tbuckley/cabot-search huggingface dataset:
Towards the clinical validity of tumor organoid drug screens: Establishing a framework for organoid disease models.
Authors: Jessica Slostad, Ashiq Masood, April T. Swoboda, Mia Alyce Levy
Journal: Journal of Clinical Oncology (2021)

e15037 Background: Despite advances in biomarker-directed cancer therapies to predict tumor response to treatment, precision oncology remains an imprecise science. Tumor organoid drug screens present an opportunity to test multiple potentially effective therapies simultaneously before exposing a patient to treatment toxicities. Preliminary studies have established the analytic validity; however, the clinical validity of the tumor organoid response to a drug to predict the tumor response in patients is unclear. Methods: In order to establish the clinical validity of an organoid drug screen, a clinical disease model should have the following features to enable comparison of the tumor’s clinical response to treatment and the organoid’s response to the same treatment. First, a fresh tissue biopsy (non-bone) needs to be obtained for organoid development prior to the start of systemic treatment. Priority should be given to tumors known to successfully grow organoids. Disease models where the standard of care systemic treatment is a single cytotoxic or targeted agent would best assess correlation between the drug screen and patient response, such as metastatic breast, cervical, or prostate cancer. This would often lead to enrolling patients on later line systemic therapies. Studies should avoid drugs whose mechanism of action leverages the patient metabolism or tumor microenvironment (e.g. immunotherapy, aromatase inhibitors, VEGF inhibitors). Patient should have measurable disease that can be measured clinically, radiographically, or pathologically and using standardized response evaluation criteria (e.g. RECIST). Next generation sequencing would assess genomic concordance between the tumor in the patient and organoid. These studies would determine the feasibility and timeliness of prospectively developing tumor organoids that is sufficient to perform a drug screen. Results: We propose two research models to evaluate the clinical validity of tumor organoid drug screens: a metastatic solid tumor and neoadjuvant solid tumor disease model. Metastatic disease models provide an opportunity to assess response across multiple cancer types at the time of progression and initiation of next line of therapy. The efficacy of chemotherapy can be determined using objective data from radiologic response (RECIST). In neoadjuvant models, pathologic (pCR) and radiologic response can provide objective data for organoid response. These study design features will lay the framework for determining the clinical utility of organoid drug screens. Conclusions: We call for clinical studies assessing the clinical validity of tumor organoid drug screens and determining their concordance with patient response to systemic therapy. Advancements in clinically validated tumor organoids have the potential to fundamentally shift clinical paradigms and improve patient outcomes in cancer treatment.
The prognosis of gastric adenocarcinoma depends on the crosstalk between immune profiles and tumor genomic alterations.
Authors: Deqiang Wang, Xiaofeng Chen, Yaping Xu, Yuange He, Lifeng Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2021)

4035 Background: Gastric adenocarcinoma (GAC) is with a complex microenvironment of tumor cells. A better understanding of the immune landscape of GACs may lead to the improved treatment strategies with ICIs. Methods: To determine whether the molecular characteristics can serve in prognostic stratification of GACs, tumor tissue and blood samples were collected from 231 GAC patients. The median follow-up time was 34 months. The TCR profile was determined by TCR-β CDR3 sequencing while mutation and gene expression profiles were determined by whole exon and whole transcriptome sequencing, respectively. Tumour-infiltrating immune cells were characterized using immunofluorescence (IF) staining. Results: The results showed the OS of patients with high levels of TCR clonality (TCR clonal expansion) was significantly improved compared with patients with low levels (HR = 1.80 and 2.22, p = 0.022 and 0.008, respectively) in the whole group and in the subgroup of patients with stages IB to III disease. Furthermore, low local clonality was an independent risk factor for OS (adjusted-HR = 1.68 and 1.95, p = 0.049 and 0.029, respectively). Thus, TCR clonal expansion in tumour tissue had a strong prognostic value for GAC patients, independent of clinicopathological factors. Based on whole exon and whole transcriptome sequencing, RNF43/FBXW7/ARID2 mutations and local TCR clonality jointly impacted prognosis (p &lt; 0.001), and functional changes in corresponding Wnt pathway/Notch pathway/SWI/SNF complex characterized a GAC subset with enhanced tumour immunogenicity and TCR clonal expansion. TCR CDR3 sequence similarity comparisons yielded clusters of TCR clones of likely similar functions. The most expansive TCR clusters negatively correlated with the percentage of subclonal mutations (Pearson r = -0.8183, p &lt; 0.001), indicating that tumors with less genomic heterogeneity might induce a greater immune response. By IF staining and mutual correlation analysis, only M1 macrophages showed a significant positive correlation with local TCR clonality for epithelia, stroma, and total cell counts. Tumors were categorized according to the density of M1 macrophages, M1 macrophage infiltrated subtype was associated with favorable OS (p = 0.040 and 0.043) and its combination with the local TCR clonality improved prognosis stratification (p &lt; 0.001). Finally, the scoring by local TCR clonality, RNF43/FBXW7/ARID2 mutations and M1 infiltration determined the best prognosis (p &lt; 0.001). Conclusions: TCR profiles were associated with genomic alterations and may serve as a prognostic biomarker for GACs. A multi-omic model including TCR profiles might produce an improved stratification for treatments and outcomes.
The landscape of intergenic-breakpoint fusion in lung cancer.
Authors: Hua Liang, Yaqing Wu, Ningning Luo, Qin Zhang, Yingxue Qi, Qianqian Duan, Chuang Qi
Journal: Journal of Clinical Oncology (2021)

e15002 Background: Kinase fusions have been proved as driver factors and drug targets for lung cancer. DNA-based next-generation sequencing (NGS) has been widely used for gene fusion detection in patients with lung cancer and intergenic-breakpoint fusions can be detected, in which breakpoints localize to intergenic regions. Theoretically, intergenic-breakpoint fusions are unlikely to be functional, but recent studies have found that intergenic-breakpoint fusions are potentially activated. However, the proportion of intergene-breakpoint fusion occurrence in lung cancer is still unclear. Hereby, next generation sequencing was performed to describe lung intergenic-breakpoint fusions for further research. Methods: Tumor tissue, pleural effusion, or blood samples of 6798 patients with lung cancer from Simceredx were collected for targeted NGS panel sequencing from June 2020 to January 2021. Gene rearrangements of ALK, ROS1, RET, NTRK(1-3) were assessed. Results: We found gene fusions in 4.43% (301/6798) patients with lung cancer totally, of which 59.1% (178/301) ALK fusions, 18.9% (57/301) RET fusions, 15.9% (48/301) ROS1 fusions and 6.64% (20/301) NTRK(1-3) fusions. The intergenic-breakpoint fusions accounted for all fusions of ALK, RET and ROS1 genes were 24.2% (43/178), 22.8% (13 /57) and 18.8% (9/48), respectively. In patients with NTRK intergenic fusions (50.0%, 10/20), NTRK1, NTRK2 and NTRK3 was involved in 2, 1, 7, respectively. Co-occurrence of different fusions was rare. Conclusions: Our data firstly revealed the specific intergenic-breakpoint fusions ( ALK, RET, ROS1, NTRK1-3) in lung cancer. The functional consequences identifying by RNA or protein assay and clinical validation need to be carried out in the future.
Retrospective cohort of total neoadjuvant therapy (TNT) in high-risk locally advanced rectal cancer (HR-LARC): Additional sintilimab (PD-1) in tri-modality approach.
Authors: Yingjie Li, Lin Wang, Xiaoyan Zhang, Yunfeng Yao, Xinzhi Liu, Qiushi Dong, Aiwen Wu
Journal: Journal of Clinical Oncology (2021)

e15604 Background: TNT is an emerging practice adapted to ensure all patients (pts) receive of systemic therapy, particularly for pts with high risk recurrence. Our previous phase II trial of TNT in MRI stratified HR-LARC demonstrated high down-staging rate and improved complete response with acceptable toxicity (manuscript under review). The aim of this retrospective cohort study was to evaluate the feasibility of sintilimab in combination with chemotherapy in TNT tri-modality treatment of pts with HR-LARC. Methods: HR-LARC pts who were given 3 cycles of sintilimab (200mg, iv, q3w) in combination with CapeOx followed by sequential long-course radiotherapy (IMRT GTV50.6 Gy/CTV 41.8 Gy/22f), 2 cycles CapeOx and surgery were enrolled from Beijing Cancer Hospital, CHN. The high risk was defined as middle to low RC (≤8cm to ARJ or 12 cm per sigmoidoscopy) with ≥1 factor from MRI features: clinical stage T3c/d-T4a/b, or N2 or MRF (+) or EMVI (+). The clinical outcomes included pathological response, major response rate (cCR+MPR), R0 resection rate, and toxicity. Results: From Feb 2019 to Oct 2020, 19 cases were identified with median distal location 4 cm (3-7), T2/T3/T4 1/15/3, N1/N2a/N2b 7/4/8, MRF+ 8/11, EMVI+ 8/11. Other characteristics were pMMR/MSS 100%, age 67y (47-78), male 57.9%, PS 1 100%, c-stage III 100% (18), median diameter of primary lesion 5.1 cm (2.1-7.5). As of 30th Dec 2020, 84.2% (16/19) received neoadjuvant therapy and completed surgical resection, with R0 resection rate 100%. One pts denied surgery and two chose watch &amp; wait since achieving cCR 10.5% (2/19). Of 16 resection pts, 13 had sphincter-sparing surgery (LAR or TaTME). One had Hartmann procedure, and two had abdominal perineal resection. The sphincter preservation rate was 84.2% (16/19). The pCR was 26.3% (5/19), and MPR was 47.3% (9/13). The major response rate was 57.9% (11/19), 4/2/13 of which completed intact TNT schema, induction and RT, and induction phase only, respectively. Treatment related adverse events (TRAE) occurred in 6 pts (31.6%) in grade (gr) 1-2 (CTCAE 5.0) without any gr 3-5 events occurred. Immune-related AEs were found in 2 pts with hypothyroidism (gr 1,2). Postoperative complications included two gr2 (Clavien-Dindo) events of anastomtic bleeding and infection. Of note, 3 pts with anastomotic stenosis got stoma reversion after dilation. Conclusions: Given the impressive response rate (57.9%), this retrospective analysis suggested a potential enhanced anti-cancer activity and good tolerability in pMMR/MSS HR-LARC from sintilimab in combination with TNT. The encouraging results warrant further evaluation of this approach in prospective trial.
OMIC-10. TRANSCRIPTOMIC ANALYSIS REVEALS SEX DIFFERENCES IN PEDIATRIC BRAIN MECHANISMS
Authors: Wei Yang, Justin D Lathia, James R Connor, Michael E Berens, Jill S Barnholtz-Sloan, Joshua B Rubin
Journal: Neuro-Oncology (2021)

Abstract A significant male overrepresentation exists in cancer incidence and in cancer-related deaths. This is true in all regions of the world and across the lifespan. We published an analysis of adult glioblastoma transcriptomes in which we identified sex-biased molecular features that distinguished the longest surviving male and female patients. Male GBM was characterized by decreased expression of positive regulators of the cell, while female GBM was characterized by decreased expression of intermediates in integrin signaling. To determine whether similar sex differences exist in pediatric brain tumors (pBTs), we accessed 860 pBT transcriptomes, representing all diagnostic categories and ages through the Children’s Brain Tumor Network. Unsupervised Bayesian nearest neighbor analysis of gene expression revealed distinct male and female expression patterns indicating fundamental differences exist in pBTs as a function of sex. Similar to our adult GBM analysis, male pBTs were distinguished from female pBTs by the involvement of cell cycle regulatory pathways. In contrast to adult GBM, female pBTs were characterized by involvement of metabolism and inflammatory/ immunity pathways. Interestingly, these sex differences were also evident in a parallel analysis of 209 of neuroblastoma cases. Focused analysis of the most common malignant pBTs (high-grade glioma, medulloblastoma, and ependymoma) revealed that each disease type exhibited significant sex differences in molecular profile, involving distinct pathways in each tumor type. Together, these data indicate that sex-based differences in molecular mechanisms exist in pBTs, and imply that sex-specific approaches to pBT treatment might yield improved outcomes for all patients.
The impact of HIV infection on overall survival among women with stage IV breast cancer in South Africa.
Authors: Yoanna S Pumpalova, Oluwatosin Ayeni, Wenlong Carl Chen, Daniel O'Neil, Sarah Nietz, Boitumelo Phakathi, Ines Buccimazza, Sharon Cacala, Laura Stopforth, Hayley Farrow, Maureen Joffe, Witness Mapanga, Judith Jacobson, Katherine D. Crew, Herbert Cubasch, Paul Ruff, Alfred I. Neugut
Journal: Journal of Clinical Oncology (2021)

6559 Background: Advanced stage at breast cancer (BC) diagnosis is common in sub-Saharan Africa. In public hospitals across South Africa (SA), 10-15% of women present with metastatic BC, compared to &lt;5% in the U.S., and 20% of new BCs are diagnosed in women living with HIV (WLWH). We evaluated the impact of HIV on overall survival (OS) among women with stage IV BC, which is associated with a poor prognosis in SA. Methods: We conducted a prospective cohort study of women diagnosed with stage IV BC between February 2, 2015 and September 18, 2019 at six public hospitals in SA. Baseline characteristics were compared by HIV status and multivariate Cox regression models were used to estimate the effect of HIV on OS. Results: Among 550 eligible women, 147 (26.7%) were WLWH. Compared to HIV-negative BC patients, WLWH were younger (median age 45 vs. 60 years, p&lt;0.001), predominantly black (95.9% vs. 77.9%, p&lt;0.001), and more likely to have hormone receptor-negative BC (32.7% vs. 22.6%, p=0.016). HER2 tumor status did not differ by HIV status (25.3% HER2 positive overall), and Ki67 index was not increased among WLWH (57.1% Ki67 &gt; 20 overall). Receipt of systemic anti-cancer therapy did not differ by HIV status (80.9% treated overall) and most women were treated with anthracycline (55.5%). HIV status was not associated with OS (Hazard Ratio (HR)=1.13, 95% confidence interval (CI)=0.89-1.44) (Table). In an exploratory subgroup analysis, WLWH and hormone receptor-negative BC had shorter OS compared to HIV-negative women (1-year OS: 27.1% vs. 48.8%, p=0.003; HR=1.94, 95% CI=1.27-2.94), which was not observed for hormone receptor-positive BC. Results were unchanged when analysis was restricted to black women only. Conclusions: HIV status was not associated with worse OS in women with stage IV BC in SA and cannot account for the poor survival in our cohort. Subgroup analysis revealed that WLWH with hormone receptor-negative BC had worse OS; this differential effect of HIV on BC survival by hormone receptor status is a novel finding that warrants further investigation.[Table: see text]
The moderating role of informal caregiver’s involvement on the relationship between patient activation and adherence to treatment: Implications for self-management intervention in cancer care.
Authors: Chiara Acquati, Judith Hibbard, Ellen Miller-Sonet, Anao Zhang, Elena Ionescu
Journal: Journal of Clinical Oncology (2021)

12083 Background: With increasing demands for a more active role on the part of individuals with cancer and their families in cancer care, patient activation (PA) is emerging as a key factor to promote self-management, adherence to treatment, and satisfaction with treatment planning. The present work investigated the relationship between patient activation and treatment decision making. Given the role informal caregivers play on patient-reported outcomes, it was additionally assessed whether caregiver involvement acted as a moderator of this relationship. Methods: Survey data collected from 504 cancer survivors recruited through online consumer panels were utilized. The survey contained questions concerning treatment options, quality of life, adherence to treatment, next to presence and involvement of informal caregivers. Additionally, the Patient Activation Measure (PAM), sociodemographic and clinical questions were included. A path analysis Structural Equation Modeling (SEM) controlling for covariates was used to examine the relationship between Patient Activation Measure (PAM), caregiver involvement, and the identified outcomes. Moderator analysis was conducted using multiple group SEM. Results: Respondents were mostly women (57.1%), non-Hispanic white (72.9%), middle aged or older adults (68% ≥ 55 y.o.) The four largest cancer type groups were prostate (16.3%), early stage breast (9.7%), gynecological (8.9%), and colorectal cancer (8.3%). Most of the respondents were diagnosed more than 4 years earlier (52.0%). Participants were evenly split between those who received care at an academic cancer center (29.4%) and those treated at community hospital (31.7%). Patient activation was significantly associated with treatment planning being reflective of survivors ’goals and values ( p &lt; 0.001); adherence to treatment ( p = 0.011); and satisfaction ( p &lt; 0.001). Caregiver’s involvement significantly moderated the association between activation and adherence to treatment. Conclusions: Patient activation was positively associated with all three selected outcomes. However, for cancer survivors reporting low rates of caregiver involvement, patient activation was not associated with treatment adherence. Research is needed to deliver and test patient activation interventions inclusive of informal caregivers to improve self-management.
OMIC-09. MAPPING THE HISTONE MUTATIONAL LANDSCAPE ACROSS ADULT AND PEDIATRIC CANCER GENOMES UNCOVERS NOVEL SOMATIC MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Erin Bonner, Krutika Gaonkar, Payal Jain, Yuankun Zhu, Sandra Laternser, Augustine Eze, Madhuri Kambhampati, Sridevi Yadavilli, Jason Cain, Sabine Mueller, Sebastian Waszak, Javad Nazarian
Journal: Neuro-Oncology (2021)

Abstract There is a growing role for mutations affecting histone linker and histone core-encoding genes across several adult and pediatric cancers. However, the extent to which somatic histone mutations may bridge across different cancers as common tumorigenic events – particularly in the context of pediatric CNS tumors – remains unclear. To address this knowledge gap, we set out to define a comprehensive pan-cancer landscape of somatic histone mutations. We first queried the ICGC PCAWG and TCGA Pan-Cancer Atlas representing &amp;gt;12,500 adult and pediatric cancer patients. We found lymphomas to be most enriched for histone mutations (50–75%) and, in particular, for mutations in linker histones (HIST1H1B-E), yet also in specific core histone genes (eg, HIST2H2BE). Moreover, we observed a significant enrichment of histone mutations in adult high-grade vs low-grade gliomas (10% vs 6%, P&amp;lt;0.05, n=922 patients). Interrogation of whole genome data from 800 pediatric CNS tumor genomes (PBTA/OpenDIPG), identified novel (non-H3K27/non-H3G34) somatic histone mutations in 5–10% of subjects, including pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs). We found an overlapping set of histone genes to be recurrently mutated in non-CNS cancers and pediatric CNS tumors alike (eg, HIST1H1B/C/E). Notably, the only pediatric primary CNS lymphoma patient also harbored a histone linker alteration (HIST1H1B), similar to adult non-CNS lymphoma patients. We validated novel somatic histone mutations in DMGs by Sanger sequencing. Ongoing studies include in vitro assessment of the impact of these mutations on cell proliferation, chromatin accessibility, histone spacing, and gene expression. In addition, we will further assess associations with clinical outcome, age, and tumor subtypes. Collectively, oncohistone vulnerabilities were identified and defined as histone gene families recurrently mutated across all cancer types. Our analyses of adult and pediatric cancer genomes have uncovered previously unknown mutations affecting histone linker and core proteins, which may play a yet-undefined role in tumor etiology.
Real-world trends in costs of next generation sequencing (NGS) testing in U.S. setting.
Authors: Kaushal Desai, Gillian Hooker, Katri Gilbert, Caiqian Cropper, Rob Metcalf, Sumesh Kachroo
Journal: Journal of Clinical Oncology (2021)

e18824 Background: Recent advances in NGS testing have revolutionized the scope for personalized medicine. The goal of this study was to describe historic trends in the average allowed cost for NGS testing. Methods: This was a retrospective database study evaluating biomarker testing claims in patients undergoing tumor and/or germline sequencing tests between 2016-2019. Molecular testing claims data and marketplace data of tests currently sold in the U.S. were analyzed in the proprietary Concert Genetics Medical Claims Data Warehouse. Results: Analysis of data highlighted high variability in utilization rates as well as allowed amounts for NGS testing. The average allowed amounts for NGS Tests varied from $1269 to $2058 per test during the study period. Higher variability in billing codes and price was also observed when analysis was done for subgroups, which included region, age, gender and cancer type. Similar trends were also observed for panels containing NGS-derived tests such as Tumor Mutation Burden (TMB), an upcoming biomarker. Average allowed amounts for NGS tests that included TMB testing varied from $438 to $3700 per test. To gain a better perspective on evolution of coding, utilization and pricing trends, additional analyses were done in hereditary cancer, given longer availability of these tests in the US Market. For Hereditary cancers, the average allowed amounts varied from $1722 to $2249 per test during the study period. Greater consistency in price was observed in hereditary cancer. Utilization is also more consistent over time and price showed a gradual decreasing trend over time. Coding was also less variable per claim for hereditary cancer and showed a converging trend. Conclusions: Understanding and quantifying the trends in cost of NGS testing for novel biomarkers is critical to predict evolution of testing costs and provide insights essential for minimizing barriers to availability and affordability of these tests. NGS testing can play an important role in improving quality of care and making the clinical decision-making process more efficient. Currently, coverage and reimbursement of NGS tests is one of the key policy challenges that needs to be addressed. Hence, development and adoption of policies is needed to ensure efficient integration of NGS testing in the US health care system.
GMC and trust facing legal action over case of doctor who took his own life
Authors: Clare Dyer
Journal: BMJ (2021)

The widow of a doctor who took his own life within hours of receiving a letter from the General Medical Council is taking legal action against his employers and the GMC, with the support of the BMA.

Sridharan Suresh, 50, a consultant anaesthetist with North Tees and Hartlepool NHS Foundation Trust, drowned himself in the River Tees on 2 May 2018. That day he had received an email from the GMC telling him that his NHS and private employers would be notified of allegations that he had inappropriately touched a 15 year old girl and that he would soon be called before an interim orders tribunal.

He had given the girl midazolam for a dental procedure, a drug associated with hallucinatory side effects. There were no witnesses, Suresh strongly denied the …