tbuckley/cabot-search huggingface dataset:
Consensus gene expression analysis to identify key hallmarks of cancer in malignant melanoma.
Authors: Emma O'Connor, Eileen E. Parkes, Leeona Galligan, James Bradford, Shauna Lambe, Gemma E Logan, Steven M. Walker, Nuala McCabe, Paul D Harkin, Richard D. Kennedy, Laura A. Knight
Journal: Journal of Clinical Oncology (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 clara T software tool that uses consensus between multiple published GES categorised by the Hallmarks of Cancer (Hanahan &amp; Weinberg, 2011) to classify cancers. As metastatic melanoma represents poor prognostic disease (5-yr survival 15-20%), we applied clara T 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 clara T 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&amp;2 had significantly improved OS compared to Groups 3&amp;4 (HR = 0.50, p&lt; 0.0001). Clustering using single Hallmarks revealed that immune-positive tumours had significantly improved OS (HR = 0.53, p&lt; 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 &lt;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.
Economic burden of immunotherapy as second-line treatment of patients with advanced non-small-cell lung cancer at a Latin American oncology center.
Authors: Feliciano Barron Barron, Luis Antonio Cabrera, Andres Felipe Cardona Zorrilla, Oscar Gerardo Arrieta Rodriguez
Journal: Journal of Clinical Oncology (2019)

e18376 Background: Lung cancer is the leading cause of cancer-related mortality in México and worldwide. More than 80 percent of lung cancers are classified as non-small cell lung cancer (NSCLC). Immunotherapy has become integrated into the treatment of patients with specific genetic alterations, which has led to improvements in survival and quality of life. Pembrolizumab is a new drug approved in several countries for second-line therapy in non-small cell lung cancer (NSCLC) being programmed cell death ligand (PD-L1) positive. Methods: A retrospective study of medical records of 60 patients treated with immunotherapy as second-line treatment of advanced non-small-cell lung cancer was conducted at the National Institute of Cancerology (INCAN) in Mexico during 2016-2018. PD-L1 biomarker was not mandatory for receiving immunotherapy. The costs associated with the total costs of tretament were estimated as a mean value with confidence intervals of 95% confidence by costing the elements of treatment of the disease and adverse events as well the frequency of consultations, hospital stays, and monitoring obtained in the records. Costs are presented in US dollars. Results: The total mean monthly cost during immunotherapy was $1,649 (95% confidence interval [CI] = $1,484–$1,814), of which 93.8% represented immunotherapy costs, 5.4% drug application and monitoring, 0.8% adverse events treatment. We identified 30 potential patients per year candidates to receive immunotherapy as second line. From which the expected costs of treatment will be $49,476 [CI] = $44,528–$57,392), of which $41,766 are immunotherapy costs, application and monitoring represent $2,400 and the rest for adverse events. Conclusions: The therapeutic approach for the second-line treatment of patients with advanced non-small cell lung cancer (NSCLC) without actionable mutations has been revolutionized by the approval of new more efficacious drugs like pembrolizumab. Healthcare costs during immunotherapy treatment with pembrolizumab were largely attributed to anti-cancer therapy and less for adverse events. Pembrolizumab as second-line treatment of patients with advanced non-small-cell lung cancer, prolong overall survival, leading to fewer adverse events than chemotherapy.
Can pediatric and adolescent patients with recurrent tumors benefit from a precision medicine program? The European MAPPYACTS experience.
Authors: Pablo Berlanga, Gaëlle Pierron, Ludovic Lacroix, Tiphaine Adam de Beaumais, Virginie Bernard, Sophie Cotteret, Nicolas Andre, Nadege Corradini, Estelle Thebaud, Samuel Abbou, Michela Casanova, Cormac Owens, Stefan Michiels, Olivier Delattre, Gilles Vassal, Gudrun Schleiermacher, Birgit Geoerger
Journal: Journal of Clinical Oncology (2019)

10018 Background: The international prospective precision medicine trial MAPPYACTS (NCT02613962) aims to define the molecular profile in recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. Methods: Patients &lt; 18 years-old at the time of initial diagnosis underwent on-purpose tumor biopsy/surgery of their recurrent/refractory malignancy for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years. 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients did not undergo intervention procedure (10 screening failures, 1 consent withdrawal). Molecular profiling was performed on samples in 433 patients and was contributive for 390 patients. For 271/390 patients (70%), there was at least one genetic alteration that could represent a potential therapeutic target and 8% had alterations considered as “ready for use” for treatment at relapse. Among them, 19 (7%) died before the CMTB. With follow-up censored in January 2019, 72 patients (27%) were treated with at least one matched targeted agent, 57 of them in a clinical trial, mostly the proof-of concept AcSé-ESMART trial (NCT02813135). Of the 166 patients (61%) that did not receive the matched treatment recommended by CMTB (80 still on follow-up), main reasons were: response/stable disease under previous therapy (50), another treatment (48), rapid disease progression/death (30) and legal representative refusal (12). Conclusions: MAPPYACTS profiling allowed tailored targeted treatment, mainly through early clinical trials, in patients with recurrent pediatric cancer. Since most detected molecular findings are within the investigational or hypothetical evidence level, therapeutic proof-of-concept trials that are exploring targeted therapies in molecularly enriched patient populations are crucial to improve knowledge and potentially outcome. Clinical trial information: NCT02613962.
Targeting EGFR Ex20 mutant lung cancer with the wild type sparing kinase inhibitor PRB001.
Authors: Martin L. Sos, Hannah Lea Tumbrink, Carsten Schultz-Fademrecht, Jonas Lategahn, Marina Keul, Janina Niggenaber, Alena Heimsoeth, Matthias Baumann, Lisa Hanna Werr, Carsten Degenhart, Sascha Menninger, Johannes M Heuckmann, Roman K. Thomas, Daniel Rauh, Bert Klebl
Journal: Journal of Clinical Oncology (2019)

e14718 Background: The majority of EGFR mutant tumors can be effectively treated with targeted drugs. Lung adenocarcinoma patients with EGFR Ex20 insertion mutations, however, lack safe and potent treatment options. These genetic alterations share homology with HER2 Ex20 insertion mutations and perturb the ATP binding pocket in a way that limits accessibility through currently available tyrosine kinase inhibitors. Second-generation EGFR inhibitors are partially active in EGFR Ex20 mutant models but their potent activity against wild type (WT) EGFR and the resulting adverse effects largely prohibit the clinical use of these drugs. To address this medical need, we developed PRB001, a novel EGFR kinase inhibitor. Methods: We facilitated protein X-ray crystallography to guide the development of small molecule inhibitors with high potency against EGFR/HER2 Ex20 mutant kinases and low activity against WT EGFR. Iterative compound optimization involved biochemical profiling concerning inhibition and binding kinetics, cellular profiling as well as mouse pharmacokinetic and mouse efficacy studies. Results: PRB001 exhibits potent activity against EGFR/HER2 Ex20 insertion mutations, in genetically engineered Ba/F3 cell line models and patient derived cell lines. At the same time, PRB001 exhibits a 10-100 fold lower activity against WT EGFR in several cellular models. Our data indicate that PRB001 and its derivatives display a therapeutic window for an effective treatment of EGFR Ex20 mutant tumors with a limited toxicity profile. Mouse xenograft experiments support these results, showing that, in contrast to second-generation EGFR inhibitors, PRB001 does not inhibit WT EGFR and does not lead to loss of weight of treated animals at effective doses of 90 mg/kg daily. Conclusions: Our data support the notion that PRB001 effectively kills a wide range of EGFR Ex20 mutant cellular models and together with its safety profile builds a basis for the development of a mutant-selective and clinically effective tyrosine kinase inhibitor.
Multimodality liquid biopsy for early monitoring and outcome prediction in first-line metastatic HER2-negative breast cancer: Final results of the prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG)— COMET study.
Authors: Jean-Yves Pierga, Amanda Silveira, Olivier Tredan, Marie-Laure Tanguy, Veronique Lorgis, Coraline Dubot, William Jacot, Anthony Goncalves, Marc Debled, Christelle Levy, Jean-Marc Ferrero, Christelle Jouannaud, Marie-Ange Mouret-Reynier, Florence Dalenc, Jerome Lemonnier, Frederique Berger, Charlotte Proudhon, Francois Clement Bidard
Journal: Journal of Clinical Oncology (2019)

3019 Background: Circulating Tumor Cells (CTC) are independent markers of progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC). Monitoring circulating tumor DNA (ctDNA) can detect mutation associated with resistance to treatment and its variations reflect changes in tumor burden. We prospectively monitored CTC, Circulating Endothelial Cells (CEC), serum markers and ctDNA during first line chemotherapy for MBC. Methods: The French cohort COMET is a prospective study including first line HER2 negative pts receiving weekly paclitaxel and bevacizumab . Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2).We present here the final planned analysis. Results: From 09/2012 to 11/2014, 286 patients were included: 198 for ctDNA, 251 for CEC and 283 for CTC. Median age was 56 years and 23% of pts had triple negative BC. At baseline, 71% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000). With a threshold of ≥5 CTC, 49% of pts were positive at baseline and 22% at C2. For ctDNA, out of the first 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). The average number of mutations per pt was 2.4 (range 1 to 9). Most commonly mutated genes were TP53 and GATA3. ESR1 was mutated in 10.6% of the pts and restricted to the ER+ subgroup. PIK3CA was mutated in 23.2% of the pts. Median Allelic Frequency was 9.1% . Only 68 pts (36%) had detectable ctDNA at C2. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p &lt; 0.0001). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Median follow-up was 53 months and median OS was 32 months. Detectable CTC and ctDNA at baseline and at C2 were significantly associated with decreased PFS and OS. CEC and serum markers level had no prognostic value. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic factors. Conclusions: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC pts. Early decrease of CTC and ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome, with a stronger value for ctDNA compared to CTC. Clinical utility of early ctDNA variations monitoring and changes in mutation profile remain to be demonstrated. Clinical trial information: NCT01745757.
Comparison of Hospital Readmission After Total Hip and Total Knee Arthroplasty vs Spinal Surgery After Implementation of the Hospital Readmissions Reduction Program
Authors: Ashwin Ramaswamy, Maya Marchese, Alexander P. Cole, Sabrina Harmouch, David Friedlander, Joel S. Weissman, Stuart R. Lipsitz, Adil H. Haider, Adam S. Kibel, Andrew J. Schoenfeld, Quoc-Dien Trinh
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The Hospital Readmissions Reduction Program (HRRP) was recently expanded to penalize excessive readmissions after total hip arthroplasty (THA) and total knee arthroplasty (TKA). These are the first surgical procedures to be included in the HRRP. <h3>Objective</h3> To determine whether the HRRP was associated with a greater decrease in readmissions after targeted procedures (THA and TKA) compared with similar nontargeted procedures (lumbar spine fusion and laminectomy). <h3>Design, Setting, and Participants</h3> A retrospective cohort study was conducted of patients 50 years or older among all payers in the Nationwide Readmissions Database who underwent THA, TKA, lumbar spine fusion, or laminectomy between January 1, 2010, and September 30, 2015. Multivariable logistic regression and interrupted time-series models were used to calculate and compare 30-day readmission trends in 3 periods associated with the HRRP: preimplementation (January 2010-September 2012), implementation (October 2012-September 2014), and penalty (October 2014-September 2015). Statistical analysis was performed from January 1, 2010, to September 30, 2015. <h3>Exposures</h3> Announcement and implementation of the HRRP. <h3>Main Outcomes and Measures</h3> Readmission within 30 days after hospitalization for THA, TKA, lumbar spine fusion, or laminectomy surgery. <h3>Results</h3> The study included 6 687 077 (58.3% women and 41.7% men; mean age, 66.7 years; 95% CI, 66.7-66.8 years) weighted hospitalizations for THA, TKA, lumbar spine fusion, and laminectomy surgery: 4 765 466 hospitalizations for targeted conditions and 1 921 611 for nontargeted conditions. After passage of the Patient Protection and Affordable Care Act, the risk-adjusted rates of readmission after all procedures decreased in a similar fashion. Implementation of the HRRP was associated with a 0.018% per month decrease in the rate of readmission (95% CI, −0.025% to −0.010%) after targeted procedures, which was not observed after nontargeted procedures (slope per month, −0.003%; 95% CI, −0.016% to 0.010%). Penalties were not associated with a greater decrease in readmission for either targeted or nontargeted procedures. <h3>Conclusions and Relevance</h3> These results appear to be consistent with hospitals responding to the future possibility of penalties by reducing readmissions after surgical procedures targeted by the HRRP.
Prescription patterns and associated cost during periods of cancer drug stockouts in a resource-limited setting.
Authors: Sonya Davey, Surbhi Grover, Dipho Irene I Setlhako, Tlotlo Bathethi Ralefala, Patrick Manshimba, Robert Gross, Angela DeMichele, Lawrence N. Shulman, Yehoda M. Martei, Warren B. Bilker
Journal: Journal of Clinical Oncology (2019)

e18129 Background: Cancer drug stockouts occur at high frequencies globally, however their clinical effects are understudied in sub-Saharan Africa (SSA). We aim to describe prescription patterns and cost of systemic chemotherapy in cancer patients in Botswana during periods of stockout. Methods: Using a retrospective cohort study of the ten most common solid tumor malignancies treated with systemic chemotherapy at Princess Marina Hospital (PMH), Gaborone in 2016, we conducted a subset analysis of suboptimal events, defined as a cycle with ≥ 7 days delay or therapy switch from initiated guideline regimen, that occurred during drug stockout vs non-stockout periods. We estimated financial cost of therapy per cycle using Management Sciences for Health International Price Indicator Guide. Chi-squared and Wilcoxon rank sum were used for comparisons. Results: 167/378 patients contributed to 320 suboptimal events. 63% (201/320) of events occurred during a drug stockout, of which 43%, 43% and 14% were delays, switches, or both, respectively. There were significantly more delays (56% vs 44%, p &lt; .0001) and switches (75% vs 26%, p &lt; .0001) during stockout periods vs no stockout. The majority of switches during drug stockouts occurred in breast cancer patients receiving curative therapy: 48% (20/42) were “paclitaxel + trastuzumab” ($4673) to “paclitaxel alone” ($35) in HER2 positive patients resulting in a 99% cost decrease; and 29% (12/42) were paclitaxel ($35) to docetaxel ($108) resulting in a 209% cost increase per cycle switched. Colon cancer patients receiving palliative-intent therapy were the second most frequent patients with therapy switches during stockout periods: 42% (8/19) were “capecitabine + oxaliplatin” ($259) to “capecitabine alone” ($105) resulting in a 59% cost decrease. Conclusions: Breast cancer patients form the majority of patients treated with systemic chemotherapy at PMH and experienced the most delays and switches in therapy during drug stockout periods. Changes in drug prescription patterns during stockout periods may be associated with switches leading to inferior but less costly regimens, and in some cases costly regimens with higher toxicity. Interventions that minimize cancer drug stockouts are imperative and further studies to understand impact of stockout on survival are needed in SSA.
Correlation analysis of radiotherapy and prognosis of elderly patients with hormone receptor-positive breast cancer in different immunohistochemical subtyping.
Authors: Jin Zhang
Journal: Journal of Clinical Oncology (2019)

e12061 Background: Our study aimed to assess the effect of radiotherapy on the recurrence and survival in elderly patients with hormone-receptor-positive early breast cancer. Methods: We performed a retrospective analysis of 327 breast cancer patients who were 65 years or older with stage I-II, hormone-receptor-positive, after breast-conserving surgery and who received endocrine therapy(ET) or radiotherapy plus endocrine therapy(ET+RT). ET group was subgroup analyzed according to luminal A type and luminal B type, the same as ET+RT group. Evaluation Criterias were five-year local relapse rate(LRR),distant metastasis rate(DMR), disease-free survival rate (DFS) and overall survival rate (OS). Results: There were significant differences in five-year LRR (HR 3.33, 95% CI 1.51-7.34, P=0.0028) and DFS (HR 1.59, 95% CI 1.15-2.19, P=0.0045), but there were no significant differences in DMR and OS between the two groups. In luminal A type, there was no significant difference in five-year LRR, DMR,DFS, and OS between the ET group and the ET + RT group. In luminal B type, the difference was statistically significant in five-years LRR(HR 5.447, 95% CI 1.65-17.98, P=0.0054), DFS (HR 2.188, 95% CI 1.37-3.49, P=0.0010) and OS (HR 1.752, 95% CI 1.01-3.054, P=0.0478). In ET group, there were significant differences between luminal A type and luminal B type in five-years DFS (HR 1.841, 95% CI 1.23-2.75, P=0.0028) and OS (HR 1.763, 95% CI 1.07-2.91, P=0.0264). Conclusions: After breast-conserving surgery, radiotherapy can reduce the LRR and improve the DFS and OS of luminal B type elderly early patients, but luminal A type elderly early patients can not benefit from radiotherapy. Without radiotherapy, luminal A type patients have a better OS and DFS than luminal B.
Use of computer algorithms in the electronic health record to identify and triage primary care patients for hereditary evaluation.
Authors: Wendy Kohlmann, Katie Tobik, Michael Flynn, Rachel Hess, Charlene R Weir, Richard L Bradshaw, Guilherme Del Fiol, Kensaku Kawamoto, Joshua David Schiffman
Journal: Journal of Clinical Oncology (2019)

e13137 Background: Identifying individuals with inherited cancer susceptibility is critical for optimal cancer prevention and screening. Family history is a significant predictor of inherited risk. Algorithms to extract and analyze family histories in electronic health records (EHRs) provide an opportunity for enhanced identification. Methods: Algorithms were developed to screen existing family history information in the EHR and identify patients meeting genetic evaluation guidelines for hereditary breast, ovarian, and/or colorectal cancer. In a pilot implementation, the patients of 5 primary care physicians at 2 community clinics were screened with the algorithms. Patients for genetic counseling were notified through the patient portal or mail. Follow-up phone calls were made to non-responders. Results: The algorithms identified 40 patients meeting criteria. Fifteen (38%) scheduled an appointment, 9 (22%) declined/will think about it, and 16 (40%) did not respond and were unable to be reached by phone. To date, 9 patients completed appointments. The family history used by the algorithm was accurate in 8 of 9 cases. For one case, the EHR family history was for adoptive relatives. Six of the 9 patients had additional family history not in the EHR, including 2 patients at-risk for familial mutations in ATM and ACVRL1. Patients who responded had their last visit within the healthcare system an average of 0.25 years ago versus 1.13 years for non-responders (p = 0.0002). Conclusions: Algorithms for screening existing family history in the EHR can identify primary care patients for hereditary cancer evaluation. While this approach has a low rate of false positives, it will likely miss appropriate individuals as 78% of patients had incomplete EHR-based family history as compared to a gold-standard genetic counselor obtained pedigree. However, use of automated algorithms will allow healthcare system to begin offering genetic services to those who can be identified. Ongoing efforts include use of natural language processing to extract family history from narrative data and use of a standards-based approach for replicability across EHRs.