tbuckley/cabot-search huggingface dataset:
Tissue immune response in epithelial ovarian carcinoma.
Authors: Jon Henriksen, Frede Donskov, Marianne Waldstrøm, Mette Hjortkjær, Christina Braad Petersen, Caroline Brenner Thomsen, Anders Kristian Moeller Jakobsen, Karina Dahl Steffensen
Journal: Journal of Clinical Oncology (2019)

2625 Background: Epithelial ovarian cancer (EOC) is a highly malignant disease with a fatal outcome for most patients. During recent years immunological mechanisms have proven important in relation to the treatment and prognosis of cancer, but within EOC the knowledge is still sparse. Understanding the importance of immune markers to the prognosis of ovarian cancer is essential for the future treatment of EOC. The aim of the present study was to investigate the prognostic impact of intratumoral PDL-1 expression, T cells, neutrophil granulocytes (NG) and Natural Killer (NK) cells in a population based cohort. Methods: All patients diagnosed with ovarian cancer in Denmark in 2005 were included in the study. Immunohistochemical staining was performed on tumor tissue from 412 patients. Antibodies for PD-L1, T cells (CD8), NG (CD66b), and NK cells (CD57) were used. Cell densities were analyzed using a digital image analysis method. The primary endpoint was overall survival (OS). Results: In high grade serous carcinoma (HGSC) the median OS in patients with a high level of tumor infiltrating T cells was 37 vs 25 months in patients with a low level(p = 0.0008). Multivariate analysis showed a hazard ratio (HR) of 0.72 (p = 0.020). The median OS in patients with a high level of tumor infiltrating NK cells was 45 vs 29 months in patients with a low level (p = 0.0310). Multivariate analysis showed a HR of 0.67 (p = 0.041). PD-L1 and NG had no statistically significant impact on OS. Only T cells showed prognostic significance across histological subtypes with a HR of 0.72 (p = 0.007) in favor of a high density of T cells. Conclusions: The present population based study demonstrated prognostic importance of tumor infiltrating T cells and NK cells in HGSC. Neither PD-L1 nor NG held prognostic significance.
Prognostic value of a new clinical-genomic model to predict 10-year risk of recurrence in patients with operable breast cancer.
Authors: Lei Lei, Tzu-Ting Huang, Andre Ching-Hsuan Chen, Tzu-Pin Lu, Skye Hung-Chun Cheng
Journal: Journal of Clinical Oncology (2019)

530 Background: Searching for a specific biomarker to predict long-term risk of recurrence for all breast cancer subtypes is challenging. DGM-CM6 (Distant Genetic Model-Clinical variable Model 6) is a new clinical-genomic prognostic model developed from the 18-gene panel which was reported previously. This study aims to validate the long-term prognostic value of this new model in all subtypes of operable breast cancer patients. Methods: We included 752 operable breast cancer patients with stage I-III in all subtypes treated in a Cancer Center from 2005 to 2014 as the internal validation (IV) cohort. The median follow-up was 94.1 months. Meanwhile, Affymetrix U133P2 (n = 1139) data obtained from GEO (GSE9195/16391/17907/19615/20711/21653/42568, EMTAB365) were collected as the external validation (EV) dataset. The prognostic effect of DGM-CM6 was then evaluated by uni- and multivariate analyses. The low- and high-risk patients ( &lt; 33 or ≥ 33 as cut-off value) classified by DGM-CM6 were evaluated by the 10-year distant relapse-free interval (DRFI), relapse-free interval (RFI), relapse-free survival (RFS) and distant relapse-free survival (DRFS), respectively. We further compared the predictive performance between DGM-CM6/DGM and PAM50-ROR score in our IV dataset. Results: In the IV dataset, DGM-CM6 was proved to be an independent prognostic factor by multivariate analysis with hazard ratios of 3.1 (1.6-6.0) for RFS (P = 0.0009) and 3.2 (1.6-6.3) for DRFS (P = 0.0009). Significant differences were observed between low- and high-risk groups with 10-year RFI (94.0% vs. 83.5%, P &lt; 0.0001), RFS (90.0% vs. 80.5%, P = 0.0003), DRFI (94.1% vs. 85.0%, P &lt; 0.0001), and DRFS (90.1% vs. 81.9%, P = 0.0004), respectively. The prognostic value of RFS was convinced in the EV dataset (HR = 1.34, P = 0.00052) by the DGM only. According to C-index estimate analysis, DGM appeared to have better performance comparing with PAM50 ROR score in prediction of long-term DR, DRFS, RFI, and RFS in N0 patients (C index for distant recurrence: 0.582 by DGM, 0.528 by ROR). Conclusions: DGM-CM6 could be a new long-term prognostic model to be applied in all subtypes of operable breast cancer patients. Further validation in a large scale of clinical trials is needed.
Comparison of pegfilgrastim (Peg), plinabulin (Plin), and the combination for chemotherapy (Chemo) induced neutropenia (CIN) prevention: Rationale for the combination.
Authors: Douglas W. Blayney, Stephan Ogenstad, Yuankai Shi, Qingyuan Zhang, Jifeng Feng, Tao Sun, Lihua Du, Lan Huang, Ramon Mohanlal
Journal: Journal of Clinical Oncology (2019)

e12030 Background: Peg is used for prevention of CIN. Plin, a novel non-GSF small molecule with anti-cancer activity has equal efficacy against CIN as Peg; Plin does not cause bone pain and mitigates thrombocytopenia and the immune suppressive hematologic profile (Blayney ASCO, ESMO, SITC 2018). Plin has a mechanism of action (MoA) consistent with IL-6 -dependent granulocyte progenitor cell expansion, increased neutrophil demargination and transit from the bone marrow (Suwa, Am J Physiol 2000; Blayney SLB/IEIIS 2018). In single agent (SA) Peg and Plin phase (Ph) 2 data, CIN with Peg occurs in the 1 st week (~day (D) 7) post Chemo, and with Plin in the 2 nd week (~ D15) post Chemo, presumably due to different MoAs (NCT03102606, NCT03294577). We evaluated whether combining these two agents/MoAs would protect against CIN throughout the entire Chemo cycle (C). Methods: Early stage Breast Cancer Ph 2 patients received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either SA standard dose Peg 6 mg (Peg; n=22) or SA Plin (20 mg/m2; n= 15), or Peg 6mg combined with Plin 20 mg/m2 (Peg/Plin; n=16). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood draws for ANC were taken daily from predose to Day (D)15, and validated bone pain assessments were done from predose D1 to D8 in C1. Results: On D7 (week 1) of C1, Plin but not Peg maintained mean ANC within normal; P&lt;0.0001 for Plin vs Peg mean ANC. On D15 (week 2 of C1) Peg, but not Plin maintained ANC within normal; P&lt;0.0001 for Peg vs Plin mean ANC. Plin added to Peg maintained mean and median ANC within normal throughout C1. (ANC normal range is 1.5 - 8 x10E9/L.) Frequency of Grade (Gr) 4 and 3/4 CIN was ~35 % lower (P&lt;0.05 for Gr3/4) and median ANC nadir was 2 times higher (1.00 vs 0.46) in Peg/Plin vs Peg in C1. FN occurred in 1 pt each with Peg and Peg/Plin. Incidence of bone pain was 95% vs 6% with Peg vs Peg/Plin (P&lt;0.0001). Conclusions: Adding Plin to standard dose Peg offers superior CIN protection throughout the entire high FN risk Chemo cycle, while almost eradicating bone pain vs Peg alone. Clinical trial information: NCT03294577 .[Table: see text]
CONTESSA: A multinational, multicenter, randomized, phase III registration study of tesetaxel plus a reduced dose of capecitabine in patients (pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (LA/MBC) who have previously received a taxane.
Authors: Joyce O'Shaughnessy, Martine Piccart, Lee S. Schwartzberg, Javier Cortes, Nadia Harbeck, Seock-Ah Im, Hope S. Rugo, Michael Untch, Denise A. Yardley, Igor Bondarenko, Stephen Chan, Veronique Dieras, Mark D. Pegram, Stew Kroll, Joseph P. O'Connell, Jeff Vacirca, Thomas Wei, Kevin Tang, Andrew David Seidman
Journal: Journal of Clinical Oncology (2019)

TPS1107 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing regimen; no observed hypersensitivity reactions; preclinical evidence of CNS penetration; and improved activity against chemotherapy-resistant tumors. Over 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a Phase 2 study in 38 pts with HER2-, HR+ MBC who received T Q3W, with a confirmed ORR per RECIST 1.1 of 45% and median PFS of 5.4 mo. The confirmed ORR in taxane-pretreated pts was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine (C) in combination with a taxane may result in reduced toxicity without reduction in efficacy. Preclinical data also suggest that T may penetrate the brain at clinically relevant concentrations. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ LA/MBC, with revised eligibility criteria to allow inclusion of pts with CNS metastases. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m 2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m 2 /day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m 2 /day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ LA/MBC previously treated with a taxane in the (neo)adjuvant setting. The protocol was newly amended to allow pts with known CNS metastases. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR, and disease control rate. Enrollment began in Dec 2017. Following review in Jan 2019, the Independent Data Monitoring Committee recommended that the Study continue as planned. Clinical trial information: NCT03326674.
RNA sequencing analysis for profiling activation of cancer-associated molecular pathways.
Authors: Anton Buzdin, Andrew Garazha, Maxim Sorokin, Alex Glusker, Alexey Aleshin, Daria Allina, Maria Suntsova, Victor Tkachev, Pieter Borger, Nikolay Borisov, Nurshat Gaifullin
Journal: Journal of Clinical Oncology (2019)

e13032 Background: Intracellular molecular pathways (IMPs) control all major events in the living cell. They are considered hotspots in contemporary oncology because knowledge of IMPs activation is essential for understanding mechanisms of molecular pathogenesis in oncology. Profiling IMPs requires RNA-seq data for tumors and for a collection of reference normal tissues. However, there is a shortage now in such profiles for normal tissues from healthy human donors, uniformly profiled in a single series of experiments. Access to the largest dataset of normal profiles GTEx is only partly available through the dbGaP. In TCGA database, norms are adjacent to surgically removed tumors and may be affected by tumor-linked growth factors, inflammation and altered vascularization. ENCODE datasets were for the autopsies of normal tissues, but they can’t form statistically significant reference groups. Methods: Tissue samples representing 20 organs were taken from post-mortal human healthy donors killed in road accidents no later than 36 hours after death, blood samples were taken from healthy volunteers. Gene expression was profiled in RNA-seq experiments using the same reagents, equipment and protocols. Bioinformatic algorithms for IMP analysis were developed and validated using experimental and public gene expression datasets. Results: From original sequencing data we constructed the biggest fully open reference expression database of normal human tissues including 465 profiles termed Oncobox Atlas of Normal Tissue Expression (ANTE, original data: GSE120795). We next developed a method termed Oncobox for interrogating activation of IMPs in human cancers. It includes modules of expression data harmonization and comparison and an algorithm for automatic annotation of molecular pathways. The Oncobox system enables accurate scoring of thousands molecular pathways using RNA-seq data. Oncobox pathway analysis is also applicable for quantitative proteomics and microRNA data in oncology. Conclusions: The Oncobox system can be used for a plethora of applications in cancer research including finding differentially regulated genes and IMPs, and for discovery of new pathway-related diagnostic and prognostic biomarkers.
Ki-67 and Cyclin D1 in subtypes of triple-negative breast cancer with different androgen profiles.
Authors: Larisa N. Vashchenko, Nikolay S. Karnaukhov, Tatiana N. Gudtskova, Mramza V. Kvarchiya, Elena A. Karnaukhova, Roza G. Luganskaya, Svetlana M. Bakulina
Journal: Journal of Clinical Oncology (2019)

e12552 Background: The purpose of the study was to analyze Ki-67 and Cyclin D1 expression in subtypes of triple negative breast cancer (TNBC) with different androgen profiles. Methods: Tissues of 60 patients with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-) were studied. Immunohistochemical staining was performed with antibodies to androgen receptors (AR), CK5/6, Ki-67, Cyclin D1, and EGFR. Basal-like (BL) subtype was identified when &gt; 25% cells were CK5/6+ and/or EGFR+ (any staining). Tumors with ≥10% positively stained cells were considered AR+. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: BL TNBC showed significantly higher Ki-67 expression (81.9±3.1%), compared to other subtypes (70.8±3.1%), p &lt; 0.05. A number of TNBC samples demonstrated Cyclin D1 overexpression ( &gt; 30% stained cells) with no correlation with Ki-67 expression (r = 0.12). High Cyclin D1 levels were less common in BL TNBC (32.4% tumors), compared to other subtypes (43.5% tumors), but its average values were significantly higher (89.9±4.7% vs. 66.5±6.6%, p &lt; 0.05). AR+ tumors were observed in 11 cases (18.3%). Levels of Ki-67 were similar in TNBC with different AR profiles. The percentage of BL tumors was similar in AR+ and AR- cancers (63.6% and 61.3%, respectively). Expression of Cyclin D1 was more frequent in AR+ TNBC (45.5%), vs. 34.7% in АR-. Average levels of Cyclin D1 were significantly higher in AR+ tumors (51.8±13.7%), vs. AR- (31.6±5.1%). Conclusions: TNBC differs in the Cyclin D1 leves; some tumors show its overexpression. Inhibition of cyclin-dependent kinases blocks the cell cycle, which may be useful in the TNBC treatment, which currently has no targets for therapy.
Tumor mutation burden and immunogenicity in gastric cancer with HER2 alterations.
Authors: Bo Wei, Xiaojing Xing, Ziyu Li, Quanli Han, Yingxue Hao, Jing Zhou, Yuzi Zhang, Jing Zhao, Shangli Cai, Yanhong Gu, Tufeng Chen
Journal: Journal of Clinical Oncology (2019)

4024 Background: Human epidermal growth receptor 2 (HER2) is considered as an oncogenic driver gene in gastric cancer (GC). Immunotherapy has been proven to be effective in GC patients. Previous studies indicated that patients harboring driver mutations were considered as poor candidate for immunotherapy. But the efficacy of immunotherapy for HER2 positive GC has not been defined. We therefore analyzed the immunogenicity of HER2 alterations in GC. Methods: Genomic profiling of DNA from 448 GC was performed using next-generation sequencing on 381 cancer associated genes. The expression of PD-L1 protein was evaluated in 192 GC with the use of an automated immunohistochemical assay (Ventana, SP263). Whole-exome sequencing, copy number variations, RNA-seq and clinical data of 443 GC from The Cancer Genome Altas (TCGA) were also analyzed to further evaluate the immunogenicity of HER2 alterations. TMB was defined as number of somatic non-synonymous mutations in coding regions. HER2 amplification in TCGA was defined as “2” derived from the copy-number analysis algorithms GISTIC. Results: HER2 alterations including amplification, missense and fusion were present in 19.2% (85/443) of TCGA cohort and 11.4% (51/448) of clinical cohort. 14.0% (62/443) of TCGA cohort and 6.0% (27/448) of clinical cohort harbored HER2 amplification. Higher TMB was observed in MSS/MSI-L patients carrying any HER2 alterations in TCGA cohort (P = 0.009). On the contrary, HER2 alterations did not show a higher neoantigen level and HER2 alterations were associated with decreased immunogenicity in terms of immune-related gene mRNA expression and immune infiltrates. In clinical cohort, HER2 alterations was also significantly associated with higher TMB (P = 0.001). Meanwhile, a trend of shrinking proportion of PD-L1 expression was observed in HER2 alteration subgroup (2/23, 8.7%) than HER2 wild-type subgroup (47/169, 27.8%, P = 0.071). Furthermore, HER2 amplification had significant positive associations with HRD score (P = 0.0169) in TCGA cohort which indicated an increased degree of genome instability. Conclusions: Although HER2 alterations in GC were associated with increased TMB, HER2 alterations exhibited poor immunogenicity. These findings indicated that HER2 alterations might confer resistance to immune monotherapy.
Comparison of United States and International Ophthalmic Drug Pricing
Authors: Dan Gong, Jonathan S. Chang, Miriam Barbany, Borja F. Corcostegui, Mehmet Fatih Kağan Değirmenci, Hiroto Ishikawa, Zaid Mammo, Emin Ozmert, Tommaso Rossi, Stanley Chang
Journal: Ophthalmology (2019)
Adjuvant FOLFOX + nab-paclitaxel (FOLFOX-A)for pancreatic cancer, BrUOG 278: A Brown University oncology research group phase II study.
Authors: Howard Safran, Kevin Charpentier, Rimini Breakstone, John Vatkevich, Celine Hamel, Taylor Kolvek, Michaela Kastura, Carolyn Bartley, John Baekey, Jordan Robison, Rachel Beard, Kara Lynne Leonard, Rachael Rossiter, Kayla Rosati
Journal: Journal of Clinical Oncology (2019)

e15733 Background: Adjuvant FOLFIRINOX increases survival in pancreatic cancer but is associated with significant toxicity. The Brown University Oncology Research Group (BrUOG) developed the FOLFOX-A regimen in a phase I study in advanced pancreatic cancer (Am J Clin Oncol, 2016). Phase II studies (BrUOG 292 and BrUOG 318) have shown substantial activity in patients with metastatic and locally advanced disease. Highly active regimens have the potential to improve survival in the adjuvant setting. The primary objective of BrUOG 295 was to determine the feasibility of administering 10 cycles of FOLFOX-A. Secondary objectives were toxicity and disease free survival. Methods: Patients received oxaliplatin, 85mg/m2 day 1, nab-paclitaxel, 150mg/m2 and leucovorin 400mg/m2 day 1 and fluorouracil 2400mg/m2 by continuous IV infusion over 46 hours. Myeloid growth factor support was optional. Cycles were repeated every 14 days for up to 10. Oxaliplatin was dose reduced to 68mg/m2 for grade 2 neurotoxicity. CTCAE version 4 toxicity scales were utilized. Results: The study reached its initial accrual goal of 25 patients. The median age was 60 (43-69). Twenty-one patients were node +. Twelve of the first 20 patients have received 10 cycles of FOLFOX-A and 17 of the first 20 patients received &gt; 8 cycles. The most common grade &gt;3 toxicities were neutropenia grade 3 (N = 3), grade 4 (N = 3) and fatigue grade 3 (n = 13). One patient had grade 3 neuropathy. Conclusions: Adjuvant FOLFOX-A is well tolerated with low incidences of grade 3 neuropathy and gastrointestinal toxicity. Toxicity, feasibility and disease free survival will be updated at the May 2019 BrUOG DSMB meeting. Clinical trial information: NCT02022033.
Management of synchronous Krukenberg tumors from gastric cancer: A single-center experience.
Authors: Pengfei Yu, Ling Huang, Yian Du, Xiangdong Cheng
Journal: Journal of Clinical Oncology (2019)

e15563 Background: Whether metastasectomy improves prognosis of gastric cancer patients with ovarian metastases (Krukenberg tumors) is not clear. In this study, we examined the survival benefit of metastasectomy combined with chemotherapy for treatment of synchronous Krukenberg tumors from gastric cancer and identified the prognostic factors. Methods: The subjects of this study were patients diagnosed as synchronous Krukenberg tumors of gastric origin in the period between December 2004 and December 2015. Patients were classified in accordance with treatment modality: metastasectomy group (metastasectomy combined with chemotherapy) and non-metastasectomy group (chemotherapy alone). Clinicopathological characteristics together with treatment records were investigated in detail and their relationship with survival outcomes was examined. Results: Out of a total of 103 patients, 54 (52.4%) underwent metastasectomy of Krukenberg tumors while 49 (47.6%) patients had chemotherapy alone. Overall survival (OS) in the metastasectomy group was significantly longer than that in the non-metastasectomy group (18.9 months vs. 12.4 months, respectively; P &lt; 0.001). Metastasectomy (hazard ratio [HR] 0.486; 95% confidence interval [CI] 0.323–0.729; P &lt; 0.001), signet ring cells (HR 1.938; 95% CI 1.182–3.175; P = 0.009), peritoneal carcinomatosis (HR 1.934; 95% CI 1.230–3.049; P = 0.004), expression of estrogen receptor-β (ER-β) (HR 0.404; 95% CI 0.251–0.648; P &lt; 0.001), and progesterone receptor (PR) (HR 0.496; 95% CI 0.301–0.817; P &lt; 0.001) were independent predictors of OS. Conclusions: Metastasectomy combined with chemotherapy showed an association with survival benefit in patients with synchronous Krukenberg tumors from gastric cancer. Metastasectomy, expression of ER-β and PR, peritoneal carcinomatosis, and signet ring cells were independent predictors of survival. Further prospective studies are warranted.
Effect of PTPRB on metastasis of colorectal carcinoma and induction of epithelial-mesenchymal transition.
Authors: Xingyue Weng, Shu Zheng
Journal: Journal of Clinical Oncology (2019)

e15099 Background: Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Metastasis and recurrence are believed to be responsible for limiting long-term survival of patients with CRC. Protein tyrosine phosphatase, receptor type B ( PTPRB) belongs to the protein tyrosine phosphatase family. Multiple studies have previously demonstrated that dysregulation of PTPRB function and expression has been shown to correlate with carcinogenesis and tumor progression in multiple cancer types. Methods: In this study, we used CRC cell lines to explore the expression of PTPRB and to analyze the biological function of PTPRB protein. Surgical tumor specimens were collected for immunohistochemical staining to evaluate PTPRB expression.Real-time polymerase chain reaction (PCR) and western blot analysis were used to confirm genes and proteins of interest, respectively. Results: PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent non-tumor tissues and in CRC cell lines with high metastasis potential. PTPRB knockdown decreased the number of invasive CRC cells in a vitro wound healing model, and also reduced tumor metastasis in vivo. Conversely, PTPRB overexpression decreased E-cadherin expression and promoted vimentin expression, while PTPRB knockdown had the opposite effect. Hypoxic conditions induced EMT and promoted metastasis in CRC cells, but these effects were eliminated by PTPRB knockdown. EMT blockade via TWIST1 knockdown inhibited the migration and invasiveness of CRC cells, and even increased PTPRB expression could not reverse this effect. Conclusions: PTPRB is upregulated in CRC and overexpression of PTPRB promotes the metastasis of CRC. Moreover, our study revealed the effect of PTPRB on promoting EMT, as reflected in increased vimentin and decreased E-cadherin expression. PTPRB is a novel therapeutic target for the treatment of CRC.