bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative assessment of tumor-infiltrating neutrophils to predict immunotherapy responses in metastatic melanoma.
Authors: Vera Aguilera Jesus , Flotte Thomas J. , Yi Eunhee S. , Kroneman Trynda , Suman VeraJean , Paludo Jonas , McWilliams Robert R. , Kottschade Lisa A. , Yan Yiyi , Block Matthew Stephen , Markovic Svetomir 
Published: May 2019

e21039 Background: Tumor-infiltrating neutrophils (TINs) and their myeloid precursors play an important role in cancer biology. While activated neutrophils have been shown to kill tumor cells, there is growing evidence that neutrophils may also support tumor progression by impairing T cell-dependent anti-tumor immunity. We hypothesized that low TINs would be associated with better responses to immunotherapy (IO). Methods: Pretreatment biopsies from 15 metastatic melanoma (MM) pts treated with anti-CTL4 and anti-PD-1 therapy from 2012-17 were collected and stained with myeloperoxidase (MPO). Slides were scanned at 40x magnification on the Aperio ScanScope AT Turbo brightfield instrument (Leica Biosystems) at a resolution of 0.25 microns per pixel. To indicate the region of analysis, the digital pen tool was used to trace a minimum 85% of tumor. Ten fixed-sized boxes were placed on the hottest staining region in a second annotation layer on the image. The boxes equaled 1mm2 in total area. If the tumor tracing had an area of 1mm2, or less, boxes were not placed on the image. The selected tissue was analyzed using an Aperio imaging quatification algorithm . The number of 3+ cells were considered positive for neutrophils and used in subsequent calculations. Quality control review was performed on a subset of cases by Anatomic Pathologists. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors (RECIST). Overall survival (OS) was calculated using the Kaplan Meier method. Results: The median number of treatment lines before the biopsy was 1 (range 0-2). The treatment immediately following the biopsy consisted of ipilimumab (n = 10, 66.6%), pembrolizumab (n = 4, 26.6%), ipilimumab/nivolumab (n = 1, 6.6%). The median number of neutrophils in the biopsy hotspot was 92/mm2 (range 6-219) for the entire cohort. For patients achieving PR and CR after 4 cycles of therapy, the median neutrophils were 36/mm2 (IQ 14-78) while the median was 106/mm2 (IQ 60-138) for patients who had progressive disease,( p = 0.04). There was no correlation between the numbers of neutrophils in the biopsy with the absolute neutrophil count in the peripheral blood (R value: 0.012). Conclusions: Decreased TINs are significantly associated with better responses to IO in MM pts. Measurements of TINs may help to select patients who are likely to benefit from anti-CTL4 and anti-PD-1 therapy. Additionally, exploration of whether combining therapies that decrease neutrophils intratumorally should be explored.
Outcomes in MAGE+ cutaneous squamous cell carcinoma with perineural invasion treated with surgery followed by postoperative radiation therapy.
Authors: Stevenson Mary , Santana Alexis , Doudican Nicole Adell , Canavan Theresa N , Pavlick Anna C. , Carucci John 
Published: May 2019

e21043 Background: Perineural invasion (PNI) is associated with a high risk for recurrence and metastasis from cutaneous squamous cell carcinoma (cSCC). Recommendations vary regarding use of post-operative radiation therapy (PORT). Biomarkers for poor outcome from cSCC with PNI are lacking. We aimed to evaluate outcomes in high-risk cSCC with PNI treated surgically +/- PORT and to evaluate tissue from the primary tumor to identify biomarkers for highest risk. Methods: We conducted a retrospective chart review of PNI SCC patients seen between 2005 and 2014. We compared outcomes for surgery vs. surgery plus PORT. Gene expression from tumor debulk was evaluated via Nanostring. MAGEA3 function was evaluated using PAM 212 SCC cells in a BALB/c mouse model. CRISPR-Cas9 MAGEA3 PAM 212 knockouts were developed to assess role of MAGEA3 in SCC growth. Results: Thirty-two patients with PNI SCC were identified. All were treated surgically, and 18/32 elected to undergo PORT. Nodal metastases were noted in 5/14 patients who did not undergo PORT, whereas no metastases were noted in any patient who underwent PORT. Thus, surgery plus PORT was associated with better outcome than surgery alone (P < 0.01). Local recurrence was not observed in any patients treated by surgery, including 30 patients treated by Mohs micrographic surgery (MMS). MAGEA3 was highly expressed in PNI SCC. MAGEA3 expression in PAM 212 SCC was associated with tumor growth and increased expression of cyclins A, B, and E. CRISPR-Cas9 MAGEA3 PAM 212 knockouts exhibited reduced growth in BALB/c mice. Conclusions: MAGEA3 expression is increased in human PNI SCC. We can mitigate against worst case outcome with surgery plus PORT. MAGEA3 merits further investigation as a potential biomarker for best candidates for surgery plus PORT.
Consensus gene expression analysis to identify key hallmarks of cancer in malignant melanoma.
Authors: O'Connor Emma , Parkes Eileen E. , Galligan Leeona , Bradford James , Lambe Shauna , Logan Gemma E , Walker Steven M. , McCabe Nuala , Harkin Paul D , Kennedy Richard D. , Knight Laura A. 
Published: May 2019

e21045 Background: Traditionally gene expression signatures (GES) are used individually to classify patients into subgroups. Signatures targeting the same biology are often developed independently and may not classify identically. We developed the claraT software tool that uses consensus between multiple published GES categorised by the Hallmarks of Cancer (Hanahan & Weinberg, 2011) to classify cancers. As metastatic melanoma represents poor prognostic disease (5-yr survival 15-20%), we applied claraT to the TCGA melanoma dataset to identify targetable biologies, validated in a cohort of melanoma patients treated with Ipilimumab. Methods: TCGA RNA-seq data ( n= 472) was analysed using the claraT platform including GES for immune ( n= 14), angiogenesis ( n= 9) and epithelial-mesenchymal transition (EMT) ( n= 12) Hallmarks. Samples were clustered for the combined and individual Hallmarks. Median progression-free (PFS) and overall-survival (OS) differences were analysed across identified subgroups. Analysis was validated in an Ipilimumab treated melanoma dataset ( n= 42) (Van Allen, 2015). Results: Clustering the combined Hallmarks identified 4 subgroups in the TCGA cohort: 1) Immune active, 2) Immune-EMT active, 3) EMT-Angiogenesis active, 4) All inactive. Groups 1&2 had significantly improved OS compared to Groups 3&4 (HR = 0.50, p< 0.0001). Clustering using single Hallmarks revealed that immune-positive tumours had significantly improved OS (HR = 0.53, p< 0.0001) compared to immune-negative tumours. Angiogenesis-negative tumours displayed improved PFS (HR = 0.73, p= 0.03) and OS (HR = 0.53, p <0.0001) compared to angiogenesis-negative tumours. Interestingly the EMT Hallmark was not found to be individually prognostic. When validated in the Ipilimumab treated dataset, patients classified as immune-positive had improved OS (HR = 0.357, p= 0.010) when compared to immune-negative. Similar trends were also observed for angiogenesis and EMT Hallmarks. Conclusions: This study demonstrates how simultaneous analysis of multiple GES ( n= 35 in this study) can identify robust biologies through consensus expression. This platform may have value in the identification of reliable biomarkers for clinical trials and could inform how combination therapies targeting key biologies may be used in cancer treatment.
Postoperative radiotherapy in resected sinonasal mucosal melanoma.
Authors: Zhou Li , Cui Chuanliang , Lian Bin , Wang Xuan , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , Yan Xieqiao , Tang Bixia , Guo Jun 
Published: May 2019

e21059 Background: Mucosal melanoma is rare but highly aggressive. Sinonasal melanoma comprised approximately 26% of the whole mucosal melanoma. Complete surgery plus postoperative radiotherapy is often recommended for early-stage sinonasal melanoma patients. However, the role of postoperative radiotherapy is still disputable. Methods: Mucosal melanoma patients with stage I-III sinonasal primaries which were completely resected were enrolled as part of the multicenter, randomized, controlled, phase 3 trial for the comparison of adjuvant chemotherapy (TMZ plus DDP 6 cycles) with high-dose interferon (HDI, 1 year) (NCT03435302). Postoperative radiotherapy was recommended in the trial for their own choice, prescribed as GTV 60-70Gy/CTV 60Gy/30f. Patients were divided into two groups, those who completed adjuvant radiotherapy after surgery (group S+R, n = 41) and those who received surgery alone (group S, n = 32). Results: Seventy three patients were enrolled from Feb 2014 to Jun 2016. Two groups were balanced regarding to age, gender, and adjuvant therapy of either HDI or chemotherapy. There are more locally advanced patients in Group S, namely T3-4 or N positive ( P= 0.001). At a median follow-up of 31.2 months (range: 5.3-60.0m), the median RFS was not reached in the S+R group, as compared with 17.1 months (95% CI: 2.3-31.9m, P= 0.008) in the S group. The median DMFS was 27.2 months (95% CI: 19.3-35.1m) in the S+R group, as compared with 24.8 months (95% CI: 13.9-35.7m, P= 0.475) in the S group. Patients in the S group had an increased probability of locoregional recurrence as a first event (46.7% vs. 14.6%), while patients in the S+R group are more likely to have metastases first (41.5% vs. 12.5%). Estimated OS was 46.8 months in the S+R group and 37.3 months (95% CI: 20.8-53.8m, P= 0.097) in the S group. T&N staging also had an influence on RFS, DMFS, and OS. In COX multivariate analysis, T&N staging was the only significant prognostic factor. Common toxicities included mucositis, dermatitis, nausea, and leukopenia. Conclusions: This study suggested that postoperative radiotherapy improved local-regional control rate and might had no effect on DMFS. OS was better in radiotherapy group but still mostly depends on T&N staging. More prospective data are needed for this subtype of melanoma. Clinical trial information: NCT03435302.
B-PRECISE-01 Study: A phase Ib trial of MEN1611, a PI3K Inhibitor, combined with trastuzumab ± fulvestrant for the treatment of HER2-positive advanced or metastatic breast cancer.
Authors: Piccart-Gebhart Martine J. , Aftimos Philippe Georges , Duhoux Francois P. , Wildiers Hans , Isambert Nicolas , Campone Mario , Tosi Diego , Varga Andrea I. , Boni Valentina , Doger Bernard , Corbacho Javier Garcia , Jimenez-Rodriguez Begona , Ruiz Borrego Manuel , Saura Cristina , Arkenau Hendrik-Tobias , Wardley Andrew M. , Troconiz Inaki F , Binaschi Monica , Simonelli Cecilia , Pellacani Andrea Ugo 
Published: May 2019

TPS1101 Background: MEN1611 is a potent, selective class I inhibitor of PI3K, a key enzyme in the transduction of various extracellular growth factor signals essential for cell survival and apoptosis. The discovery in human cancers of frequent PIK3CA mutations, that have been linked to a worse outcome in advanced HER2-positive breast cancer, makes PI3K an attractive therapeutic target. Preclinical and clinical evidences support the development of MEN1611 in combination with other agents in the context of solid tumors. Methods: B-PRECISE-01 is an open-label, multicenter, phase Ib dose escalation study in patients with PIK3CA mutant tumors, HER2-positive advanced or metastatic breast cancer which has progressed after at least 2 lines of anti-HER2 based therapy. PIK3CA mutations are assessed centrally by real-time PCR assay in DNA derived from archived tumor samples. MEN1611 will be administered orally BID for continuous 28-day cycles until disease progression, in combination with weekly IV infusions of trastuzumab. In addition, HR-positive postmenopausal patients will also be treated with fulvestrant. After the completion of the dose escalation phase (Step 1), the study will continue in an expansion cohort (Step 2) testing the Recommended Phase 2 dose (RP2D) in a total of 15 patients in each of the treatment groups. The primary study objective is to assess combination safety and select RP2D. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics, preliminary clinical activity of MEN1611 in combination with trastuzumab +/- fulvestrant, and correlation with PIK3CA mutations and other relevant cancer genes mutational status. Adverse events will be graded according to NCI CTCAE v4.03. Responses will be evaluated according to RECIST v1.1. Study variables will be presented by dose-cohort and overall using appropriate descriptive statistics. The enrollment began in July 2018 at European sites and US sites will shortly participate; up to date the first dose cohort level has been achieved. Clinical trial information: NCT03767335.
VIOLETTE: A randomized phase II study to assess the DNA damage response inhibitors AZD6738 or AZD1775 in combination with olaparib (Ola) versus Ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC).
Authors: Tutt Andrew , Stephens Christine , Frewer Paul , Pierce Andrew , Rhee Joon , Edgington Sarah , Ottesen Lone , Ah-See Mei-Lin , Hollingsworth Simon J. , Dean Emma 
Published: May 2019

TPS1112 Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.
A randomized phase II study of nab-paclitaxel + durvalumab + neoantigen vaccine versus nab-paclitaxel + durvalumab in metastatic triple-negative breast cancer (mTNBC).
Authors: Hernandez-Aya Leonel Fernando , Gao Feng , Goedegebuure Peter S. , Ma Cynthia X. , Ademuyiwa Foluso Olabisi , Park Haeseong , Peterson Lindsay Leuthen , Bagegni Nusayba Ali , Bose Ron , Gillanders William E. 
Published: May 2019

TPS1114 Background: mTNBC is associated with poor outcomes and lacks targeted therapies. Immune modulation with PD-1/L1 inhibitors are emerging as effective anticancer therapies. In mTNBC, atezolizumab (anti-PD-L1) plus nab-paclitaxel demonstrated an improvement in PFS compared to nab-paclitaxel alone. Cancer vaccines targeting neoantigens may enhance the activity of immune checkpoint inhibition (ICI). Neoantigens are targets for CD8 T-cells following ICI. T-cell responses to neoantigens are high in affinity and are not limited by central mechanisms of self-tolerance. Next-generation sequencing and epitope prediction algorithms are used to identify/prioritize neoantigens for vaccine design and development. Preclinical studies have shown that neoantigen vaccines are well tolerated and may be synergistic with anti-PD-1/L1 therapy. Methods: Eligible mTNBC patients are randomized to either Arm-1 ( nab-paclitaxel + durvalumab + neoantigen vaccine) or Arm-2 ( nab-paclitaxel + durvalumab). Initially, all participants are treated with a run-in of gemcitabine + carboplatin (18-weeks; Part A). During this time sequencing and neoantigen vaccine production is performed. Subsequently, patients are treated with nab-paclitaxel + durvalumab + neoantigen vaccine vs. nab-paclitaxel + durvalumab (Part B). The neoantigen vaccine is given subcutaneously. Participants in Arm-1 receive vaccinations on Days 1, 4, 8, 15, 22, 50 and 78. Durvalumab is administered at 1500 mg IV every 4 weeks. Nab-paclitaxel is administered at 100 mg/m2 IV on Days 1, 8, and 15 of each 28-day cycle. Key eligibility criteria include patients with newly diagnosed mTNBC; measurable disease; and tumor accessible for biopsy. The primary endpoint is PFS defined as time from the initiation of Part B to progression or death. Secondary endpoints include safety, objective response rate, clinical benefit rate and OS. The exploratory endpoints include evaluating the immune response induced by the neoantigen vaccine, investigating biomarkers of response including TILs, PD-L1, and immune signature by gene expression, and mutational landscape. This trial is currently recruiting patients (NCT03606967).
Phase I trial of endoxifen gel versus placebo gel in women undergoing breast surgery.
Authors: Alber Katrina , Benante Kelly A. , Xu Yanfei , Tull Mary Beth , Segura Adrian J. , Kalinichenko Kiril , Hou Lifang , Jovanovic Borko , Perloff Marjorie , Heckman-Stoddard Brandy M. , Dimond Eileen P. , Khan Seema Ahsan 
Published: May 2019

TPS1588 Background: Despite large Phase III clinical trials that have established the success of selective estrogen receptor modulators (SERMs) for breast cancer prevention and therapy of duct carcinoma in situ (DCIS), acceptance by women likely to benefit has been low, primarily because of toxicity related to systemic exposure. Local drug delivery to the breast in gel form is an attractive alternative since low systemic levels could minimize toxicity. Endoxifen (ENX) is an active metabolite of tamoxifen, that has unique activity compared with 4-hydroxytamoxifen (4-OHT). It is smaller and more polar than 4-OHT making it potentially more suitable for transdermal delivery. The NCI PREVENT program has developed ENX transdermal alcoholic gel products. Methods: We are conducting a randomized, double-blinded, placebo-controlled, Phase I trial to establish the dermal tolerability and safety of endoxifen (ENX) gel. 38 women planning unilateral or bilateral mastectomy will be enrolled across 3 institutions in 3 cohorts: (a) ENX gel 10mg (N = 8) vs. placebo gel (N = 4) daily; (b) ENX gel 20mg (N = 8) vs. placebo gel (N = 4) daily; (c) the maximum tolerated dose (N = 8) with last dose 72 hours prior to surgery. Treatment duration will be 4 ± 1 weeks. All participants will be evaluated for toxicity and skin tolerability. Secondary endpoints include TAM metabolite measurements in breast tissue and plasma; serum hormone concentrations, serum estrogenic response, changes in coagulation parameters, gene expression changes reflective of therapeutic effects, and experienced symptoms. 65 potential participants have been pre-screened for eligibility. 33 were ineligible prior to contact, most commonly due to the use of neoadjuvant chemotherapy. Of 32 potential participants who have been eligible to be contacted, 21 did not consent for screening, most commonly because they were too overwhelmed with their recent diagnosis. 7 have consented, 4 are pending consent, and 6 have started study intervention. No adverse events have been reported to date. This pre-surgical trial testing transdermal ENX for breast cancer prevention is accruing as projected. The results will establish the skin safety of this agent, provide data on skin permeability, and the duration of drug retention in the breast. Clinical trial information: NCT03317405.
The IRX-2 regimen combined with nivolumab in recurrent/metastatic solid tumors: A phase 1b study to evaluate the safety, determine recommended phase 2 dose (RP2D), and investigate the biologic and clinical activity.
Authors: Jain Rohit K. , Zhang Jingsong , Eroglu Zeynep , Creelan Ben C. , Brohl Andrew Scott , Shafique Michael Rahman , Gray Jhanelle Elaine , Muzaffar Jameel , Ida Julia , Lacevic Mensura , Kim Youngchul , Chung Christine H. , Sahebjam Solmaz 
Published: May 2019

TPS2662 Background: IRX-2 is a biologic immunotherapeutic containing a mixture of cytokines including IL-2, IL-1β IL-6, IL-8, TNFα, GM-CSF, and IFN-γ. It is derived from stimulating human PBMCs with phytohemagglutinin. Preclinical studies have shown that IRX-2 enhances dendritic cell maturation, T cell activation, and NK cell stimulation. In a Phase 2 trial of head and neck squamous cell carcinoma (HNSCC) patients, IRX-2 increased immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival. Moreover, it has been shown that the degree of lymphocyte infiltration is an important prognostic factor for treatment with anti- programmed cell death protein 1 (PD-1) monoclonal antibodies. These data provide a compelling rationale for incorporating IRX-2 regimen into anti-PD-1 treatment strategies to increase the level of lymphocyte infiltration in the TME and improve immune response. Methods: This is a phase Ib trial exploring safety and tolerability of IRX-2 regimen in combination with nivolumab. Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections in 2 or 4 lymph node-bearing regions (based on dose level) for 10 days every 3 months. Two dose levels of IRX-2 regimen will be studied. Nivolumab is administered at 240 mg Q2W. Once the RP2D is determined, an additional 88 pts will be enrolled in an expansion phase, for a planned total enrollment of approximately 100 pts. Dose expansion phase will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies. The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. Study Progress: Study is actively accruing. Clinical trial information: NCT03758781.