serafin , Bermejo Begona , Ruiz Isabel , Cubedo Ricardo , Merino Luis De la Cruz , Anton Antonio , Carrasco Eva Maria , Kneissl Michelle , Zohren Fabian , Martinez Noelia
Published: September 2018

TPS1118

Background: Antiestrogen therapy, including AI, is standard for ER+ tumors in the adjuvant and metastatic setting; however, resistance is common. These tumors may respond to alternative second-line anti-estrogen therapies such as fulvestrant but response durations are often short. Preclinical and clinical studies suggest that simultaneous inhibition of ER and PI3K/mTOR could prevent/delay the emergence of hormone-independent cancer cells, thereby improving patient (pt) outcomes. This study will test whether fulvestrant plus TAK-228, a dual TORC1/2 inhibitor, can overcome endocrine therapy resistance in ER+ mBC. This is an open-label, randomized, phase 2 study of continuous once-daily TAK-228 (4 mg) or once-weekly TAK-228 (30 mg) plus fulvestrant (per label), vs fulvestrant alone, in pts with ER+/HER2– advanced or mBC that has progressed during/after AI therapy (EudraCT 2015-003612-20). Methods: 153 pts will be randomized 1:1:1 and stratified (presence or absence of visceral metastasis, prior hormonal therapy sensitivity, and prior exposure to CDK 4/6 inhibitors). Pts will receive study drug(s) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts with histological confirmation of ER+/HER2– advanced or mBC with measureable disease, ECOG 0–1, PD during/after prior AI therapy (progression ≤12 mos after discontinuation of adjuvant therapy or ≤1 mo after discontinuation in the metastatic setting) and adequate organ function, but not prior therapy with mTOR, PI3K, dual PI3K-mTOR or AKT inhibitors, or fulvestrant, > 1 prior line of chemotherapy for mBC or recurrent or progressive disease on > 2 endocrine therapies for mBC are eligible. This study aims to determine the efficacy (primary endpoint: PFS; secondary endpoints: OS, TTP, ORR), safety and tolerability of TAK-228 plus fulvestrant vs fulvestrant alone. The primary hypothesis (TAK-228 plus fulvestrant can improve median PFS to 8 mos [hazard ratio, HR 0.5] vs fulvestrant-alone median PFS of 4 mos) is to be tested at the 0.10 significance level (2-sided; dropout rate 10%). To date, 24 pts have been enrolled. Clinical trial information: EudraCT 2015-003612-20.
ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC).
Authors: Tripathy Debu , Tolaney Sara M. , Seidman Andrew David , Anders Carey K. , Ibrahim Nuhad K. , Rugo Hope S. , Twelves Chris , Dieras Veronique , Müller Volkmar , Hannah Alison , Tagliaferri Mary , Cortés Javier
Published: September 2018

TPS1120

Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087; p = 0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86]; p < 0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting); pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC); ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT]; stereotactic RT or surgical resection as single-agent or combination); signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR = 0.67); 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment will begin early 2017. Clinical trial information: NCT02915744.