tbuckley/cabot-search huggingface dataset:
Comparison of FOLFIRINOX and gemcitabine with nab-paclitaxel in metastatic pancreatic cancer: Using Korean Pancreatic Cancer (K-PaC) Registry.
Authors: Jong-Chan Lee, Dong Woo Shin, Se Yeol Yang, Min Jae Kim, Jaihwan Kim, Sang Myung Woo, Woo Jin Lee, Kui Son Choi, Jae Hyup Jung, Jingu Kang, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2019)

e15762 Background: Although FOLFIRINOX and gemcitabine with nab-paclitaxel (GNP) are widely used in metastatic pancreatic cancer (MPC), the multi-center study comparing two regimens is rare. Recently, a multi-center, web-based registry for pancreatic cancer (K-PaC, Korean pancreatic cancer) was firstly launched in South Korea. We aimed to compare the clinical outcomes for FOLFIRINOX and GNP in MPC patients using K-PaC registry. Methods: In the K-PaC registry, we constructed the web-based database of anonymized 3,748 patients with histologically-proven pancreatic ductal adenocarcinoma. For this study, MPC patients who have received first-line FOLFIRINOX or GNP were enrolled. The baseline characteristics, overall survival (OS), grade III-IV toxicity, and other subgroup characteristics were analyzed. Results: From 2011 to 2017, a total of 413 (FOLFIRINOX 231 vs. GNP 182: with the same order below) patients met the eligible criteria. Median age was 63 year (60 vs. 68) and male were 46% (51% vs. 39%). Origins of tumor were head (41%), body (25%), and tail (34%). Major metastatic sites were liver (62%), peritoneum (32%), lung (18%), and others (34%), including multiple metastases. Median OS was 11.6 month (11.3 vs. 12.4, hazard ratio [HR] 0.91, confidence interval [CI] 0.71–1.16). The major hematologic toxicity was 32% of neutropenia (37% vs. 23% with P-value 0.116) and 12% of febrile neutropenia (16% vs. 10% with P-value 0.172). The major non-hematologic toxicity was 33% of fatigue (29% vs. 37% with P-value 0.455) and 28% of vomiting (27% vs. 29% with P-value 0.516). According to metastatic site, median OS by agents (months, FOLFIRINOX vs. GNP) were as follows: 9.5 vs. 10.2 with HR 0.898, CI 0.66–1.22 in liver; 11.8 vs. 12.5 with HR 0.90, CI 0.61–1.33 in lung; 9.1 vs. 12.6 with HR 0.94, HR 0.70–1.19 in peritoneal seeding. According to the sequential treatment, median OS of 1 st -line FOLFIRINOX followed by GNP group (n = 53) was 11.2 month and that of 1 st -line GNP followed by FOLFIRINOX group (n = 43) was 12.4 month (HR 0.82, CI 0.68–1.18). Conclusions: In this study using K-PaC registry in Korea, FOLFIRINOX and GNP showed comparable efficacy and toxicity. In the subgroup analysis, sequential treatment did not showed significant difference, but GNP showed a better trend in the group of peritoneal seeding.
Safety and immunobiological activity of guadecitabine sequenced with ipilimumab in metastatic melanoma patients: The phase Ib NIBIT-M4 study.
Authors: Anna Maria Di Giacomo, Alessia Covre, Francesca Finotello, Dietmar Rieder, Luca Sigalotti, Diana Giannarelli, Florent Petitprez, Laetitia Lacroix, Ornella Cutaia, Carolina Fazio, Sandra Coral, Andrea Anichini, Christoph Bock, James N. Lowder, Mohammad Azab, Wolf-Herman Fridman, Catherine Sautes-Fridman, Zlatko Trajanoski, Michele Maio
Journal: Journal of Clinical Oncology (2019)

2549 Background: DNA hypomethylating agents show broad immuno-modulatory activity in neoplastic cells, and may improve the effectiveness of cancer immunotherapies. The phase 1b NIBIT-M4 trial investigated a previously unexplored therapeutic strategy using the next-generation DNA hypomethylating agent guadecitabine sequenced with ipilimumab for the treatment of advanced melanoma. Methods: Patients with unresectable Stage III/IV melanoma received escalating doses of guadecitabine 30, 45 or 60 mg/m 2 subcutaneously on Days 1–5 every three weeks, and ipilimumab 3 mg/kg intravenously on Day 1 every three weeks, starting one week after guadecitabine, for four cycles. Primary endpoints were the safety, tolerability and maximum tolerated dose of treatment; secondary endpoints included immune-related disease control and objective response. Genome-wide methylation, RNA sequencing, and immunohistochemistry analyses were performed on tumor samples collected at baseline, W4 and W12. (NCT02608437). Results: 19 patients were treated and evaluable for safety and efficacy. The most common treatment-related adverse events of any grade were myelotoxicity (n = 17; 89%) and immune-related adverse events (n = 12; 63%). Grade 3 or 4 myelotoxicity occurred in 15 (79%) patients. There were no dose limiting toxicities. Rates of immune-related disease control and objective response were 8/19 (42%) and 5/19 (26%), respectively. Exploratory analyses of tumour samples (n = 8) showed that median CpG site methylation at Week 4 (74.5%) and Week 12 (75.5%) was significantly lower (p &lt; 0.05) than at baseline (80.3%), with a median of 2454 (Week 4) and 4131 (Week 12) differentially expressed genes identified compared to baseline; among the 136 pathways significantly modulated by treatment, the most frequently activated were immune-related. Tumour immune contexture analysis (n = 11) demonstrated up-regulation of Human Leukocyte Antigen (HLA) class I molecules on melanoma cells, and an increase in CD8 + , PD-1 + T cells and in CD20 + B cells in post-treatment tumour core specimens. Conclusions: Sequential guadecitabine and ipilimumab is safe and tolerable in patients with metastatic melanoma, and has promising immunological and anti-tumour activity. Clinical trial information: NCT02608437.
Use of PD-L1 and ICOSL to discriminate innate and adaptive dendritic cells in the head and neck cancer microenvironment.
Authors: Caroline Hoffmann, Aurore Surun, Floriane Noel, Paula Michea, Maximilien Grandclaudon, Lilith Faucheux, Philemon Sirven, Jerzy Klijanienko, Nathalie Badois, Maria Lesnik, Olivier Choussy, Maud Kamal, Charlotte Lecerf, Christophe Le Tourneau, Maude Guillot-Delost, Vassili Soumelis
Journal: Journal of Clinical Oncology (2019)

e14184 Background: Inflamed head and neck squamous cell carcinomas (HNSCC), have a better prognosis independently of the treatment modalities, and have an increased response rate to PD(L)1 blockade. Dendritic cells (DC) infiltration is associated to T cell infiltration and DC are critical in the immune response to cancer, but little is known on HNSCC infiltrating DC. The objectives were to determine the differences between DC infiltrating inflamed vs non inflamed tumors, to understand which mechanisms modulate DC phenotypes and which are the associated functions. Methods: 22 untreated HNSCC were characterized by flow cytometry for their immune infiltrate. RNA sequencing of sorted tumor infiltrating myeloid subsets and blood DC were analyzed for differentially expressed genes. The TMod database (Grandclaudon et al.), testing the effect of various stimuli on DC and subsequently on co-cultured T cells, was used to decipher DC and T cell modulation. Results: The level of CD3 infiltration was positively associated to the level of DC infiltration and PDL1 expression on myeloid cells, and negatively to the level neutrophils and of ICOSL expression on myeloid cells. PDL1high ICOSLneg DC from inflamed tumors were matched with the “innate DC” phenotype described in vitro, highly efficient at secreting cytokines and chemokines but poorly activating naïve CD4 T cells. DC from non-inflamed tumor resembled immature medium DC. A third type of DC, “adaptive DC”, expressing high levels of ICOSL and low of PDL1, poorly efficient at cytokine and chemokine secretion, but highly efficient at activating T cells is was described in vitro, but not found in tumors. RNAseq analysis confirmed this innate polarization and highlighted that those cells present a mature and NFkB activated phenotype. Conclusions: Inflamed HNSCC contain stimuli able to induce the recruitment and the differentiation of DC into mature, NFkB activated “innate” DC, highly efficient at secreting cytokines and chemokines but poorly activating naïve CD4 T cells. These data partly explain the superiority of CPS over TPS for the prediction of response to PD(L)1 blockade. More importantly, the stimuli identified here may be used as adjuvants to induce this DC « innate » maturation in non-inflamed tumors, but should only be used in combination with anti-PD(L)1 immunotherapy.
Cognitive impairment in breast cancer patients before surgery?: Results of a subgroup of the French CANTO cohort.
Authors: Marie Lange, Isabelle Léger, Olivier Rigal, Idlir Licaj, Shanna Rajpar, Johan Lefel, Christelle Levy, Aurélie Capel, Ines Maria Vaz Duarte Luis, Jonathan Meyer, Florence Lerebours, Jean Petrucci, Laurence Vanlemmens, Marine Brion, Anne-Laure Martin, Christel Mesleard, Patrick Arveux, Fabrice Andre, Sarah Dauchy, Florence Joly
Journal: Journal of Clinical Oncology (2019)

561 Background: Cognitive impairment has been reported among breast cancer (BC) patients (pts) after adjuvant chemotherapy. However, very few studies focused on cognitive function at diagnosis. Here we aimed to describe cognitive impairment among recently diagnosed BC before any treatment. Methods: A predefined sub-study of the French national prospective cohort of cancer and toxicities performed extensive objective and subjective cognitive assessment before any BC treatment (surgery or neo-adjuvant treatment). This study included a group of pts with newly diagnosed invasive Stage I-III BC and a group of healthy control (HC) women matched on age and education level. Episodic and working memory, executive functions, processing speed, attention, cognitive complaints (FACT-COG), anxiety and depression (HADS) and fatigue dimensions (FA12) were assessed with neuropsychological tests and the referred self-report questionnaires. Objective and cognitive impairment were defined according to International Cognition and Cancer Task Force recommendations. Results: 264 women (median age 54±11 years) recently diagnosed (average of 37 days after initial diagnosis) with invasive BC (stage I-II, 69%) and 132 matched HC participated in this study. Impaired working memory (20% vs 4%), information processing speed (36% vs 17%), attention (16% vs 1%) and executive function (21% vs 8%) were higher among pts than in HC (p &lt; 0.001). In addition, 24% (n = 64) of pts reported cognitive complaints versus 12% of HC (n = 16, p &lt; 0.01). Emotional and cognitive fatigue were higher in pts than HC (mean 24 vs 15 and 18 vs 11, p &lt; 0.01). Similarly, higher levels of anxiety and depression were observed in patients when compared with HC (respectively in 41% and 3% of patients vs 10 and 1% for HC, p &lt; 0.001). Objective cognitive impairment was not associated with cognitive complains. Both objective and subjective cognitive impairment were not associated with anxiety or depression. However cognitive complain was associated with fatigue (p &lt; 0.001). Conclusions: In this large study, compared to HC, patients recently diagnosed with a localized BC reported more cognitive complains and objective cognitive impairment before surgery, without link with emotional status, but with fatigue. Further understanding of the biology and correlates of cognitive dysfunction at BC diagnosis is needed (CANTO-NCT01993498).
TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.
Authors: Joaquin Mateo, Nuria Porta, Ursula Brigid McGovern, Tony Elliott, Robert J Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Anna Varughese, Omi Parikh, Simon J. Crabb, Susana Miranda, George Seed, Claudia Bertan, Aude Espinasse, Peter Chatfield, Diletta Bianchini, Emma Hall, Suzanne Carreira, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

5005 Background: We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to &lt; 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772.
The relative contributions of the Genomic Prostate Score and comorbidity profile in predicting outcomes in surgically treated men with clinically low and intermediate-risk prostate cancer.
Authors: Jennifer Cullen, Dudith Pierre-Victor, H. Jeffrey Lawrence, Huai-Ching Kuo, Isabell Sesterhenn, Inger L. Rosner
Journal: Journal of Clinical Oncology (2019)

e16607 Background: The 17-gene Oncotype Dx Genomic Prostate Score® (GPS™) assay has been validated as a predictor of aggressive prostate cancer (PCa) in men treated with radical prostatectomy (RP) for clinically low and intermediate risk PCa. This study examined the performance of the GPS assay as a predictor of adverse pathology (AP) and biochemical recurrence (BCR)-free survival (BRFS), after adjusting for the presence of major comorbidities commonly seen in older men. Methods: Additional analyses were performed using data from a prior clinical validation study of the GPS assay. GPS values (scaled 0-100), determined from diagnostic biopsy tissue, were categorized into 3 levels: lowest quartile (Q1), middle quartiles (combined Q2-Q3) versus the highest quartile (Q4). Major comorbidities included heart disease, stroke, COPD, and other cancers. The associations between GPS result and the presence of ≥1 major comorbidity and outcomes were examined. AP was defined as high-grade (Gleason Score ≥ 4+3) and/or pT3 tumor. BCR was defined as 2 successive PSA levels &gt; 0.2 ng/mL. Logistic regression analysis was used to examine AP; Cox proportional hazards analysis was used to model BRFS. Results: Among 389 eligible men, median age at diagnosis and follow-up time was 62 and 5.6 years, respectively. The prevalence of ≥1 major comorbidity differed significantly across GPS category, rising from 10.2% to 19.7% to 25.5% for GPS Quartiles 1, 2-3, and 4, respectively (p = 0.0024). However, presence of ≥1 major comorbidity was not a significant predictor of AP or BCR in multivariable models with GPS, age, race, and NCCN risk stratum. Men whose GPS result was in the highest quartile had 4-fold higher odds of AP (OR: 4.1; 95% CI = 2.1-7.99, p &lt; 0.0001) at RP and a 3.5 times higher risk of BCR (HR = 3.49; 95% CI = 1.59-7.64, p = 0.002) compared to men in the lowest GPS quartile (Table 1). Conclusions: A high GPS result remains the strongest predictor of BCR and AP in this cohort of low and intermediate risk PCa men, after adjusting for the presence of major comorbidities. Further work will explore the relationships between specific comorbidities and metabolic syndrome, with GPS testing and PCa outcomes.
Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): Design of a confirmatory, double-blind, randomized, controlled study.
Authors: Yaroslav V. Shparyk, Igor Bondarenko, Alexandra Paravisini, Amalia Florez, Camino Huerga, Marta Abad, Felicitas Bullo, Susana Millan
Journal: Journal of Clinical Oncology (2019)

e20731 Background: MB02 is a bevacizumab biosimilar developed to stringent guidelines, including non-clinical and preclinical investigations and a clinical trial as first-line treatment in metastatic colorectal cancer (Romera A et al. Lancet Gastroenterol Hepatol 2018;3 (12): 845-855). A clinical trial (STELLA) has been initiated to confirm there are no clinically meaningful differences between MB02 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity (NCT03296163). Methods: STELLA study is a multinational, double-blind, randomized, parallel-group, equivalence study comparing the efficacy and safety of MB02 vs reference bevacizumab plus chemotherapy in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). Subjects aged 18-80 years, with ECOG status ≤1 and histologically confirmed NSCLC not receiving curative intent surgery or systemic therapy for advanced disease are randomized (1:1) to receive: chemotherapy (paclitaxel 200 mg/m 2 and carboplatin AUC6) and either MB02 or reference bevacizumab 15 mg/kg every 3 weeks for up to 6 cycles (unless disease progression or treatment intolerance). Randomization is stratified by sex, smoking status, disease diagnosis (newly/recurrent), and stage. After 6 cycles, subjects can continue to receive MB02/reference bevacizumab in monotherapy every 3 weeks (until disease progression, treatment intolerance, death, withdrawal or end of study). The primary objective is to compare the objective response rate (ORR) between arms by week 18 (independently assessed) measured by RECIST v1.1. Progression free survival and overall survival (at 18 and 52 weeks), safety and immunogenicity will be assessed as secondary objectives. A sample size of 600 subjects was assumed providing about 89% power to show equivalence of MB02 plus chemotherapy with reference bevacizumab plus chemotherapy on a primary endpoint of risk ratio based on ORR. To date, 596 subjects have been recruited from more than 15 countries worldwide (Europe, Asia, Latin-America, Africa and Middle-East). At their last meeting in September, 2018 the independent data safety monitoring board (DSMB) recommended that the study continue without change. Clinical trial information: NCT03296163.
Outcomes of salvage surgery for anal squamous cell carcinoma: A systematic review and meta-analysis.
Authors: David Patrick Cyr, Paul Savage, Evangelia Theodosopoulos, Tyler R Chesney, Carol Jane Swallow
Journal: Journal of Clinical Oncology (2019)

3571 Background: Following primary chemoradiotherapy for squamous cell carcinoma of the anal canal (A-SCCa), 10% of patients have persistent cancer, and 30% develop local recurrence after initial complete response. Both persistent and recurrent A-SCCa may be amenable to salvage surgery, which typically involves intense health care resource utilization. Because only small cohorts have been reported, we synthesized the evidence for salvage surgery to gain a comprehensive understanding of outcomes. Methods: We systematically searched MEDLINE, Embase, and Cochrane Library (until October 11, 2018) for studies reporting on persistent or recurrent A-SCCa treated with salvage surgery. Quality assessment was performed using the Institute of Health Economics Quality Appraisal Checklist. Overall survival (OS) and disease-free survival (DFS) were pooled using two approaches: survival curve meta-analysis, and exact binomial likelihood random-effects model for survival probabilities. We used meta-regression, subgroup and sensitivity meta-analyses to explore sources of heterogeneity. Results: We identified 39 observational studies that included 1388 patients. Pooled 5-year OS was 45.5% (95% CI 40.6 to 49.9; 33 studies; 1308 patients), and did not differ in patients resected for recurrent (14 studies, n=259 patients) vs. persistent (n=238 patients) disease. There was no association of OS with study year, tumor size, or resection margin at the aggregate-level. Pooled 5-year DFS was 38.3% (95% CI 31.4-43.9; 14 studies; 554 patients). Pooled 30-day complications were 65.3% (95% CI 50.2-77.9; 17 studies; 720 patients): major complications 27.7% (95% CI 22.3-33.8), reoperations 12.7% (95% CI 8.7-18.2), and mortality 1.7% (95% CI 1.1-2.6%). Pooled perineal complications were 32.7% (95% CI 25.0-41.4). Conclusions: Salvage surgery offers 5-year OS of ≈45% and DFS of ≈40% for recurrent/persistent A-SCCa. Major complications and perineal wound complications are common, but postoperative mortality is rare. Presently, there are no reports of patient-reported outcomes such as quality of life after salvage surgery for A-SCCa. Comparative effectiveness studies comparing surgery to other treatments are warranted.
Comparing the American Joint Committee on Cancer (AJCC) breast cancer staging eighth versus seventh edition and breast cancer biology in large databases.
Authors: Jessica S. Young, Kazuaki Takabe, Mariko Asaoka, Stephen B. Edge
Journal: Journal of Clinical Oncology (2019)

e12077 Background: The AJCC 8th edition Breast Cancer Staging system includes biomarkers (estrogen receptor, progesterone receptor, Her2), grade and a genomic assay, to better reflect outcomes, compared to the 7th edition. We used databases with anatomic, biomarker and genomic information to determine if the 8th edition reflects biology better than the 7th edition. Methods: 696 breast cancer patients in The Cancer Genome Atlas (TCGA) and Text Information Extraction System (TIES) were staged both with 7th and 8th edition. Results: From the 7th to 8th editions, 66% of stage 2 patients migrated (64% to stage 1, 1.5% to stage 3). 36% of stage 3 patients migrated (22% to stage 1, 13% to stage 2). We analyzed the differences between stage 1 and 2 in both editions, and the overall survival hazard ratio calculated using Cox regression was greater in the 8th edition than the 7th (HR=1.50, HR=1.22 respectively). We performed Gene Set Enrichment Analysis (GSEA) and found that gene sets related to cell cycle and cell proliferation (E2F targets, G2M checkpoint) were significantly enriched in higher stage in 8th edition but not 7th. Mutant Allele Tumor Heterogeneity (MATH) and Homologous Recombination Defects (HRD) were elevated in higher stages in the 8th edition (p=0.022, p&lt;0.001 respectively), but not the 7th. Immune cells (CD8 Tcell, NK cell) as well as CYT (Immune cytolytic activity score), and Tcell exhaustion markers (PD1, PDL1) were all found to be elevated in higher stage in 8th edition, but not 7th. Conclusions: The 8th edition AJCC Breast Cancer Staging system categorizes cancers by aggressive biology better than the 7th edition. We also found that higher stage tumors trigger an enhanced immune response, but are unable to overcome the aggressive cancer biology.