tbuckley/cabot-search huggingface dataset:
The randomised induction for high-risk neuroblastoma comparing COJEC and N5-MSKCC regimens: Early results from the HR-NBL1.5/SIOPEN trial.
Authors: Alberto Garaventa, Ulrike Poetschger, Dominique Valteau-Couanet, Victoria Castel, Martin Elliott, Shifra Ash, Godfrey Chi-Fung Chan, Genevieve Laureys, Maja Beck Popovic, Kim Vettenranta, Walentyna Balwierz, Henrik Schroeder, Cormac Owens, Maja Cesen, Vassilios Papadakis, Toby Trahair, Roberto Luksch, Gudrun Schleiermacher, Peter F Ambros, Ruth Lydia Ladenstein
Journal: Journal of Clinical Oncology (2018)

10507 Background: From 2013-2017 the HRNBL1.5/SIOPEN trial tested the hypothesis that the N5-MSKCC induction regimen (Kushner, JCO 2004) increases metastatic complete response (mCR) or event-free survival (EFS) compared to Rapid COJEC (Ladenstein, JCO 2010). Methods: Eligible patients had stage 4 or 4s with MYCN amplification (MNA) aged < 21 years, or without MNA aged 12-18 months with segmental chromosome alterations, and > 18 months with any genomic profile. Patients were stratified for national groups and metastatic sites. Further treatments included addition of 2 TVD (Amoroso, Cancer Res Treat 2018) if < mCR, primary tumour resection, BuMel megatherapy, primary site irradiation, ch14.18/CHO antibody ± IL2 plus 13-cis-RA. Primary endpoints were to increase mCR rate to 45% with N5 MSKC (33% for Rapid COJEC) and by 12.5% the 2-year EFS to 52.5%. Results: 630 patients were randomised (313 for Rapid COJEC, 317 for N5). 56% were female. 99% had stage 4. Median age: 3.2 years (0.2-20.4) with 16 infants and 56 aged 12-18 mos. Median follow-up: 1.7 years. No primary endpoint differences were observed: 2-year EFS was 53% ±4 for Rapid COJEC vs 51%±4 for N5-MSKCC. mCR rate after induction was 33% for Rapid COJEC vs 37% for N5-MSKCC. No difference was detected also in secondary endpoints: overall survival was 72%±3 for Rapid COJEC vs 69%±3 for N5-MSKCC. 2-year relapse-unrelated mortality was 8%±2 with Rapid COJEC vs 6%±2 with N5-MSKCC. Cumulative incidence of relapse/progression was 39%±3 for Rapid COJEC vs 43%±4 for N5-MSKCC. A comparison of CTC Grade 3-4 toxicities showed significant differences favouring Rapid COJEC over N5-MSKCC: non-haematological 47% vs 68% (P= .000), compromise of general conditions 12% vs 19% (P= .055); neutropenia 94% vs 98% (P= .020); low platelet count 91% vs 96% (P= .031); infections 24% vs 35% (P= .005); stomatitis 3% vs 26% (P= .000); nausea/vomiting 7% vs 16% (P= .001); diarrhoea 3% vs 7% (P= .033); hypertension 10% vs 6% (P= .050); central neurotoxicity 0% vs 1% (P= .049). Conclusions: As Rapid COJEC was less toxic and no differences in primary and secondary outcomes were observed it was maintained as standard induction for future SIOPEN studies. Clinical trial information: NCT01704716.
Role of Host GPR120 in Mediating Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer
Authors: Pei Liang, Susanne M Henning, Johnny Guan, Tristan Grogan, David Elashoff, Jerrold M Olefsky, Pinchas Cohen, William J Aronson
Journal: JNCI Journal of the National Cancer Institute (2018)

GPR120, a G protein-coupled receptor for long-chain polyunsaturated fatty acids (FAs), mediates the anti-inflammatory effects of omega-3 (ω-3) FAs. We investigated whether host or tumor GPR120 plays a role in the anti-prostate cancer effects of ω-3 FAs.MycCap prostate cancer allografts were grown in immunocompetent wild-type (WT) and GPR120 knockout (KO) mice fed ω-3 (fish oil) or ω-6 (corn oil) diets. Immune cell infiltration was quantified by flow cytometry, and gene expression of immune cell markers in isolated tumor-associated macrophages (TAMs) was quantified by quantitative real-time polymerase chain reaction. Archived tissue from a fish oil intervention trial was used to correlate gene expression of GPR120 with cell cycle progression (CCP) genes and Ki67 index (n = 11-15 per group). All statistical tests were two-sided.In WT mice (n = 7 per group), dietary ω-3 FAs decreased MycCap allograft tumor growth (mean [SD] final tumor volume ω-6 = 491 [437] mm3 vs ω-3 = 127 [77] mm3, P = .04), whereas in global GPR120KO mice (n = 7 per group) ω-3 FAs had no anticancer effects. Dietary ω-3 FAs inhibited GPR120KO-MycCaP allografts grown in WT mice (n = 8 per group; mean [SD] final tumor volume ω-6 = 776 [767] mm3 vs ω-3 = 36 [34] mm3, P = .02). Omega-3 FA treatment decreased the number of M2-like TAMs in tumor tissue and gene expression of M2 markers in isolated TAMs compared with ω-6 controls in WT (n = 7 per group) but not in GPR120KO mice (n = 7 per group). In human tissue, higher expression of stromal GPR120 correlated with greater reduction in expression of CCP genes in men with prostate cancer on a high-ω-3 diet (r = -.57, P = .04).Host GPR120 plays a central role in the anti-prostate cancer effects of dietary ω-3 FAs. Future studies are required to determine if the anticancer effects of ω-3 FAs are mediated through inhibition of M2-like macrophages and if host GPR120 status predicts anticancer effects of dietary ω-3 FAs in men with prostate cancer.
Intratumor heterogeneity of stage IA lung adenocarcinoma by multiregion whole exome sequencing and association with survival.
Authors: Kelly Quek, Jun Li, Junya Fujimoto, Jianhua Zhang, Jinliang Wang, Chi-Wan Chow, Carmen Behrens, Latasha Little, Curtis Gumbs, Mara Antonoff, Neda Kalhor, Annikka Weissferdt, William N. William, Stephen Swisher, J. Jack Lee, John Heymach, Ignacio Ivan Wistuba, Andrew Futreal, Jianjun Zhang
Journal: Journal of Clinical Oncology (2017)

8545 Background: Our previous study has suggested that complex genomic intratumor heterogeneity (gITH) was associated with an increased risk of relapse in patients with localized lung adenocarcinomas (LUAD). We have launched a study to investigate molecular and immune profile ITH of Stage IA NSCLC (a patient population with no optimal biomarker to guide postsurgical therapy) to understand the molecular evolution during early carcinogenesis and to identify biomarkers for early detection and intervention. Here, we report the preliminary analysis on gITH. Methods: We performed multiregion whole exome sequencing on 30 Stage IA LUAD and matched normal lung tissue to a median sequencing depth of 494x. 15 patients have relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are 1:1 matched for the key prognostic factors including tumor size, smoking status, age, gender, ethnicity and lobectomy or wedge resection. Shannon diversity index (SDI) was used to quantify ITH in each individual tumor. Kaplan-Meier method was used to evaluate the relationship between ITH and disease-free survival (DFS) as well as overall survival (OS). Results: Consistent with our previous study, 108 of 110 (98.2%) canonical cancer gene mutations were shared events by all regions of individual tumor. Compared to non-relapsed controls, tumors from relapsed cases demonstrated significantly higher degree of ITH (SDI of 1.78 in cases vs 1.58 for controls, p = 0.016). Higher degree of gITH was associated with shorter DFS (p = 0.008) and shorter OS (p = 0.0153). Significantly higher mutation burden was observed in tumors from relapsed patients (median of 10.86 mutations per MB in cases vs 7.45 mutations per MB in controls, p = 0.03). Analysis of gITH on a larger cohort and on predicted neoantigen, methylation, gene expression and immune profiles are in progress. Conclusions: Majority of cancer gene mutations are clonal events during early carcinogenesis of LUAD. Complex gITH may be associated with more aggressive biology and inferior clinical outcome in patients with Stage IA LUAD, therefore, may be evaluated as a potential biomarker.
Effect of dexamethasone in glioblastoma (GBM) patients on systemic and intratumoral T-cell responses induced by personalized neoantigen-targeting vaccine.
Authors: David A. Reardon, Donna S. Neuberg, Derin B. Keskin, Itay Tirosh, Annabelle Anandappa, Nathan D. Mathewson, Jing Sun, Sachet A Shukla, Evisa Gjini, Shuqiang Li, Anita Giobbie-Hurder, Kai Wucherpfennig, Mario Suva, Edward Fritsch, Scott Rodig, Keith L. Ligon, Kenneth J Livak, Nir Hacohen, Catherine J. Wu, Patrick Alexander Ott
Journal: Journal of Clinical Oncology (2018)

2020 Background: The impact of individualized neoepitope vaccination targeting neoantigens arising from tumor-specific mutations for GBM, a low mutation burden tumor with an immunologically cold tumor microenvironment, as well as that of concurrently administered dexamethasone (dex), are unknown. Methods: Individualized vaccination of up to 20 synthetic, long neoepitope peptides with high predicted HLA binding affinity admixed with poly-ICLC, were administered subcutaneously using a prime-boost schedule after RT to newly diagnosed, MGMT unmethylated, at least partially resected, GBM patients without progression after radiation (RT) in our phase 1b study. Results: 9 of 10 screened patients had sufficient (≥ 10) identified neoepitope peptides. 8 patients without progression after RT received vaccine consisting of a median of 12 peptides (range, 7-20) beginning a median of 18.6 wks (range 16.0-23.2) after surgery. Adverse events were limited to infrequent grade 1/2 local reactions and fatigue. Median PFS and OS were 7.5 mths (90% CI: 6.2, 9.7) and 16.8 mths (90% CI: 9.6, 21.3). Evaluation of neoepitope-specific immune responses and tumor immune infiltrate analyses were performed on five patients with pre- and post-vaccination samples. Three patients on dex for post-RT edema during vaccine had no immune responses and no change in tumor infiltrating effector cells. In contrast 2 patients not on dex had robust, de novo immune responses against multiple predicted personal neoantigens including polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched for memory and activated phenotypes as well as increased numbers of tumor-infiltrating CD4+ and CD8+ T cells. T cell receptor analysis from one patient identified identical clonotypes isolated from post-vaccination tumor tissue and peripheral blood including a clonotype specific for ARHGAP35, a neoantigen targeted by vaccination. Conclusions: Individualized, multi-neoepitope vaccines are feasible, safe and capable of generating systemic and intra-tumoral immune responses in GBM patients that appear to be abrogated by dex. Clinical trial information: NCT02287428.
Phase II trial of carboplatin, paclitaxel and temozolomide in metastatic melanoma.
Authors: Emilio Paul Araujo-Mino, Montaser F. Shaheen
Journal: Journal of Clinical Oncology (2016)

e21012 Background: Temozolomide (TMZ) as single agent and combination of carboplatin paclitaxel are active as first and second line therapies for metastatic melanoma (MM). Although immune and targeted therapies have trumped the role of chemotherapy; it is still useful in refractory cases or as an adjunct to immunotherapy. Basic research suggests chemo or radiation therapy can prime the immune system and enhance immunotherapy. We reasoned a combination of chemo agents with distinct mechanisms of action and good tolerability to enhance the response rate in MM. The objective of this study was to evaluate the efficacy of Carboplatin, Paclitaxel and TMZ in first line therapy for MM. Methods: Single center, Phase II study (NCT01009515), used an optimal minimax two-stage design to determine the primary endpoint of objective response rate (ORR). Secondary endpoints were TTP, OS and toxicity. Eligible patients had biopsy proven MM, measurable disease, performance status 0-2. Chemotherapy was Carboplatin AUC 5, Paclitaxel 175 mg/m2 on day 1, on a 28 day cycle, and TMZ 125 mg/m2 PO given on days 2-6 of every cycle based on an earlier phase 1 trial. Additionally, an unplanned analysis to assess ORR was performed in a retrospective review of patients who received the same regimen at our institution up to 01/2016. Results: After enrolling 19 patients from 10/2009 through 03/2013, the probability of achieving a predefined ORR was not reached in the first stage and the study was closed. The median age was 58 y (+15), 68% males, 74% White non-Hispanic and 21% white Hispanic. The ORR was 25%, median TTP: 7.8 mo and median OS: 11.8 mo. The regimen was well tolerated and common G3 adverse events were neutropenia (11%), fever, fatigue, weight loss, and diarrhea (5% each). The unplanned assessment of additional 9 patients (total 25 evaluable patients when added to the trial population) noted ORR 36% (PR 32% and CR 4%) Conclusions: The combination of Carboplatin, Paclitaxel and TMZ has moderate activity in MM. The regimen was reasonably tolerated and might have a role in refractory cases or as an adjunct to immunotherapy. Future efforts will examine intermittent administration of this regimen and immunotherapy in cases that do not show a clear early benefit to the modern immune drugs. Clinical trial information: NCT01009515.
Neoadjuvant anti-OX40 (MEDI6469) prior to surgery in head and neck squamous cell carcinoma.
Authors: Richard Bryan Bell, Rebekka Duhen, Rom S. Leidner, Brendan D. Curti, Carmen Ballesteros-Merino, Brian Piening, Brady Bernard, Joanna Pucilowska, Carlo Bruno Bifulco, Bernard A. Fox, Thomas Duhen, William L Redmond, Yoshinobu Koguchi, Allen Cheng, Ashish A. Patel, George Morris, Raina Tamakawa, Mark W. Schuster, Walter John Urba, Andrew D. Weinberg
Journal: Journal of Clinical Oncology (2018)

6011 Background: This phase Ib clinical trial was performed to investigate an agonistic murine antibody to OX40 (MEDI6469) at various dose intervals prior to definitive surgical resection in patients with head and neck squamous cell carcinoma (HNSCC). Methods: 17 patients with resectable stage III-IVA HNSCC (11 = HPV-; 7 = HPV+) received MEDI6469 0.4mg/kg x 3 doses administered on day 1, day 3-4 and day 5-6 of the study, followed by definitive surgical excision and neck dissection either 2 days, 1 week or 2 weeks after infusion of anti-OX40. Primary tumor, lymph nodes and peripheral blood (PB) were obtained at baseline and at the time of surgery to characterize the circulating and tumor infiltrating lymphocyte (TIL) cell populations based on flow cytometry (FC) and multiplex immunohistochemistry (mIHC) as well as whole transcriptome analysis via RNA-sequencing (seq). Results: MEDI6469 administration was well tolerated, surgery was not delayed, and there were no grade 3 or 4 adverse events related to MEDI6469 treatment. With a median follow up of 20 months, 13/17 patients are alive without disease. 4 patients had evidence of an immunological response to treatment on FC and mIHC that peaked between 12 and 19 days after MEDI6469 infusion and was characterized by: 1) increased Ki67+CD38+ICOS+ CD4+ and CD8+ memory T-cell populations in both the TME and PB, 2) increased expression of CD39, ICOS and PD-1 on CD4+ TIL (N = 10), and 3) increased frequency of tumor-reactive, tissue resident CD39+CD103+CD8+ T cells (N = 5). RNA-seq analysis of the primary tumor in a subset of patients (N = 7) revealed significant differences between immunological responders and non-responders in genes associated with MHC I-mediated antigen processing and presentation. Subsequent immune-subtype deconvolution analysis of the RNA data revealed all responders segregated with above median levels of CD39+CD103+CD8+ T cells, consistent with flow and mIHC. Conclusions: Preoperative MEDI6469 administration is safe and resulted in increased activation and proliferation of T cells within the tumor, peaking two weeks following infusion. Immunologic changes are associated with MHC I-mediated antigen processing machinery. Clinical trial information: NCT02274155.
Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): Results of the randomized phase 3 study A.R.R.O.W.
Authors: Maria-Victoria Mateos, Philippe Moreau, James R. Berenson, Katja Weisel, Antonio Lazzaro, Kevin W. Song, Meletios A. Dimopoulos, Mei Huang, Anita Zahlten-Kumeli, A. Keith Stewart
Journal: Journal of Clinical Oncology (2018)

8000 Background: Twice-weekly K at 20/27 mg/m2 is approved for the treatment of RRMM. To develop a more convenient K regimen, once-weekly K plus d was assessed in the phase 1/2 CHAMPION-1 study, establishing a maximum tolerated dose of K 20/70 mg/m2 for RRMM pts. We present results from the pre-planned interim analysis of the phase 3 study A.R.R.O.W. comparing Kd once-weekly at 20/70 mg/m2 (once-weekly group) vs twice-weekly at 20/27 mg/m2 (twice-weekly group). Methods: Pts with 2–3 prior therapies and prior exposure to proteasome inhibitor and immunomodulatory agent were eligible. Pts were randomized 1:1 to receive either once- or twice-weekly K plus d. The once-weekly group received K (30-min IV) on days (D) 1, 8, and 15 of all cycles (20 mg/m2 on D1 [cycle 1]; 70 mg/m2 thereafter). The twice-weekly group received K (10-min IV) on D1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1 and 2 during cycle 1 and 27 mg/m2 thereafter). All pts received d at 40 mg on D1, 8, 15 (all cycles), and 22 (cycle 1–9 only). Treatment was given in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), overall survival, safety, and pharmacokinetics. Results: Baseline characteristics were generally balanced. Median PFS (once- vs twice-weekly) was 11.2 mo vs 7.6 mo (hazard ratio = 0.69; 1-sided P= 0.0014). ORR (once- vs twice-weekly) was 62.9% vs 40.8% (P< 0.0001); 7.1% vs 1.7% had a complete response or better. Grade ≥3 adverse events (AEs) occurred in 67.6% (once-weekly) and 61.7% (twice-weekly). Treatment-related grade 5 AEs occurred in 5 pts (2.1%) (once-weekly) and 2 pts (0.9%) (twice-weekly). The incidence of grade ≥3 hypertension and cardiac failure (once- vs twice-weekly) was 5.9% vs 5.5% and 2.9% vs 4.3%, respectively. Conclusions: Once-weekly Kd at 20/70 mg/m2 significantly improved PFS and ORR vs twice-weekly Kd at 20/27 mg/m2. The incidence of AEs was comparable between groups. No new safety risks were found in the once-weekly group. Overall, once-weekly Kd showed favorable benefit-risk profile with a convenient dosing regimen vs twice-weekly Kd. Clinical trial information: NCT02412878.
Evaluation of the prognostic value of RANK, RANKL, OPG and OPN mRNA expression in high-risk early breast cancer patients treated with anthracycline-containing adjuvant chemotherapy.
Authors: Eleni Timotheadou, Konstantine T. Kalogeras, Flora Zagouri, Zoi Alexopoulou, Ralph M Wirtz, Helen Gogas, Vasilios Karavasilis, Elke Veltrup, George Klouvas, George E. Pentheroudakis, Angelos Koutras, Maria Sotiropoulou, Alexandra Papoudou-Bai, Helena Linardou, Pavlos Papakostas, Gerasimos Aravantinos, Paris A. Kosmidis, Maria Skondra, Meletios A. Dimopoulos, George Fountzilas
Journal: Journal of Clinical Oncology (2016)

e23244 Background: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival with metastatic disease is anticipated. Therefore, development of bone metastasis biomarkers is of paramount importance. Methods: High-risk early breast cancer patients who had previously been treated within two randomized trials (HE10/97 and HE10/00) by the Hellenic Cooperative Oncology Group were included in the study. Chemotherapy consisted of epirubicin and CMF with or without paclitaxel, given concurrently or sequentially to epirubicin with G-CSF support. We evaluated, by qRT-PCR, 819 fixed tumor tissue samples for mRNA expression of RANK, RANKL, OPG and OPN for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival (OS). Results: Median age was 53 years, while 54.2% of the patients were postmenopausal, 76.5% ER/PgR-positive and 81.1% received either tamoxifen with ovarian ablation or anastrozole for 5 years. After a median follow-up of 119.9 months, 242 patients (29.5%) recurred and 226 (27.6%) died, while 93 patients (11.4%) developed bone metastases. Low mRNA expression of RANKL and high expression of OPN were associated with postmenopausal status, while high expression of RANK, RANKL and OPG with the luminal A subtype. All correlations among the studied markers were positive (Spearman’s Rho > 0). Low mRNA expression of RANKL was found to be associated with bone metastases (Fisher’s exact test, p = 0.026) and unfavorable DFS (HR = 1.33, 95% CI 1.05-1.68, Wald’s p = 0.018). In addition, high mRNA expression of OPN was associated with shorter DFS (HR = 1.26, 95% CI 1.00-1.59, Wald’s p = 0.050) and OS (HR = 1.37, 95% CI 1.05-1.78, p = 0.019). OPN retained its significance in the multivariate analysis, in terms of DFS and OS. Conclusions: Low RANKL mRNA expression in high-risk early breast cancer patients may predict increased risk for bone metastases. Further investigations for the potential prognostic value of RANK, RANKL and T-cell markers assessed by immunohistochemistry are currently under way.
Coupling a phenotypic assay-based platform, multi-plex IHC and quantitative pathology to predict anti-tumor efficacy to immune checkpoint blockade in melanoma.
Authors: Padhma Radhakrishnan, Manjusha Biswas, Munisha Smalley, Biswanath Majumder, Raanan Berger, Aaron Goldman
Journal: Journal of Clinical Oncology (2017)

e21041 Background: Emerging clinical evidence using immunotherapy suggests there is extraordinary antitumor potential by releasing the brakes on the immune system. However, clinical responses vary widely among patients, and a majority do not experience positive response. There is a huge unmet need to understand these disparities at the individual patient level. Methods: Here, we describe a quantitative approach to predict the antitumor effect of immune checkpoint blockade using a live-tissue ex-vivoplatform technology, CANscript™, which captures the native 3D tumor microenvironment. Utilizing fresh melanoma resections we interrogated phenotypic changes to the tumor-immune contexture in response to PD-1 and PD-L1 inhibitors in combination and as single agents. To do this, we used a multi-plexed immunohistochemistry (primarily CD8, CD45, FOXP3, CXCR4, CD68, PDL1, PD1, ERK-phosphorylation), and quantification of immune cell migratory potential, which were correlated to antitumor indications such as tumor cell proliferation, and cell death. Results: The data confirmed that CANScript™ preserves the tumor-immune contexture and native heterogeneity across different patients. Importantly, we observed that PD-1 and PD-L1 blockade resulted in patient-specific therapeutic response, which was characterized by differential, quantitatively distinct distribution and infiltration of immune cells, distinct patterning of cytokines linked to functional dysregulation, and changes in tumor proliferation and apoptosis. Interestingly, the data demonstrated unique immune signatures associated with single agent vs. combination therapy, inducing functionally distinct mechanisms in the tumor immune compartment, and disparate antitumor effects within an individual patient tumor. Conclusions: Together, these findings demonstrate that quantitative pathology can help predict therapeutic response of immune checkpoint inhibitors at the individual patient level. Such information can re-shape our understanding of patient selection and rational combinations for novel immune checkpoint inhibitors.