tbuckley/cabot-search huggingface dataset:
Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: Clinical update.
Authors: Heinz-Josef Lenz, Sara Lonardi, Vittorina Zagonel, Eric Van Cutsem, M. Luisa Limon, Ka Yeung Mark Wong, Alain Hendlisz, Massimo Aglietta, Pilar Garcia-Alfonso, Bart Neyns, Andrea Spallanzani, Dana Backlund Cardin, Tomislav Dragovich, Usman Shah, Ajlan Atasoy, Jean-Marie Ledeine, Michael J. Overman
Journal: Journal of Clinical Oncology (2020)

11 Background: In the phase 2 CheckMate 142 trial, nivolumab plus low-dose ipilimumab provided robust and durable clinical benefit and was well tolerated as first-line therapy for microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events; 3 (7%) had any grade treatment-related adverse events leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. Nivolumab plus low-dose ipilimumab may represent a new first-line treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Scoop: Multicenter phase I/II trial of BBI608 and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503).
Authors: Hiroki Hara, Akihito Kawazoe, Yasutoshi Kuboki, Yoshito Komatsu, Tomohiro Nishina, Eiji Shinozaki, Satoshi Yuki, Koji Takahashi, Yuichi Mikamoto, Nami Hirano, Shogo Nomura, Yosuke Togashi, Hiroyoshi Nishikawa, Akihiro Sato, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2020)

107 Background: The anti–PD-1 antibody pembrolizumab (P) provides response rates of 28-57% in patients (pts) with MSI-H metastatic colorectal cancer (mCRC) vs 0% in those with non-MSI-H cancers. STAT3 has been previously reported as a potential key driver of immune evasion. This study investigates efficacy and safety for the combination of BBI608 (napabucasin), which blocks phosphorylated STAT3 and downregulates IDO1 and PD-L1, with P, in pts with mCRC. BBI608 480 mg BID with P was determined as the recommended phase II dose in phase I. Methods: Phase II included Cohorts A (MSI-H) and B (non-MSI-H). Pts with mCRC not responding to or intolerant of standard chemotherapies were enrolled. The primary endpoint was immune-related objective response rate (irORR), according to irRECIST. The sample size for Cohort A (10 pts) was derived in an exploratory manner. In Cohort B, assuming null and alternative hypotheses of irORR = 5% and 20% led to an estimated required sample size of 40 pts, with a 1-sided alpha of 5% and power of 90%. Genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were determined by whole exome sequencing and RNA sequencing as previously described. Results: From Feb/2017 to Jun/2018, 10 pts were enrolled in Cohort A and 40 in Cohort B. The irORR was 50% (5 of 10 pts) in Cohort A and 10% (95% CI 2.8 to 23.7) (4 of 40 pts) in Cohort B. Of evaluable 19 pts for CMS classification in Cohort B, CMS1, CMS2, CMS3, and CMS4 were detected in 3, 6, 4, and 6 cases, respectively. The irORR was 33% (1 of 3 pts), 0% (0 of 6 pts), 25% (1 of 4 pts), 33% (2 of 6 pts) in CMS1, CMS2, CMS3, and CMS4, respectively. One CMS3 patient with partial response had POLE mutation, while 1 CMS1 and 2 CMS4 pts with partial response did not. The most common grade 3 or higher treatment-related adverse events included fever (10%) in Cohort A, and diarrhea (5%) and appetite loss (7.5%) in Cohort B, without unexpected safety signals. No treatment-related deaths occurred. Conclusions: BBI608 with P showed encouraging anti-tumor activity with acceptable toxicity for non-MSI-H mCRC pts as well as MSI-H mCRC pts. Impact of CMS on the efficacies of this combination warrants further investigation in the additional cohort of this study. Clinical trial information: NCT02851004.
Neuroendocrine and carcinoid tumors of the gastrointestinal tract: Epidemiology and outcomes from the National Cancer Database.
Authors: Johannes Uhlig, James Nie, Stacey Stein, Michael Cecchini, Jill Lacy, Hyun S. Kim
Journal: Journal of Clinical Oncology (2020)

609 Background: While carcinoid and neuroendocrine tumors (NET) can manifest throughout the human body, approximately 2/3 of these tumors arise in the gastrointestinal (GI) tract. Methods: The 2019 version of the National Cancer Database was searched for adult patients with carcinoid or neuroendocrine tumors of the GI tract. Tumor incidence, patient demographics, treatment and cancer variables of GI carcinoid/NETs were compared to other GI cancers. Cox proportional hazards models were used to evaluate overall survival (OS). Results: A total of 101,744 patients were included. Carcinoid/NET incidence varied with primary location, with highest proportion in the small intestine (55.7% of all small intestinal cancers). Compared to other histologies, carcinoid/NETs were more common in younger patients (median age 60 vs. 68years, p &lt; 0.001) and African Americans (18 vs 12%, p &lt; 0.001). Median carcinoid/NET diameter 15mm vs. 40mm for other cancers (p &lt; 0.001). Carcinoid/NETs were diagnosed at lower stages than other histologies (AJCC stage 3/4, 30% vs. 47%, p &lt; 0.001), with most metastases in the liver (8.9%). Stage 1/2 carcinoid/NETs were most often treated by surgical resection with or without concurrent chemotherapy (65%; 22%), whereas stage 3/4 patients received chemotherapy alone or in combination with surgical resection more commonly (39%; 25%). After multivariable adjustment, primary cancer site emerged as an independent prognosticator: longest OS was observed in patients with carcinoid/NET of the small intestines (vs. colonic frame HR = 0.40, 95% CI: 0.37-0.44, p &lt; 0.001). Comparable results were evident in patients with hepatic metastases (small intestines vs. colonic frame carcinoid/NETs; HR = 0.20, 95% CI: 0.17-0.24, p &lt; 0.001). Other independent OS prognosticators were patient age, gender, race and comorbidities, as well as tumor size, stage and treatment. Conclusions: Compared to other GI-associated tumors, carcinoid/NETs are more common in younger patients, African Americans, diagnosed with smaller diameter at low stage. Carcinoid/NETs of the small intestines are associated with improved overall survival compared to other primary disease sites.
Proteomic features of HCC tumors reveal clinically distinct subtypes independent of somatic mutations.
Authors: Sun Young Yim, Jaejun Shim, Yun Seong Jeong, Bo Hwa Sohn, Ji Hoon Kim, Ju-Seog Lee
Journal: Journal of Clinical Oncology (2020)

561 Background: Recent massive sequencing studies of HCC genomes revealed many new genetic alterations that might be accountable for HCC development and provided comprehensive view of malignant disease. However, genomic profiling of tumors is limited by a loose correlation between genetic alterations and their functional products such as proteins and metabolites. To overcome current limitation, we generated genomic and proteomic data together from HCC tumors and performed integrated analysis of both data sets. Methods: We analyzed proteomic data and genomic data such as somatic mutations, mRNA expression, miRNA expression, and copy number alterations from 300 HCC tumors to uncover most correlated genomic alterations with proteins. Clinical significance of identified key protein features were validated in multiple independent cohorts of HCC patients. Results: Analysis revealed three subtypes of HCC with substantial difference in proteomic patterns. Based on proteomic characteristics, three subtypes were named to mesenchymal (MES), metabolically active (MA), and kinase-active and genome stable (KAGS) subtypes. When assessed clinical relevance, the overall survival rate of patients in MES subtype was significantly worse than those in MA and KAGS subtype (P = 0.001). Poor clinical outcomes of mesenchymal subtype is validated in multiple independent cohorts (in total of &gt;500 patients). Gene network analysis with integrated genomic and proteomic data further revealed association of subtypes with currently available treatments of HCC such as sorafenib and immunotherapy. In addition, multiple in-depth analysis of integrated data identified potential therapeutic target candidates for each subtype. Functional validation with cell lines demonstrated that some of candidates are essential for survival of HCC cells. Conclusions: HCC is classified into three subtypes by integrating genomic and proteomic data. These analyses has identified potential therapeutic targets as well as biomarkers associated with therapeutic targets. Our study demonstrated merit of integrated analysis of proteomic data with genomic data to uncover potential driver genes of HCC development.
Efficacy and safety of regorafenib as third-line therapy in metastatic colorectal cancer: An indirect meta-analysis.
Authors: Yinying WU, Yangwei Fan, Dan Feng Dong, Xuyuan Dong, Yuan Hu, Yu Shi, Jiayu Jing, En Xiao Li
Journal: Journal of Clinical Oncology (2020)

119 Background: The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib in comparison to other available third-line therapies in mCRC. Methods: Literature search for randomized controlled trials was conducted in PubMed, Embase and Cochrane library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102 and nintedanib as third-line therapies in mCRC patients. The primary outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) and safety as the secondary outcome. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response and safety data, respectively. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results: We identified 8 RCTs studies comparing regorafenib (2 studies), fruquintinib (2 studies), TAS-102 (3 studies) and nintedanib (1 study) against placebo. The OS with regorafenib was significantly better when compared to nintedanib (HR= 0.66, 95% CI 0.45, 0.95, p=0.02), but was similar to that of fruquintinib (HR=1.01, 95% CI 0.67, 1.52, p=0.94) and TAS-102 (HR= 0.97, 95% CI 0.68, 1.38, p=0.88). The PFS and ORR for regorafenib were slightly better than TAS-102 (PFS: HR= 0.86, 95% CI 0.54, 1.37, p=0.5; ORR: RR= 1.13, 95% CI 0.11, 11.05, p=0.92) and nintedanib (PFS: HR= 0.68, 95% CI 0.42, 1.10, p=0.12, ORR: not reported) but was lower than fruquintinib (PFS: HR= 1.53, 95% CI 0.93, 2.52, p=0.08; ORR: RR= 0.68269, 95% CI 0.045, 10.32, p=0.79). Safety analysis showed that the relative risk of adverse events was lesser in patients treated with regorafenib in comparison to fruquintinib but was similar to that of nintedanib and TAS-102. Conclusions: Regorafenib with its efficacy and safety coupled with comprehensive continuously anti-angiogenic therapy, might be the first option in third-line mCRC. Head-on comparisons are required for further validation.
Polymorphisms of genes encoding for regulatory proteins in the coagulation cascade to predict outcome for stage II and III colon cancer.
Authors: Martin D. Berger, Inti Zlobec, Shu Cao, Yuji Miyamoto, Mitsukuni Suenaga, Shivani Soni, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Francesca Battaglin, Wu Zhang, Alessandro Lugli, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

227 Background: In cancer patients, an activated coagulation cascade might promote tumor cell dissemination. There are preliminary data suggesting that fibrinogen in combination with platelets can build a meshwork that entraps cancer cells enabling them to escape from immunosurveillance. We therefore hypothesize that variations in genes encoding for regulatory proteins within the coagulation pathway may predict outcome in patients with stage II and III colon cancer. Methods: The impact of three functional single nucleotide polymorphisms (SNPs) within the FGB, SERPINC1 and ITGA2B genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was isolated from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 42.8% / 57.2%; 111 patients had stage II, and 98 stage III colon cancer. The FGB rs4220 SNP showed significant association with recurrence rate in the overall population. Patients harboring any A allele had a higher 3-years recurrence rate compared to those with a G/G genotype (28% vs 17%) in both univariate (HR 1.83, 95% confidence interval (CI) 0.99-3.36, p = 0.048) and multivariate analyses (HR 1.94, 95% CI 1.05-3.57, p = 0.034). This trend was most evident among pts with stage II and especially the subgroup of high-risk stage II colon cancer. Again, A allele carriers had a higher 3-years recurrence rate compared to those having a G/G genotype (24% vs 10% and 44% vs 15% respectively) in both univariate (HR 3.32, 95% CI 1.26-8.74, p = 0.010 and HR 5.34, 95% CI 1.38-20.68, p = 0.006) and multivariate analyses (HR 3.34, 95% CI 1.27-8.78, p = 0.015 and HR 5.44, 95% CI 1.40-21.15, p = 0.015). Conclusions: Here, we demonstrate that the FGB polymorphism rs4220 might serve as a prognostic biomarker in stage II colon cancer. Assessment of FGB rs4220 might help us to identify those stage II colon cancer patients who will derive the most benefit from adjuvant chemotherapy.
Clinical and molecular profiling of locally advanced compared with metastatic pancreatic adenocarcinoma.
Authors: Sarah Louise Picardo, Grainne M. O'Kane, Sandra Fischer, Amy Zhang, Robert Edward Denroche, Gun Ho Jang, Anna Dodd, Robert C. Grant, Barbara Grunwald, Shari Moura, Elena Elimova, Rebecca M. Prince, George Zogopoulos, Faiyaz Notta, Julie Wilson, Steven Gallinger, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2020)

747 Background: It is unclear whether locally advanced pancreatic cancer (LAPC) should be treated similarly to metastatic pancreatic cancer (MPC). Clinical trials often exclude LAPC. We compare clinical and genomic characteristics of LAPC and MPC. Methods: Patients with LAPC and MPC were enrolled in the COMPASS trial (NCT02750657). Clinical, demographic and survival data was collected (cut off 8/31/19). WGS, RNAseq and modified Moffitt classification was performed. Results: Patients with LAPC (n = 28) and MPC (n = 180) did not differ in terms of age, gender, smoking or diabetes history. Patients with LAPC had lower BMI (p = 0.005) and lower baseline Ca19-9 (p = 0.02) than those with MPC. LAPC/MPC tumors had similar rates of KRAS, p53, CDKN2A and SMAD4 mutations and similar levels of ploidy, indels and neoantigens. There were increases in single nucleotide variants (p = 0.026) and structural variants (p = 0.04) in MPC compared with LAPC. No LAPC tumors were homologous recombination deficient (HRD) or KRAS wild type (WT), compared with 14 (8%) HRD and 16 (9%) KRAS-WT MPC. All LAPC were classical subtype compared with 77% MPC (p = 0.0052). OS data is shown in the table. MPC classical subtype tumors had improved OS compared with basal-like tumors (p = 0.008). Patients with MPC and p53 mutation trended towards worse OS compared with those without p53 mutation (p = 0.07); this was not seen in LAPC. There was a significant correlation between time on chemotherapy and OS in LAPC (p = 0.002) and MPC (p &lt; 0.0001). Conclusions: Patients with LAPC have similar molecular profiles to those with MPC with similar rates of altered drivers. LAPC tumors are more likely to be Moffitt classical subtype and have similar OS to classical subtype MPC. LAPC patients benefit from local therapy; all patients benefit from increased time on chemotherapy. These data suggest that patients with LAPC should be treated similarly to those with classical subtype MPC but should be offered local therapy when possible. Clinical trial information: NCT02750657 . [Table: see text]
Causes of death following neuroendocrine tumors diagnosis: A United States population-based analysis.
Authors: Anas M. Saad, Thorvardur Ragnar Halfdanarson, Mohamad Bassam Sonbol
Journal: Journal of Clinical Oncology (2020)

630 Background: Neuroendocrine tumors (NET) are heterogeneous in terms of prognosis based on location, grade, and stage. In this study we report causes of deaths (COD) in patients with NET. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) Program to query data of NET patients diagnosed between 2000 and 2016 and report COD following NET diagnosis. Results: We reviewed 94,399 NET cases of which 38,692 died during the follow-up period. The highest number of deaths (5,721) occurred within less than a year following grade 3 (G3) NET diagnosis while most deaths in grade 1/2 (G1/G2) cases occurred within 1-5 years of diagnosis (1,889 and 987, respectively). During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (CD) (4.6%). As time passed, NET deaths decreased to be responsible for 24.3% of deaths after &gt; 10 years of diagnosis, while other cancers (14%) and CD (19.7%) became more common. When dividing NET cases by grade, NETs were responsible for 42.8%, 63.4%, and 81.2% of deaths in G1, G2, and G3, respectively, while other cancers were responsible for 16.2%, 11.8%, and 7.2% of deaths, respectively and CDs were responsible for 12.3%, 7.2%, and 3.2% of deaths, respectively. For G1 localized NET: non-NET cancers (22.2%) was the most common COD followed by NET (19.7 %) and CD (16.8%). For G2 localized NET, NET was COD in 31.1% of cases followed by non-NET cancers (22.4%) and CD (13.8%). In metastatic disease, NET was the most common COD regardless of grade. Conclusions: In G1 and G2 localized NET, deaths were mostly secondary to non-NET causes. Therefore, counseling patients regarding survivorship with cancer-screening and focusing on prevention from non-cancer deaths is important. On the other hand, NET is responsible for most deaths in metastatic NET regardless of grade. Further advances in systemic therapies are needed to improve the outcomes of advanced disease.
Pediatric Palliative Care in Oncology
Authors: Jennifer Snaman, Sarah McCarthy, Lori Wiener, Joanne Wolfe
Journal: Journal of Clinical Oncology (2020)

Pediatric palliative care aims to alleviate suffering and improve the quality of life of children with serious disease and increase support for their parents and other family members. Integration of palliative care into the routine care of children, adolescents, and young adults with cancer has resulted in improved outcomes in patients and their families. The field of pediatric palliative oncology-encompassing primary palliative care provided by the multidisciplinary oncology team as well as subspecialty palliative care provided by the palliative care team for more complex cases-is unique from palliative care in adults given its focus on care of the child and the larger family. In this review, we focus on advancements in the specific domains within pediatric palliative oncology care including family-centered communication, assessment and management of physical symptoms and distress, psychosocial concerns, and spiritual considerations of the patient, parents, and siblings.
Which treatments for fungal nail infections work better, those taken by mouth work or those applied to the nail?
Authors: A.K. Gupta, K.A. Foley, R.R. Mays, N.H. Shear, V. Piguet
Journal: British Journal of Dermatology (2020)

Onychomycosis is a fungal infection of the nail and is more likely to occur in toenails. In Europe and North America, approximately 4.3% of people have this infection. The infection accounts for approximately 50% of all nail‐related disease. To treat toenail infection, oral (taken by mouth) and topical (applied to the skin) medications are available. Topical treatments have lower success rates than oral treatments, but oral treatments may produce side effects or affect how other medications work. Published studies of clinical trials do not directly compare oral and topical treatments. This study, from Canadian researchers, aimed to use a statistical analysis called network meta‐analysis in order to estimate how oral and topical treatments compare to each other in terms of mycological cure (eradicating the fungal infection) and in adverse events (side effects). The authors found 26 published studies to include in their analysis. The authors wanted to include device‐based treatments (e.g. laser) and combination treatments, but there were not enough randomised controlled trials on these treatments. The results showed that daily use of the oral treatments of terbinafine 250 mg and itraconazole 200 mg were significantly more likely to eradicate the fungal infection compared to topical treatments. Other oral treatments and regimens were similar to topical treatments in producing mycological cure and every treatment was better than controls. In terms of side effects, there was no difference between oral and topical medications, and this may be because reports of side effects with oral medications arose after these clinical studies were completed. This current review suggests that patients have safe oral and topical medication options for toenail fungal infection. This summary relates to the study: Monotherapy for toenail onychomycosis: a systematic review and network meta‐analysis