tbuckley/cabot-search huggingface dataset:
Classification of prostate cancer based on clinical and omics data using neural networks techniques to improve prognostic power.
Authors: Laura Marin, Fanny Lys Casado, Daniel Racoceanu, Joseph A. Pinto
Journal: Journal of Clinical Oncology (2019)

e16569 Background: In 2017, prostate cancer (PCa) was the second most common cancer in men after lung cancer. While there are different courses of action to treat the disease, its mortality in Peru is higher than 50%. Conventionally, PCa is diagnosed by evaluating tissue biopsies, and classified according to the Gleason grading system. Novel molecular classifications of PCa have been proposed for diagnostic and prognostic purposes. The main goal of this work is to implement a tool predicting the disease free time of patient according to the genomic expression and highlight the genes playing an influential role on the prediction. Methods: Modern techniques to classify data keep getting broader and more accurate, in particular with the introduction of Neural Networks(NN). We implement an Artificial Neural Network automatic genomic classification strategy based on a Local Interpretable Model-Agnostic Explanations (LIME) algorithm because it allows the network to choose the features of major discriminative significance. As a proof-of-concept, we selected a sub-set of 3530 genes related to recurrence from 499 PCa genomes to build the neural networks. Results: The resulting neural network, trained and tested on cancer cell 2010 database and validate on the MSKCC data the can predict the time of recurrence within a range of three months based on the genomic expression with an accuracy of 96,9% and a loss of less than 9%. Using the implemented LIME algorithm, our results indicate that this subset of genes is informative of recurrence and plays a substantial role in the prediction. Conclusions: Instead of using a classic fully connected layer, we implemented different types of Deep Learning networks where the final network provides the predicted survival rate or time to recurrence. This information will allow the doctors to propose the best course of treatment. Our method is able to generate an augmented score, enabling a more accurate evaluation of risk and personalized treatment strategy
Real-world prevalence of autoimmune disease (AD) among patients (pts) receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ database.
Authors: Li Chen, Mark S. Walker, Jizu Zhi, George Anthony Komatsoulis, Monika Jun, Edward Stepanski, Ryan Fukushima, Denise Lau, Jeremy Roberts, Brigham Hyde, Robert S. Miller, Sean Khozin, Wendy S. Rubinstein
Journal: Journal of Clinical Oncology (2019)

6583 Background: Although pts with AD are routinely excluded from ICI clinical trials, evidence suggests they may be receiving ICI therapy once approved. We sought to understand the prevalence of AD among all pts receiving ICIs in real world clinical care, as well as in advanced non-small cell lung cancer (aNSCLC) alone, and to describe the characteristics of ICI pts with and without evidence of AD. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database. Adult pts who received ≥ 1 dose of an ICI and had ≥ 2 clinical visits were eligible for inclusion. A sub-analysis examining only aNSCLC pts was also carried out. To reduce the likelihood of capturing pts who may have been on a clinical trial, pts were excluded if they received the ICI prior to its first FDA approval date. AD status was determined by the presence of select ICD-9/ICD-10 codes or a medication used to treat autoimmune disease (including steroids) prior to ICI treatment start date. Symphony claims data were linked to CLQ via tokenization to build out cohorts. Characteristics of pts with and without autoimmune disease were compared using Chi-square or Fisher’s exact tests. Results: Prevalence of AD was 23% (538/2425 pts) in the aNSCLC population and 27% (3407/12712 pts) in the all ICI patient population. Median age did not differ between AD pts and those with no evidence of AD (All ICI: 67.6 v 67.3 years; aNSCLC: 68.5 v 67.9). AD pts were more likely to be female (All ICI: 46% v 40%, p &lt; 0.001; aNSCLC: 55% v 44%, p &lt; 0.001). Among all ICI pts, AD pts were less likely to be Stage IV (62% v 65%) or to have melanoma (4.6% versus 8.7%) compared to pts with no evidence of AD. The most common ADs among all ICI and aNSCLC patients were glucocorticoid deficiency (6.3% and 3.9%), rheumatoid arthritis (4.2% and 5.8%), and sacroiliitis (2.7% and 3.9%), respectively. Conclusions: This analysis of real-world data finds that a large proportion of pts receiving ICI may have pre-existing AD. Further examination is warranted to examine how AD status may impact outcomes.
A phase II randomized control trial of erlotinib in combination with celecoxib in patients with operable oral squamous cell carcinoma (OSCC): Erlo-Xib Study.
Authors: Sudhir Vasudevan Nair, Amit Joshi, Vijay Maruti Patil, Vanita Noronha, Nilesh Sable, Abhishek Mahajan, Bhasker Dharavath, Nilesh Gardi, Munita Bal, Deepa Nair, Tejpal Gupta, Sarbani Laskar, Jaiprakash Agarwal, Pankaj Chaturvedi, Amit Dutt, Anil D'Cruz, Sudeep Gupta, Kumar Prabhash
Journal: Journal of Clinical Oncology (2019)

6054 Background: When combined with COX-2 inhibitors, the EGFR tyrosine kinase inhibitor Erlotinib has shown a better antitumor response in preclinical studies. Since high volume hospitals in many countries usually have a longer waiting period for surgery, neoadjuvant targeted therapy may be helpful in reducing disease progression and downstaging oral squamous cell cancers. Methods: Sixty-four treatment-naïve operable oral cancer patients were randomized into a four-arm window of opportunity study consisting of treatment with erlotinib 150mg daily, celecoxib 200mg twice daily, the combination of both or observation alone (NCT02748707). Since the regular wait period for surgery at our hospital was four to five weeks, we planned a 21-day drug treatment versus observation followed by definitive surgery in the fourth week. MRI scans and biopsies were done before and after drug treatment. Post-operative adjuvant treatments were given as per the standard guidelines used for regular patients. Results: There were 10 females and 54 males with a mean and median age of 44 and 45 years respectively. Taking a 20% reduction in the maximum tumor dimension after drug treatment (assessed clinically and radiologically) as partial response, the combination arm had a 60% partial response and a 25% stable disease. Whereas, 60% in the control arm had disease progression. The ratio of the longest tumor dimension at day 21 versus day 0 (Clinical &amp; MRI assessment) also showed a significant difference between the observation vs erlotinib arms (p &lt; 0.001) using Mann-Whitney Test. Grade II/III rashes was the commonly observed toxicity predominantly in the combination arm. Though not powered for survival analysis, a significant difference (p = 0.048) was observed for two-year overall survival for celecoxib + control (60%) versus erlotinib + combination groups (86%) using Kaplan Meier estimator. Biomarker analysis (transcriptome sequencing and IHC) is being done on pre and post-treatment tumor specimens and the final results will be presented. Conclusion: Preoperative targeted therapy with erlotinib and celecoxib combination can arrest disease progression and downstage tumors with possible impact on survival. The identified biomarkers can further refine a future cohort for effective neoadjuvant targeted therapy in oral cancers. Clinical trial information: CTRI/2012/07/002828.
Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up.
Authors: Alexander David Guminski, Annette May Ling Lim, Nikhil I. Khushalani, Chrysalyne D. Schmults, Leonel Fernando Hernandez-Aya, Badri Modi, Lara Dunn, Brett Gordon Maxwell Hughes, Anne Lynn S. Chang, Axel Hauschild, Michael Robert Migden, Ralf Gutzmer, Murad Alam, Vladimir Jankovic, Elizabeth Stankevich, Jocelyn Booth, Siyu Li, Israel Lowy, Matthew G. Fury, Danny Rischin
Journal: Journal of Clinical Oncology (2019)

9526 Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.
The regulation effect of EGFR signaling pathway on PD-L1 expression on esophageal squamous cell carcinoma cell lines.
Authors: Ran Lin Wang, Tao Li, Jianming Huang, Jiahua Lv
Journal: Journal of Clinical Oncology (2019)

e15577 Background: To explore the effect of radiation combined with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKI) on the expression of PD-L1 in ESCC cell lines, and to provide theoretical support for radiotherapy combined with EGFR-TKI for esophageal cancer. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) method was used to assess EGFR and PD-L1 mRNA expression on ESCC cell lines when different doses of X-ray irradiation were conducted on ESCC cell lines TE-1 and ECA-109 combining with EGFR-TKI or not. Results: In ESCC cell lines TE-1 and ECA-109, the expression of EGFR and PD-L1 mRNA was increased significantly by the activation of EGFR signaling pathway and decreased after the use of gefitinib (P &gt; 0.01). Both EGFR (P &lt; 0.01) and PD-L1(P &lt; 0.01) mRNA expression of ESCC cell lines TE-1 and ECA-109 were increased by radiotherapy alone. EGFR-TKI could block the increase of both EGFR mRNA (P &lt; 0.01) and PD-L1 mRNA (P &lt; 0.01) which was induced by radiation. Conclusions: EGFR signaling pathway is involved in the regulation of PD-L1 expression in ESCC cell lines. Radiation could up-regulate the expression of EGFR and PD-L1 mRNA in ESCC cells which could be blocked by the use of EGFR-TKI.
Targeting CLL-1 for acute myeloid leukemia therapy
Authors: Hongbing Ma, Iyer Swaminathan Padmanabhan, Simrit Parmar, Yuping Gong
Journal: Journal of Hematology & Oncology (2019)

Despite major scientific discoveries and novel therapies over the past four decades, the treatment outcomes of acute myeloid leukemia (AML), especially in the adult patient population remain dismal. In the past few years, an increasing number of targets such as CD33, CD123, CLL-1, CD47, CD70, and TIM3, have been developed for immunotherapy of AML. Among them, CLL-1 has attracted the researchers' attention due to its high expression in AML while being absent in normal hematopoietic stem cell. Accumulating evidence have demonstrated CLL-1 is an ideal target for AML. In this paper, we will review the expression of CLL-1 on normal cells and AML, the value of CLL-1 in diagnosis and follow-up, and targeting CLL-1 therapy-based antibody and chimeric antigen receptor T cell therapy as well as providing an overview of CLL-1 as a target for AML.
Molecular landscape of colorectal cancers harboring R-spondin fusions.
Authors: Andreas Seeber, Florian Kocher, Joanne Xiu, Gilbert Spizzo, Alberto Puccini, Jeffrey Swensen, Michelle Ellis, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Mohamed E. Salem, Francesca Battaglin, Wafik S. El-Deiry, Ryuma Tokunaga, Madiha Naseem, Philip Agop Philip, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz, Zoran Gatalica
Journal: Journal of Clinical Oncology (2019)

3588 Background: Gene fusions involving R-spondin ( RSPO) family members have been shown to drive Wnt-dependent tumor initiation in colorectal cancer (CRC). Therapies targeting Wnt pathway are being actively investigated for tumors harboring RSPO2/3 fusions. Here we set out to characterize the molecular features of CRC with and without RSPO fusions to gain insight into potential rationale combination therapy strategies. Methods: Tumor DNA sequencing of 592 genes (NextSeq, Illumina), RNA sequencing of 53 gene fusions (ArcherDx FusionPlex) and immunohistochemistry for PD-L1 on tumor cells (SP142) were tested on CRC tumors at Caris Life Sciences, Phoenix, AZ. Molecular profiles of RSPO2/3 positive (pos) were compared with negative (neg) tumors, Fisher-Exact was used for comparative analysis. Results: A total of 1356 CRC samples were analyzed. RSPO3 and RSPO2 fusions were detected in 42 (3.1%) and 4 (0.3%) samples, respectively, including 5 fusion events not previously reported (e.g., IFNGR1-RSPO3). A female predominance was seen in RSPO fusion pos vs. neg tumors (71.7% vs 45.0%, p &lt; 0.001); no association with age or tumor sidedness was seen. RSPO2/3 fusions were mutually exclusive of MSI-high (0 vs. 5%), ERBB2 alterations (0 vs. 1% mutation, 4% amplification) and other Wnt pathway activation drivers including APC (2 vs. 75%), CTNNB1 (0 vs. 1.4%) and RNF43 (0 vs. 5.3%) mutations. Significantly higher BRAF (26 vs. 7%), RAF1 (4.5 vs. 0.4%) and SMAD4 (30 vs. 11%) mutation rates were seen in RSPO pos vs. neg tumors (p &lt; 0.05). A universal co-activation of MAPK pathway ( KRAS, NRAS or BRAF) was seen with RSPO fusions. There was a significantly elevated PD-L1 expression in RSPO3 pos tumors (14%) compared to RSPO neg (6%, p = 0.04) and APC-mutated (5%, p = 0.02) tumors that are MSS. Conclusions: This is the largest series of CRC cases harboring an RSPO rearrangement reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO fusions in CRC and suggested potential combinatorial approach to target Wnt/MAPK pathway. The immune modulatory effects specific to RSPO2/3 fusion revealed by PD-L1 expression suggest co-targeting Wnt pathway with PD1/PDL1 inhibitors in RSPO pos tumors.
Population-based outcomes comparing radical cystectomy with trimodal therapy for patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Tamer Dafashy, Daniel Phillips, Yong Shan, Hogan K Hudgins, Usama Jazzar, Mohamed Danny Ray-Zack, Sapna Kaul, Preston Kerr, Ashish M. Kamat, Douglas S. Tyler, Stephen J. Freedland, Todd A. Swanson, Hemalkumar B Mehta, Stephen Bentley Williams
Journal: Journal of Clinical Oncology (2019)

e16029 Background: Radical cystectomy is the guideline-recommended treatment for muscle-invasive bladder cancer; however, use of trimodal therapy, which utilizes a combination of surgery, radiation, and chemotherapy, has increased in recent years with conflicting survival outcomes. Methods: Utilizing data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, a total of 2,963 patients aged 66 years or older diagnosed with clinical stage T2-4a bladder cancer from January 1, 2002 to December 31, 2011 were analyzed. Conventional regression, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to compare radical cystectomy and trimodal therapy for overall and cancer-specific survival, and cost. Results: Patients who underwent TMT had significantly decreased overall (conventional regression: Hazard Ratio (HR) 1.54, 95% Confidence Interval (CI), 1.39-1.71; PSM: HR 1.49, 95% CI 1.31-1.69; IPTW: HR 1.54, 95% CI 1.39-1.71) and cancer-specific (conventional regression: HR 1.51, 95% CI 1.40-1.63; PSM: HR 1.55, 95% CI 1.32-1.83; IPTW: HR 1.51, 95% CI 1.40-1.63) survival. Median total costs were significantly higher with trimodal therapy than with radical cystectomy at 6-month ($171,401 vs. $99,890, p &lt; 0.001). Conclusions: Using population-based data and different analytic methods to control for imbalance between study groups, we found that trimodal therapy was associated with decreased overall and cancer-specific survival at increased costs compared to radical cystectomy.
Clinical application of circulating cell-free DNA for monitoring the biological course of thymic epithelial tumors.
Authors: Margaret Ottaviano, Mario Giuliano, Marianna Tortora, Daniela Terracciano, Pietro Formisano, Antonietta Liotti, Nicoletta De Rosa, Gerardo Botti, Severo Campione, Stefania Staibano, Evelina La Civita, Carlo Curcio, Gianluca Guggino, Brigitta Mucci, Fernanda Picozzi, Francesco Habetswallner, Vincenzo Di Lauro, Sabino De Placido, Giovannella Palmieri
Journal: Journal of Clinical Oncology (2019)

8566 Background: Thymic epithelial tumors (TETs) are rare thoracic malignancies. Widely recognized as different histopathological entities, thymoma (T) and thymic carcinoma (TC), show a different biological behavior with a higher tendency to hematogenous dissemination for TC and thoracic recurrence for T, sharing, however, a poor prognosis when characterized by high tumor burden. Up to date, there are no specific biomarkers for monitoring the biological course of these rare tumors. Analysis of circulating cell-free DNA (cfDNA) has potential applications throughout the natural course of cancer development, diagnosis and treatment, never the less several studies have suggested that cfDNA levels closely parallel overall tumor burden. For the first time the detection and the correlation of cfDNA levels with tumor burden and histological subtype of TET, has been carried on in this monocentric study. Methods: Starting from July 2018, serum samples from 19 patients with TET, 4 with completely resected TET (rTET) and 15 with advanced (aTET), were prospectively obtained before the initiation of therapy. Serum samples from 15 healthy donors were used as control. Five ml of blood was collected and processed within one hour or less, followed by centrifugation at 3000g for 10 minutes and storage at -80°C. The serum samples were processed for QiAamp MinElute cell-free DNA mini kit extraction (Qiagen). cfDNA quantification was assessed using Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Clinical, and histo-pathological features of TET were assessed. Results: A median cfDNA amount in healthy donors of 0.108 ng/µl (0.083-0.868) was registered. A median cfDNA of 0.512 ng/µl (0.178-1.42) resulted for the rTET, including the value of 0.178 for the resected TC. A median cfDNA of 2.53 ng/µl (1.20-6.11) resulted for the aTET, with respectively a median of 2.845 ng/µl (1.3-5.24) and of 1.5 ng/µl (1.2-6.11) for TC and T. The highest registered level for both group of thymoma (6.11 ng/µl) and thymic carcinoma (5.24 ng/µl) correlates with the highest tumor burden. Conclusions: To the best of our knowledge, this is the first study that explore detection and quantification of cfDNA in TET. Higher baseline levels than the control group and the rTET group have been registered for both advanced T and TC. Highest levels of cfDNA may be associated with high tumor burden despite the histological subtype. We envision that further valuable information will be obtained with mutational analysis.
Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI).
Authors: Gilbert Spizzo, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Sukeshi Patel Arora, Moh'd M. Khushman, Mohamed E. Salem, Francesca Battaglin, Wafik S. El-Deiry, Ryuma Tokunaga, Philip Agop Philip, Michael J. Hall, John Marshall, Florian Kocher, Wolfgang Michael Korn, Heinz-Josef Lenz, Andreas Seeber
Journal: Journal of Clinical Oncology (2019)

4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p &lt; 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p&lt;0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p &lt; 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.