bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunologic and genomic characterization of high grade serous ovarian cancer (HGSOC) in patients (pts) treated with pembrolizumab (Pembro) in the phase II INSPIRE trial.
Authors: Colombo Ilaria , Lien Scott , Yang Cindy , Clouthier Derek L. , Bonilla Luisa , Cyriac Sunu , Ethier Josee-Lyne , Lee Yeh Chen , Kanjanapan Yada , Mandilaras Victoria , Dhani Neesha C. , Butler Marcus O. , Oza Amit M. , Quintos Judy , Chow Helen , Pugh Trevor John , Ohashi Pamela S , Siu Lillian L. , Lheureux Stephanie 
Published: September 2018

5581 Background: Checkpoint inhibitors have shown to be effective in different tumors and are under investigation in HGSOC. Methods: INSPIRE (NCT02644369) is a prospective multi-cohort study investigating tumor genomic and immune landscapes in pts treated with Pembro at 200 mg IV Q3W. Patients underwent tumor biopsy pre, on-treatment and at progression for DNA/RNA sequence, immune-profile, and PD-L1 expression by immunohistochemistry (IHC). Serial blood samples for immunophenotyping were collected. Correlative data are available for 6 pts: 3 with shrinkage in target lesion and 3 with progressive disease (PD). Results: At interim analysis as of January 2017, 18 pts with HGSOC have been enrolled and 16 have platinum-resistant disease, with median 3 prior lines of treatment (range 1-7). Of 14 evaluable pts, best response by RECIST 1.1 was stable disease (SD) in 5 (36%) and PD in 9 (64%). Mean Tumor Proportion Score of PD-L1 by IHC (Qualtek) was 6.4% (range 0-30%). Grade 3/4 adverse events possibly related to Pembro were observed in 4/18 (22%) pts; none was fatal and the most common were fatigue and hyponatremia. Preliminary correlative data showed no significant change in CD4, CD8 and myeloid-derived suppressor cells in peripheral blood after Pembro treatment. Mean PD-1 expression on CD4 and CD8 T cells on baseline tumor tissue (measured as product of PD-1+ cells and the per cell expression of PD-1 [% of mean fluorescence intensity]) was significantly higher in pts with tumor shrinkage compared to pts with PD (CD4: 2658 vs 678, p = .02; CD8: 1999 vs 451, p = .048). Genomic analysis of baseline tumor tissue was available for 3 pts with tumor shrinkage and 2 with PD. Mean mutation burden was higher for pts with tumor shrinkage (2.38 vs 1.0 mutations/Mb covered). The pt with the longest SD in our cohort (6 months) had the highest mutation burden (2.72), including somatic POLE (c.6331-6C > G) and germline BRCA2mutations. Conclusions: In HGSOC, pts with higher PD-1 level on tumor CD4 and CD8 T cells and higher mutation burden at baseline may have a better outcome following treatment with Pembro. POLE mutation is rare in HGSOC but may correlate with checkpoint inhibitor activity. Clinical trial information: NCT02644369.
Clinical activity of the selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC).
Authors: Rodriguez-Rodriguez Lorna , Mehnert Janice M. , Silk Ann W. , Chan Nancy , Malhotra Jyoti , Aisner Joseph , Saunders Tracie , Yu Bangning , Dickerson Siobhan , Tarapore Rohinton , Allen Joshua E. , Stogniew Martin , Oster Wolfgang , Kaufman Howard , Haffty Bruce George , Bertino Joseph R. , Stein Mark N. 
Published: September 2018

5592 Background: mEC is a generally incurable, with limited therapeutic options. ONC201 is the founding member of the new class of compounds called imipridones that are orally active small molecules. ONC201 a specific antagonist of the G protein-coupled receptor DRD2 exerts antitumor activity via a series of established signaling pathways (dual inhibition ERK/AKT, integrated stress response). DRD2 expression is elevated in malignant versus normal endometrial tissue. Furthermore ONC201 has shown anti-cancer activity in preclinical models of EC. Methods: In a Phase I trial that included an expansion cohort, a total of 28 evaluable patients (pts) were treated with ONC201 at doses from 125mg every 3 weeks to 625 weekly. Five of these patients had advanced mEC. Results: The median age for the mEC patients was 60 years (56-72), the median number of prior treatments was 5 (3-6), 3 patients had prior radiation and all patients had prior surgery. One patient received 375mg ONC201 while the other 4 patients received 625mg ONC201, orally every 3 weeks. The median number of doses was 3 (2-14). Two of 5 patients exhibited regressions in individual metastatic lesions, however they did not qualify as overall objective responses by RECIST criteria. One of these two patients experienced stable disease for 42 weeks. There were no reported SAEs and no Grade > 1 AEs attributed to study drug. Conclusions: ONC201 is clinically active and well tolerated with oral administration in refractory mEC patients. Clinical trial information: NCT02250781. [Table: see text]
Spectroscopy of blood samples for the diagnosis of endometrial cancer and classification of its different subtypes.
Authors: Paraskevaidi Maria , Morais Camilo L. M. , Raglan Olivia , Lima Kassio M. G. , Martin-Hirsch Pierre L. , Paraskevaidis Evangelos , Kyrgiou Maria , Martin Francis L. 
Published: September 2018

5596 Background: Symptoms of endometrial cancer often appear in early stages, thus a diagnosis, based on microscopic histological examination of endometrial tissue, can be given relatively on time. However, this procedure interferes subjective interpretation allowing human error, while screening of the asymptomatic population is not widely performed because of the high cost of the available tests (e.g. transvaginal ultrasound) and the relative invasiveness [biopsy or dilation and curettage (D+C)]. Consequently, there is a widespread need to develop inexpensive, non-invasive techniques that would accurately diagnose endometrial cancer, as well as classify the different subtypes. Spectrochemical methods generate a signature fingerprint of biological material in the form of spectra. Unlike immunological methods, which detect only one molecule at a time, the spectra obtained from a clinical sample represent all the molecular constituents within that sample, including proteins, lipids and carbohydrates; this provides a holistic picture of the sample. Previous studies have confirmed spectroscopy’s ability to diagnose gynecologic cancers in blood. Methods: Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy was used to analyse blood plasma and serum from 71 women with endometrial cancer and 18 age-matched healthy controls; classification algorithms were then applied to extract the underlying biological information. Results: Principal component analysis followed by support vector machine (PCA-SVM) diagnosed endometrial cancer with 100% accuracy in plasma and 95% in serum. Discrimination between the different subtypes [endometrioid adenocarcinoma (n = 43) vs carcinosarcoma (n = 14)] was achieved with 98.33% accuracy in both plasma and serum. The spectral regions responsible for discrimination were attributed to protein and lipid alterations. Conclusions: Our preliminary results suggest an accurate and objective diagnostic tool for endometrial cancer with blood testing, allowing therefore thoughts for a potential screening test in high risk populations. Future work will include higher number of normal cases and different subtypes and grades.
Safety of MEDI4736 (anti-PD-L1 antibody) administered concomitant with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide (ddAC) as neoadjuvant chemotherapy for stage I-III triple negative breast cancer (TNBC): A Phase I/II trial.
Authors: Pusztai Lajos , Silber Andrea , Hofstatter Erin Wysong , Chung Gina G. , Horowitz Nina Ruth , Lannin Donald R. , Killelea Brigid K. , Chagpar Anees B. , Szekely Borbala , Frederick Courtney , Rispoli Lawrence , DiGiovanna Michael 
Published: September 2018

572 Background: Pathologic complete response (pCR) rates to neoadjuvant chemotherapy in TNBC plateaued at 40% with existing regimens, the co-administration of an immune checkpoint inhibitor might increase pCR rate. The objective of the Phase I portion of this trial was to assess the safety of administering MEDI4736 concomitant with sequential taxane and anthracycline chemotherapy. Methods: The Phase I part followed the 3+3 design exploring two dose levels of MEDI4736 (3 and 10 mg/kg iv q2wk) in combination with weekly nab-paclitaxel (100 mg/m2) x 12 followed by ddAC x 4. Dose limiting toxicities (DLT) were evaluated during the entire 20 weeks of therapy and were defined as (1) gr 4 immune related adverse event (irAE), (2) gr 3 irAE that did not resolve to gr 2 within 3 days or to ≤ gr 1 within 14 days, (3) > gr 3 colitis or pneumonitis, (4) ≥ gr 3 non-irAE causally related to MEDI4736. Results: 3 patients completed therapy at the 3 mg/kg dose without any DLT, 1 additional patient refused further study medication because of recurrent gr 2 fatigue after 7 weeks of therapy. At the 10 mg/kg dose level, all 3 patients completed the nab-paclitaxel+MEDI4736 treatment without any DLT and 2 patients also completed 3 of the 4 planned treatments with ddAC without DLT. Among all 7 patients who started therapy, 1 at the 3 mg/kg group experienced gr 3 dehydration and dyspnea without chest X ray abnormalities which resolved within 48 hours with hydration. There were no other gr 3 AEs. Among the 3 patients who have completed therapy as per protocol (not including the patient who withdraw consent), 1 achieved pCR, 1 had minimal, and 1 had extensive residual cancer. No surgical AE were seen. All patients at the 10 mg/kg dose level will complete surgery by March 2017 and final Phase I toxicity and efficacy results will be presented. Conclusions: Concomitant administration of MEDI4736 10 mg/kg with weekly nab-paclitaxel and subsequently with ddAC neoadjuvant chemotherapy appears safe. The Phase II portion of the trial is open and will accrue a maximum of 50 patients to assess the efficacy of the combination. Clinical trial information: NCT02489448.
Association of molecular subtype, proliferation, and immune genes with efficacy of carboplatin versus gemcitabine addition to taxane-based, anthracycline-free neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC): Results of the randomized WSG ADAPT-TN trial.
Authors: Gluz Oleg , Liedtke Cornelia , Prat Aleix , Christgen Matthias , Gebauer Daniel , Kates Ronald E. , Grischke Eva-Maria , Forstbauer Helmut , Braun Michael Wilhelm , Warm Mathias , Hackmann John , Uleer Christoph , Aktas Bahriye , Schumacher Claudia , Kummel Sherko , Wuerstlein Rachel , Pelz Enrico , Nitz Ulrike , Kreipe Hans Heinrich , Harbeck Nadia ,   West German Study Group
Published: September 2018

573 Background: In the ADAPT-TN neoadjuvant trial, 12-week nab-paclitaxel (nab- pac)+carboplatin (carbo) was highly effective and superior to nab-pac+gemcitabine (gem). However, within TNBC, reliable predictive markers for carbo use have yet to be identified. Methods: Patients with early TNBC (centrally confirmed) were treated by nab-pac 125 mg/m2 with either carbo AUC2 or gem 1000 mg/m2 d 1,8 q21 given for 4 cycles. Genomic data (80 genes) and Prosigna (PAM-50) scores were available in 306 pre-therapeutic samples of 331 treated patients. Fisher’s exact test was performed for pCR differences; associations of continuous measurements or scores with pCR were analyzed by the Mann-Whitney statistic. Results: pCR was 44.5% to 28.4% (p=.004) in favor of nab-pac - carbo. Specifically within the carbo- containing arm, immunological (CD8, PD1, PFDL1) genes and proliferation markers (proliferation score and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3, TYMS) were positively associated with pCR (p<.05 for all). Specifically within the gem-arm, angiogenesis genes were negatively associated with pCR (ANGPTL4: p=.05; FGFR4: p=.02; VEGFA: p=.03). In the whole collective, basal-like (83.3%) was favorable for pCR (38% vs. 20%, p=.015) compared to other subtypes (HER: 6.4%; luminal-A: 1.7%; normal: 8.7%), as was lower HER-2 score (p<.001). Proliferation was positively associated with pCR: i.e., Pam50 proliferation score, ROR scores (all p<.004), and higher Ki67 by central IHC (p<.001) -- though not MKI67 RNA expression, despite their moderate correlation. Conclusions: In early TNBC, basal-like subtype, higher Ki67 (by IHC), and lower HER-2 score were associated with chemo-sensitivity for both neoadjuvant arms. Chemo-resistance pathways differed between the two taxane-based combinations (low proliferation and immune marker gene expression for carbo, high angiogenesis for gem). The positive predictive impact of immunological genes in the nab-pac - carbo arm could influence optimal patient selection for immune-modulative therapy. Clinical trial information: NCT01815242.
Effect of TCHL-based therapy on immune cell content in on-treatment, neoadjuvant-treated HER2-positive breast cancer patients.
Authors: Keegan Niamh M. , Toomey Sinead , Fay Joanna , Madden Stephen F. , Moran Bruce , Milewska Malgorzata , Das Sudipto , O'Connor Darran , Kennedy M. John , Power Colm , Hill Arnold D. , Egan Keith , Teiserskiene Ausra , Kay Elaine , Crown John , Eustace Alex J , Hennessy Bryan 
Published: September 2018

583 Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.
A phase 1b/2 study of amcasertib, a first-in-class cancer stemness kinase inhibitor in advanced head and neck cancer.
Authors: Cote Gregory Michael , Chau Nicole Grace , Spira Alexander I. , Edenfield William Jeffery , Laurie Scott Andrew , Richards Donald A. , Richey Stephen Lane , Gao Yuan , Li Youzhi , Li Wei , Hitron Matthew , Li Chiang 
Published: September 2018

6032 Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib showed safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors during dose-escalation and RP2D expansion, including pts with advanced head & neck cancer. Methods: Pts with advanced, pre-treated head & neck cancers were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 10 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines every 8 weeks. Results: A total of 21 pts were enrolled, 15 with HNSCC and 6 with salivary or parotid gland cancers. Prior treatments included radiation in 90% (19/21), surgery in 71% (15/21) and prior systemic therapy in 90% (19/21, average 3 prior lines, range 1 to 6). Amcasertib was well tolerated with 43% of pts treated at 300 mg daily (n = 9), 33% at 150 mg BID (n = 7), 19% at 200 mg daily (n = 4), and 5% at 10 mg daily (n = 1). Grade 3 AE included diarrhea (n = 4) and nausea (n = 1). Among all patients who received an evaluation per RECIST (n = 16), the objective responses rate (ORR, proportion with partial response [PR] or complete response [CR] per RECIST) was 13% and the disease control rate (DCR, proportion with stable disease [SD] at 8 weeks, PR or CR) was 50%. At 12 months, in the intent-to-treat population (n = 21) 38% of pts were alive. Median overall survival (mOS) of 7.2 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced head and neck cancers who have received treatment with amcasertib. Objective response, prolonged disease control, and extended survival have been observed in this pre-treated population with a poor prognosis. Further clinical evaluation of amcasertib in patients with head and neck cancers is warranted. Clinical trial information: NCT01781455.
The negative predictive value (NPV) of FDG-PET/CT in the Head and Neck Squamous Cell Carcinoma (HNSCC) N0 patient, the first report of the ACRIN 6685 trial.
Authors: Stack Brendan C. , Duan Fenghai , Sicks JoRean , Romanoff Justin , Opanowski Adam , Horng Dunstan , Mahon Irene , Hollenbeak Christopher S. 
Published: September 2018

6041 Background: This study evaluated the negative predictive value for node negativity in HNSCC. Methods: Patients were enrolled from 8/10 until 12/16 from 38 centers in the US and 1 center in China. This was a prospective, non-randomized trial. The study was designed to recruit 292 patients; however, 287 were enrolled by study closure. Inclusion criteria were newly diagnosed cT2-T4 SCC patients from the head and neck with one side cN0 who were willing to undergo an elective neck dissection. CN0 was determined by a negative neck CT or MR scan. Exclusions included non-SCC, non-surgical candidates, skin, nasopharynx or sinus primaries. PET/CT imaging reading performed centrally and pathology were analyzed at the neck level (left or right). To estimate confidence intervals, we used a nonparametric bootstrap to account for the correlation of data between sides of neck of the same patient. Correlative data and other image analyses will be reported separately. Results: PET/CT scans and pathology were available for 211 (table) N0 sides of neck for review at last interim analysis. NPV estimate with 95% CI for bilateral necks: 0.896 (0.831, 0.950) and specific to the N0 sides: 0.922 (0.862, 0.973). Conclusions: FDG PET/CT has high NPV for node negativity in HNSCC. This may obviate the need for elective neck dissection in N0 HNSCC patients. This trial was open about three times longer than planned, and a major obstacle to accrual was the generalized assumption among the oncology community that PET/CT had a high NPV. Therefore, patients sent to study centers for further diagnosis and treatment often had their PET/CT scans performed on non-ACRIN certified equipment. This required investigators to forgo offering the trial or the PET/CT was repeated. Our results may suggest application for pre-operative PET/CT nodal imaging of other primaries/lymphatic basins staged cN0. Funding from the National Cancer Institute through the grants U01 CA079778, U01 CA080098, CA180820, CA180794. Clinical trial information: NCT00983697. [Table: see text]
Association of DRB1 and DRBQ haplotype 04:01~03:01 with HPV positive head and neck squamous cell carcinoma.
Authors: Khattri Arun , Zuo Zhixiang , Tan Y-H Carol , Agrawal Nishant , Lingen Mark W. , Vokes Everett E. , Seiwert Tanguy Y. 
Published: September 2018

6054 Background: The incidence of human papilloma virus (HPV) associated oropharyngeal head and neck cancer (HNC) is increasing rapidly in the US, Europe, and Asia. HPV16 is etiologic in 90-95% of HPV+ HNC. Sexual transmission and inability to clear infection leading to viral genome integration or chronic presence of episomal HPV16 DNA are precursors to HPV+ HNC carcinogenesis. However it remains unclear why a majority of HPV16 exposed individuals are able to clear the initial infection and avoid the risk of cancer. We hypothesized that difference in the ability eradicate infection may be mediated by certain HLA haplotypes. Methods: HPV(+) HNC patients from the TCGA cohort were HLA-typed based on available exome sequencing data. HLA typing was performed using the ATHLATES algorithm. We compared the distribution of alleles and haplotypes of classical HLA genes (A, C, B, DRB1 and DQB1) among HPV(+) HNC patients with those found in HPV(-) patients. Furthermore we evaluated enrichment of candidate alleles compared to publically available data in Caucasian non-cancer individuals. Results: Out of 528 HNC samples in the TCGA cohort, 450 were of Caucasian ancestry. The DRB1~DQB1 haplotype 04:01~03:01 was significantly increased in HPV(+) HNSCC patients compared to normal, non-cancer individuals ( p-value = 0.0045, OR = 2.52, 95% CI = 1.2–5.03). This was not the case for HPV(-) HNC patients. The number of African American samples in TCGA was comparably small (N = 48, with N = 5 being HPV+) however the frequency of DRB1~DQB1 haplotype 04:01~03:01 in the general African American population is significantly lower. Conclusions: DRB1~DQB1 haplotype 04:01~03:01 associates with an elevated risk for HPV+ HNC. Similar findings were reported 17 years ago for cervical cancer (Br J Cancer, 82(7), 1348–1352), and further validate our findings across tumor types. Mechanistic studies to understand potential DRB1~DQB1 haplotype 04:01~03:01 HPV specific immune dysfunction, as well as evaluation in different risk and racial populations are indicated.