tbuckley/cabot-search huggingface dataset:
Impact of expression levels of mRNA HER2 and ESR1 on the pathologic complete remission (pCR) rate after neoadjuvant treatment with anthracycline-taxane containing chemotherapy in combination with trastuzumab in the GeparQuattro trial.
Authors: Jens Bodo Huober, Carsten Denkert, Gunter Von Minckwitz, Judith Prinzler, Ralf Kronenwett, Silvia Darb-Esfahani, Keyur Mehta, Bruno Valentin Sinn, Michael Untch, Sibylle Loibl
Journal: Journal of Clinical Oncology (2012)

523 Background: Recent data suggest that benefit from (neo)adjuvant trastuzumab might be related to expression of HER2 and estrogen receptor (ESR1). We investigated mRNA levels of HER2 and ESR1 in core biopsies in HER2 positive tumors of the GeparQuattro trial and compared it to response to neoadjuvant treatment. Methods: In the GeparQuattro trial 445 HER2+ pts were included based on local testing and received neoadjuvant trastuzumab and chemotherapy (either 4 x EC →4 x docetaxel (D) or 4 x EC → 4 x D/capecitabine (C) or 4 x EC →4x D →4 X C). In 217 available pretherapeutic core biopsies HER2 levels were analysed by IHC, SISH and quantitative RT-PCR using predefined cutoffs; pCR was defined as ypT0is;ypN0. Results: Only 73% of the tumors (158 of 217) were centrally HER2 positive (cHER2+) by IHC/SISH, while 59 tumors (27%) were centrally HER2 negative (cHER2-). As all pts had received neoadjuvant trastuzumab, this gave us the possibility to evaluate response of HER2- tumors to trastuzumab. The pCR rate of cHER2+ tumors was significantly increased (46.8%, p&lt;0.0005) compared to cHER2-, who had a pCR rate of only 20.3%. Similar results were obtained if HER2 positivity was determined by RT-PCR (pCR rate 50% vs. 17.4%, p&lt;0.0005). Assessment of HER2 status by RT-PCR showed a concordance of 86.2% with the IHC/SISH status. In uni- and multivariate logistic regression analysis of cHER2+ cases including continuous HER2 and ESR1 mRNA levels the HER2 mRNA expression was significantly associated with prediction for a pCR in (univ.: OR 1.43, 95% CI 1.11-1.83, p=0.005; multiv.: OR 1.42, 95% CI 1.11-1.83, p=0.006). In the cHER2+ tumors, the pCR rate was similar for ESR1 mRNA positive (47.4%) and ESR1 negative tumors (46.3%). Conclusions: Only pts with cHER2+ tumors independently of the method used have an additional benefit in terms of a pCR from adding trastuzumab to chemotherapy. In cHER2-negative patients the pCR rate is comparable to the pCR rate in the non trastuzumab treated population. Increasing HER2 mRNA levels were associated with a better response to trastuzumab based treatment in cHER2 + tumors.
Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: Preliminary data from MyPathway.
Authors: Milind M. Javle, John D. Hainsworth, Charles Swanton, Howard A. Burris, Razelle Kurzrock, Christopher Sweeney, Funda Meric-Bernstam, David R. Spigel, Ron Bose, Shuangli Guo, Coen Bernaards, Mary Stanley Beattie, Frank A. Scappaticci, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2017)

402 Background: Biliary cancers have a high mortality rate, with limited treatment options. While HER2 is overexpressed in 9-20% of biliary cancers, it has not been fully explored as a therapeutic target. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. We present preliminary data for patients with HER2-positive metastatic biliary cancer receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Patients in this subset analysis had refractory metastatic biliary cancer with HER2 amplification/overexpression or putative activating mutations by gene sequencing, FISH, or IHC. Patients received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 11 patients with HER2-positive biliary cancer (HER2-amplified/overexpressed, n = 8; HER2-mutated, n = 3 [D277Y, S310F, and A775-G776insYVMA]) have been enrolled. At a median follow-up of 4.2 (range 2.0–12.0) months, 4 patients had partial responses (PR) and 3 had stable disease (SD) for &gt; 4 months (Table). Safety was consistent with the package inserts. Conclusions: Preliminary results indicate that pertuzumab + trastuzumab has activity in HER2 amplified/overexpressed/mutated metastatic biliary tumors, suggesting HER2 as a therapeutic target for these rare cancers. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain
Authors: Johannes Gojo, Daniela Lötsch, Sabine Spiegl-Kreinecker, Kristian W Pajtler, Katharina Neumayer, Pia Korbel, Asuka Araki, Anita Brandstetter, Thomas Mohr, Volker Hovestadt, Lukas Chavez, Dominik Kirchhofer, Gerda Ricken, Harald Stefanits, Andrey Korshunov, Stefan M Pfister, Karin Dieckmann, Amedeo A Azizi, Thomas Czech, Martin Filipits, Marcel Kool, Andreas Peyrl, Irene Slavc, Walter Berger, Christine Haberler
Journal: Neuro-Oncology (2017)

Ependymomas account for up to 10% of childhood CNS tumors and have a high rate of tumor recurrence despite gross total resection. Recently, classification into molecular ependymoma subgroups has been established, but the mechanisms underlying the aggressiveness of certain subtypes remain widely enigmatic. The aim of this study was to dissect the clinical and biological role of telomerase reactivation, a frequent mechanism of cancer cells to evade cellular senescence, in pediatric ependymoma.We determined telomerase enzymatic activity, hTERT mRNA expression, promoter methylation, and the rs2853669 single nucleotide polymorphism located in the hTERT promoter in a well-characterized cohort of pediatric intracranial ependymomas.In posterior fossa ependymoma group A (PF-EPN-A) tumors, telomerase activity varied and was significantly associated with dismal overall survival, whereas telomerase reactivation was present in all supratentorial RelA fusion-positive (ST-EPN-RELA) ependymomas. In silico analysis of methylation patterns showed that only these two subgroups harbor hypermethylated hTERT promoters suggesting telomerase reactivation via epigenetic mechanisms. Furthermore, chromosome 1q gain, a well-known negative prognostic factor, was strongly associated with telomerase reactivation in PF-EPN-A. Additional in silico analyses of gene expression data confirmed this finding and further showed enrichment of the E-twenty-six factor, Myc, and E2F target genes in 1q gained ependymomas. Additionally, 1q gained tumors showed elevated expression of ETV3, an E-twenty-six factor gene located on chromosome 1q.Taken together we describe a subgroup-specific impact of telomerase reactivation on disease progression in pediatric ependymoma and provide preliminary evidence for the involved molecular mechanisms.
Phase I/II study of adoptive T-cell therapy following in vivo priming with a HER2/neu vaccine in patients with advanced-stage HER2<sup>+</sup> breast cancer.
Authors: Mary L. Disis, Andrew L Coveler, Doreen Higgins, Leonard A D'Amico, Chihiro Morishima, James Ross Waisman, Jessica Reichow, Jennifer Childs, Yushe Dang, Lupe G. Salazar, Edmond Marzbani
Journal: Journal of Clinical Oncology (2014)

615 Background: We have reported that infusion of ex vivo expanded T cells derived from previously HER2-vaccine-primed PBMC is safe and able to mediate an anti-tumor response in patients with HER2+ breast cancer (Disis 2013). In this study, we evaluated the safety and clinical efficacy of infusion of HER2 specific T cells after rapid HER2 vaccinations in patients with advanced stage HER2+ breast cancer. Methods: 19patients were vaccinated three times weekly with a HER2 peptide based vaccine. HER2 specific T-cells were expanded 2 weeks after 3rd vaccine. The patients received 2-3 escalating doses of T-cells given at 7-10 day intervals. Cyclophosphamide was administrated before the first dose of T- cells. One patient underwent indium-111 labeling of T-cells for SPECT/CT scanning. Results: All patients received at least two doses of HER2 specific expanded T-cells. The infused T-cell products were >98% of CD3+ with an average of 43% CD4+ and 54% CD8+ T-cells. The total number of T-cells infused was 0.3x109 – 57.1x109 (median 17.5x109). Subjects tolerated the infusions well with 95% of adverse events of grade 1 or 2. There were no complete or partial responses. 59% had stable disease (SD) 1-3 months after infusion and 41% of the patients demonstrated progressive disease (PD). The frequencies of HER2 specific T-cells in the infused products were significantly higher in patients with SD than that in PD (p=0.039). The percentage of CD4+ cells in products was positively correlated with HER2 specific T-cells (p=0.017). HER2 immunity was generated in vivo and augmented in magnitude after infusion and was maintained 3-9 months post infusion in the majority of patients. SPECT/CT of In-111 labeled T-cells demonstrated cell trafficking to all sites of metastatic disease. Conclusions: Adoptive transfer of HER2 specific T-cells generated from PBMC after rapid immunization is feasible and safe. Clinical outcome is associated with the frequency of HER2 specific CD4 T-cells present in the infusion product. Clinical trial information: NCT00791037.
Prospect: A randomized, double-blind, phase III efficacy trial of PROSTVAC.
Authors: Olga Bandman, Alain Delcayre, Reiner Laus, Wayne Russell Godfrey, Philip W. Kantoff, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2012)

TPS4699 Background: PROSTVAC is a candidate cancer vaccine comprised of two recombinant poxviral vectors: vaccinia (V) and fowlpox (F), each with insertions of four human genes: PSA and three costimulatory molecules (TRICOM) - LFA-3, B7.1 and ICAM-1. This off the shelf vaccine demonstrated a statistically significant overall survival (OS) benefit of 8.5 months while displaying a favorable side effect profile in patients (pts) with asymptomatic to minimally symptomatic prostate cancer (mCRPC) in a randomized, placebo –controlled 122-pt Phase II trial. Data from this Phase II trial supported the design of a Phase III protocol that will rigorously test the hypothesis of OS benefit, as well as expand our understanding of immune system response to cancer vaccines. Methods: 1200 pts will be randomized in a double-blind fashion to three arms: PROSTVAC, PROSTVAC+GM-CSF, or Placebo, at 1:1:1 ratio. A five-month treatment regimen will include a priming vaccination with PROSTVAC-V, and six booster vaccinations with PROSTVAC-F. Eligible pts will have asymptomatic or minimally symptomatic mCRPC, and progression despite androgen ablation and be chemotherapy-naïve. Pts with rapidly progressing disease will be excluded, as well as pts with risk factors for developing vaccinia-associated complications. The projected trial size is 400 pts per arm for at least 85% power. Primary endpoint is OS. The final analyses will be event-driven and will compare each active arm independently with placebo. Pts will be followed for 12 months after the projected number of events in each arm is realized. Secondary endpoint is proportion of event-free pts at 6 months compared to placebo. A number of exploratory endpoints are planned, including immune response to immunizing antigen, non-vaccine-contained prostate antigens, tumor-associated antigens; changes in baseline biomarker levels and CTC levels, as well as characterization of T cell subpopulations. The thorough immune monitoring program would provide basis for future studies on the effects of cancer immunotherapy on immune system and facilitate search for potential biomarkers of such effects. The trial is currently open for enrollment. ClinicalTrials.gov registry number: NCT00450463.
Evaluation of treatment patterns and costs for patients with prostate cancer and bone metastases.
Authors: Adriana Valdarrama, Jianying Yao, Lonnie Kent Wen
Journal: Journal of Clinical Oncology (2017)

215 Background: To describe treatment patterns and costs of care associated with the use of FDA-approved agents for metastatic castrate-resistant prostate cancer (mCRPC). Methods: Two large integrated claims databases (MarketScan, PharMetrics) were used to identify males ≥ 18 years old diagnosed and treated for prostate cancer (ICD9 = 185.xx or 233.4) with bone metastases (ICD9 = 198.5) from 06/2013 to 09/2014. Patients were required to be continuously enrolled ≥ 6 months pre- and post-initiation of treatment with abiraterone, cabazitaxel, docetaxel, enzalutamide, mitoxantrone, radium-223, or sipuleucel-T. Results: There were 953 and 565 patients meeting all inclusion criteria in each database, with a median follow-up time of 18 and 14 months, respectively. Mean age was 69 to 71 years. Prior to mCRPC treatment initiation, 14.0% to 18.2% of patients received radiation therapy, 36.1% to 40.0% denosumab, 16.5% to 16.8% zoledronic acid, and 0.2% to 0.8% pamidronate. Across both databases, abiraterone was most commonly received agent across all lines of therapy, except fourth line (Table 1). The median cost per patient per month during the post-index period was $10,292 to $10,916 in the each database, respectively, compared to $2,643 to $2,742 per patient per month during the 6-month pre-index period. Conclusions: Patients were treated mainly with abiraterone across most lines of care, with bone-targeted therapy being used in &lt; 3% of patients. Median costs per patient per month increased approximately ~$8,000 over this period. [Table: see text]
Survival rates in neuroendocrine tumors of small intestine (NESIT): A SEER database study.
Authors: Shams Aziz Mistry, Joseph Ramzy, Marcello Schmidt, Jill Gernand, Michale Roxas, Kavitha Kesari, Radhika Kakarala, Madan L. Arora
Journal: Journal of Clinical Oncology (2015)

e14706 Background: Carcinoid tumors are the most common tumors of the small intestine. There has been an increased incidence of this small intestinal cancer, but it is underrepresented in research studies. The aim of our study is to compare the characteristics and survival rates of carcinoid tumors outcome in duodenum (D-NESIT), ileum (I-NESIT) and jejunum (J-NESIT) using the SEER database. Methods: We analyzed a retrospective cohort of patients diagnosed with carcinoid tumors of small intestine in the SEER National Cancer Registry from 1991 through 2010. Univariate analysis was done using t-test and chi-square tests. Multivariate Cox regression analysis was used to evaluate risk adjusted outcomes and to determine the significant covariates of the hazard of dying. Kaplan-Meier method was used to estimate the survival function. Results: We included 7,133 patients in our study. Caucasians had more NESIT compared to other races (74.6% vs. 25.4%). The majority of patients had ileal NESIT as compared to duodenum and jejunum (59.7% vs. 32.1% & 8.2% respectively). D- NESIT patients were less likely to have cancer directed surgery when compared to the other groups (63.8%, vs 92.5% & 93.9%; p<0.001). D-NESIT had less distant metastasis when compared to others (6.8% vs. 25.8% & 28.4%; p<0.001). Ileal group has the greatest survival among regional and distant metastasis groups. However, D-NESIT has the best overall survival (Table). Patients with tumors > 2 cms are 27% more likely compared to those with tumors < cms ( HR 1.27, p-value 0.008.)In comparison to D-NESIT, the adjusted hazard of dying is not significantly different in J-NESIT and I-NESIT groups (HR 1.28, p-value 1.01 & 0.854 respectively.) Conclusions: Five year survival rate of NESIT within a particular stage may be affected by the location of the tumor. Five-year Kaplan-Meier survival rates for small intestine cancer patients. Duodenum n=2,287 Jejunum n=585 Ileum n=4,261 P- VALUE Stage of small intestine cancer Localized, (%) 573 (95.7) 102 (94.6) 441 (95.8) 0.279 Regional, (%) 63 (84.4) 85 (83.5) 865 (92.1) <0.001 Distant, (%) 39 (58.1) 56 (69.2) 423 (72.2) <0.001 OVERALL, (%) 738 (91.6) 211 (82.7) 1,735 (87.0) <0.001
Eligibility criteria requirements and adherence in advanced prostate cancer trials.
Authors: Sarah Wong, Christopher Sweeney, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2017)

245 Background: Eligibility criteria for advanced (metastatic and locally advanced) prostate cancer trials vary between trials and are specific to the therapy evaluated, and may not represent the general population. This reduces comparability between studies, generalizability of results, and may contribute to high screen failure rates (~25%). In this study, we aimed to better understand the eligibility criteria across trials and adherence to eligibility criteria. Methods: We compared eligibility criteria between trials and collected baseline demographics to assess for adherence to criteria for 13 phase III advanced prostate cancer trials published from 1999-2016. Results: Disease characteristics, age, performance status, tumor markers, and most hepatic, renal, and hematological criteria were consistent across trials. However, discrepancies in hemoglobin, absolute neutrophil count, glomerular filtration rate (GFR) and bilirubin criteria were observed (Table). Overall, 8/13 trials included patients that did not meet criteria but were analyzed by intent-to-treat. Criteria that were not followed included: hemoglobin and albumin (lower than permitted); while testosterone, serum creatinine, pain scores, and ECOG performance status were higher (more unwell) than permitted. Conclusions: Specific eligibility criteria vary across the trials, and a number of trials accrued ineligible patients. After accounting for drug-specific criteria, greater standardization of and consideration of general population for eligibility criteria is needed to improve homogeneity of trial populations across studies, generalizability of results, and possibly reduce screen failure rates in prostate cancer trials. [Table: see text]
手術可能な節陽性乳癌におけるドキソルビシンおよびシクロホスファミドに続くタキサン対タキサン単体およびパクリタキセル対ドセタキセルの第III相2×2要因比較-NSASBC02試験の第一回中間解析の結果
Authors: Ohashi Y, Yamaguchi T, Tanaka S, Mukai H, Iwata H, Oono S, Aogi K, Masuda N, Inoue K, Kuranami M, Watanabe T
Journal: Cancer Research (2009)
Vectorized gene therapy of liver tumors: Safety and proof of concept of TG4023 (MVA-FCU1)/5-FC combination.
Authors: Faress Husseini, Jean-Pierre Delord, Cécile Fournel-Frederico, Jean-Emmanuel Kurtz, Philippe Erbs, Michel Homerin, Céline Halluard, Chloé Jemming, Clélia Orange, Jean-Marc Limacher
Journal: Journal of Clinical Oncology (2012)

2605 Background: TG4023 is a non-integrative and non-propagative Modified Vaccinia virus Ankara (MVA) expressing a chimeric yeast transgene (FCU1) coding for cytosine deaminase and uracil phosphoribosyl transferase that transform the pro-drug 5-flucytosine (5-FC) respectively into 5-FU and 5-FUMP in infected cells; these derivatives then diffuse and kill additional tumor cells (bystander effect). Methods: This phase I study determined safety and Maximal Tolerated Dose (MTD) of a single intra-tumor injection of TG4023 combined with a 2-week dosing period of 5-FC 200 mg/kg/day. Plasma and tumor 5-FC (PK) and 5-FU (PD) concentrations were measured. Other assessments were tumor response, changes in tumor markers and immune response. Patient requirements were ≥ 1 injectable primary or metastatic unresectable liver tumor of 2-5 cm, no treatment option left, ECOG PS ≤ 2. Consenting patients were allocated to cohorts according to a 3+3 dose-escalating design driven by Dose-Limiting Toxicities (DLTs) and Data Safety Monitoring Board recommendations. Results: Among 16 enrolled patients (13 colorectal, 1 pancreatic and 1 liver cancers, 1 cancer of unknown primary) 6 were injected in one tumor with 10 7 plaque forming units (pfu) TG4023, 3 with 10 8 pfu and 7 with 4.10 8 pfu, using a multiport needle and ultrasound imaging guidance. 5-FC was given IV the first days then orally. One DLT (grade 3 transient increase in AST/ALT) was recorded at 4.10 8 pfu; other severe adverse events, diarrhea, hypertension, alkaline phosphatase increase were related to 5-FC; most frequent AEs were transient fever, asthenia, site injection pain, nausea/vomiting. 5-FU concentrations in tumor biopsies at Day 8 were 56±30 ng/g and 1.9± 2.6 ng/mL in plasma. 11/16 injected, 12/23 non-injected target tumors were stable and 10/16 patients progressed at week 6. One patient had a 3-fold decrease in CEA and CA 19.9. Conclusions: This study showed that vectorized gene therapy of liver tumors with TG4023/5-FC combination is feasible and safe, as supported by a high therapeutic index; MTD for TG4023 was 4.10 8 pfu for one injected tumor. A proof of concept of the in vivo conversion of the pro-drug 5-FC into 5-FU was obtained.
Incidence of thromboembolic events in a prospective nationwide registry of cancer patients initiating systemic chemotherapy
Authors: A. A. Khorana, E. Culakova, G. H. Lyman, C. W. Francis
Journal: Journal of Clinical Oncology (2004)

8019 Background: Thromboembolic disease (TED) is increased in cancer patients, with an estimated annual rate of 0.5% compared to 0.1% in the general population. TED rates may be further increased with chemotherapy. We conducted a prospective study to determine incidence of symptomatic TED in cancer outpatients on chemotherapy, and a retrospective analysis of TED rates in cancer patients hospitalized with febrile neutropenia. Methods: Cancer outpatients initiating chemotherapy were registered at 137 community practices nationwide, and followed prospectively for 4 cycles. Primary outcomes included documented symptomatic venous thrombotic or embolic events. TED in cancer patients hospitalized with febrile neutropenia at 115 medical centers from 1995 to 2000 was identified using the discharge database of the University Health System Consortium. Results: A total of 1,891 patients treated to date are available for analysis. Pulmonary embolism occurred in 9 patients, and 28 patients developed deep venous thrombosis for a TED incidence of 2% over a median follow-up of 2.3 months. Incidence varied significantly by site of disease (p=0.027) with highest rates in Hodgkin's disease (n=4/38 10.5%), pancreatic cancer (n=2/26, 7.7%) and lung cancer (11/365, 3%). Other sites included ovarian cancer (n=3/147, 2%), NHL (n=3/174, 1.7%), colon (n=3/193, 1.6%), and breast (n=7/672, 1%). TED rates did not vary by age (p=0.86), performance status (PS) (p=0.63), or stage (p=0.96). Patients with TED reported a chemotherapy delay of ≥ 7 days in 44% compared to 23% in the study population (p=0.003, OR 2.73). Among 89,078 cancer patients admitted with febrile neutropenia, TED events were reported in 1,204 (1.3%). Conclusion: Symptomatic TED is a frequent complication across a broad range of cancer sites and chemotherapies, with an annualized rate of 10.3%. An additional 1.3% develop TED if hospitalized with complications of chemotherapy. TED can lead to significant delays in chemotherapy. TED is unrelated to PS or stage suggesting that it is not a terminal event. Trials of prophylactic anticoagulation in cancer patients on chemotherapy are warranted. No significant financial relationships to disclose.
In vitro and in silico evidence against a significant effect of the<i>SPINK1</i>c.194G&gt;A variant on pre-mRNA splicing
Authors: Hao Wu, Arnaud Boulling, David N Cooper, Zhao-Shen Li, Zhuan Liao, Jian-Min Chen, Claude Férec
Journal: Gut (2017)

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