tbuckley/cabot-search huggingface dataset:
The value of defining molecular resistance in patients with progressive <i>EGFR</i> and <i>ALK</i>-driven lung cancer in a public system.
Authors: Carly C. Barron, Tracy Stockley, Jennifer H. Law, Muqdas Shabir, Roxanne Fernandes, Tong Zhang, Lisa W. Le, Ming Sound Tsao, Suzanne Kamel-Reid, Prodipto Pal, Michael Cabanero, Joerg Schwock, Hyangmi Ko, Geoffrey Liu, Penelope Ann Bradbury, Adrian G. Sacher, Frances A. Shepherd, Natasha B. Leighl, Kirstin Perdrizet
Journal: Journal of Clinical Oncology (2021)

3126 Background: Repeat molecular profiling, except to detect EGFR T790M, is not routinely performed in Canadian patients with lung cancer progressing on EGFR tyrosine kinase inhibitors (TKIs). We performed genomic profiling on post-progression biopsies in patients with stage IV non-small cell lung cancer (NSCLC) and known EGFR/ ALK aberrations treated with TKIs to identify resistance mechanisms, evaluate options for subsequent treatment, and to assess clinical trial eligibility and costs. Methods: From Feb 2018-Aug 2020, post-progression tumour biopsies from consenting patients at a major cancer centre underwent genomic profiling (ThermoFisher OCA v3.0 including hotspots, fusions, and copy number variations in 161 cancer-associated genes). Outcomes of interest were the identification of resistance mutations, actionable targets, clinical trial eligibility (per clinicaltrials.gov), and costs. Results: Thirty-two patients consented to the study. Most, 84% (n = 27), had successful testing completed while 16% (n = 5) had insufficient tissue. Median age of the cohort was 56 yrs, 59% (n = 16) were female, 74% (n = 20) were never-smokers, 81% (n = 22) had ECOG performance status 0-1, and 67% (n = 18) were Asian. The majority, 81% (n = 22) had EGFR mutated NSCLC, and had progressed on EGFR TKIs (15 with previously identified T790M had progressed on osimertinib), and 19% (n = 5) had ALK fusions. Patients had received a median of 2 prior lines of targeted therapy prior to re-biopsy (IQR 1.5,3). One patient had evidence of small cell transformation and associated TP53 and RB1 mutations, 11% (n = 3) had acquired EGFR C797S mutations, and 11% (n = 3) had acquired ALK resistance point mutations (G1202R n = 2, I1171N n = 1). Genomic profiling identified additional actionable targets in 19% of patients (n = 5: MET exon 14 skip mutation n = 1, MET amplification n = 2, BRAF V600E n = 2). Overall, 33% (n = 9) patients had management-changing resistance mechanisms identified (small cell transformation n = 1, actionable targets n = 5, ALK inhibitor resistance = 3). New clinical trial options based on genomic profiling results were identified for 67% (n = 18) of patients. Incremental costs for repeat genomic profiling were approximately $880 CAD per case. Conclusions: Molecular profiling upon development of resistance to targeted therapy in our cohort revealed actionable resistance mechanisms for over a third of patients and clinical trial options for 67%. These incremental benefits for patients highlight the importance of routine molecular profiling in the setting of acquired TKI resistance in lung cancer.
Phase Ib, international, dose-escalation study to evaluate the safety, pharmacokinetics (PK) and efficacy of ST-617 for the attenuation of oral mucositis (OM) in patients receiving chemoradiation (CRT) for head and neck (H&amp;N) cancer.
Authors: Daniel Osei-Fofie, Julie Wetter, Greg A. Landers, Peter Alfred Kraus, Shawgi Sukumaran, Hui Mun, Brian N. Stein, Victoria Jane Bray, Bomi Framroze, Jeffrey Gelfand, Paul Y. Song, Andries Lategan, Mikaela Dimitriu, Stephen T. Sonis
Journal: Journal of Clinical Oncology (2021)

6075 Background: OM is a common, painful, and costly toxicity associated with cytotoxic regimens used to treat H&amp;N cancers, which may result in radiotherapy treatment interruptions to negatively impact tumor control. There are currently no approved interventions to successfully prevent or delay OM onset among patients being treated with radiation therapy, with or without concomitant chemotherapy (CRT). Oxidative stress is a critical event in OM’s pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM onset, duration and severity. The objective of this trial was to assess the safety, tolerability, PK, PD and efficacy of ST-617 in patients at high risk of severe OM (SOM). Methods: A dose escalation trial in which ST-617 administered as an oral suspension, 1-2 hours before the administration of daily RT fractions was performed at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells. Results: 17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. The 100 mg/day dose has been well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM has been observed. Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. Conclusions: ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day. Clinical trial information: 20180138.
IMMU-04. FIRST-IN-CHILDREN PHASE 1B STUDY USING THE IDO PATHWAY INHIBITOR INDOXIMOD IN COMBINATION WITH RADIATION AND CHEMOTHERAPY FOR CHILDREN WITH NEWLY DIAGNOSED DIPG (NCT02502708, NLG2105)
Authors: Theodore S. Johnson, Rafal Pacholczyk, Dolly Aguilera, Ahmad Al-Basheer, Manish Bajaj, Zuzana Berrong, Robert C Castellino, Bree R Eaton, Natia Esiashvili, Nicholas Foreman, Ian M Heger, Eugene P Kennedy, William Martin, Eric Ring, Ramses F Sadek, Amy Smith, Chris Smith, Rachel Vaizer, Tobey J MacDonald, David H Munn
Journal: Neuro-Oncology (2021)

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no available cure. Indoximod blocks the IDO (indoleamine 2,3-dioxygenase) pathway, thereby reversing IDO-mediated immune suppression in the tumor microenvironment. Methods Patients aged 3 to 21 years with treatment-naive DIPG were eligible for this phase 1b dose-confirmation study of indoximod. The treatment regimen comprised continuous oral indoximod (38.4 mg/kg/day divided twice daily) with conformal photon radiation (54 Gy in 30 fractions), followed by cycles of indoximod with temozolomide (200 mg/m2/day, days 1–5 in 28-day cycles). Results Thirteen patients (median age 9 years, range 5 to 20 years) with DIPG were treated. Median OS was 14.5 months (follow-up ranged 4.8 to 29.3 months), 12-month OS was 61.5% (8/13), and 18-month OS was 30.8% (4/13), with 1 patient remaining in follow-up at the data cutoff. This compared favorably to expected median OS of approximately 10.8 months, 12-month OS of 45.3%, and 18-month OS of 16.2% taken from published historical data from the Pediatric Brain Tumor Consortium. Two patients showed near-complete responses lasting until relapsing after 7.6 months and 13.3 months of study therapy, respectively. Many patients had increased circulating non-classical monocytes (nc-Monos, CD16+, CD14neg, CD33+, HLA-DR+) within the first 3 treatment cycles, and elevation of this early pharmacodynamic marker was predictive of subsequent OS. Patients with nc-Monos &amp;gt;10% (n=7) had median OS of 19 months, whereas patients with nc-Monos below 10% (n=5) had median OS of 7 months (p=0.0047). No patients stopped therapy for toxicity. The most common indoximod-attributed adverse events were thrombocytopenia, neutropenia, nausea, vomiting, dizziness, and fatigue. Conclusions Adding indoximod immunotherapy to conventional radiation and chemotherapy for front-line treatment of pediatric patients with DIPG was well-tolerated. Improved outcomes were observed in patients having evidence of pharmacodynamic response. A follow-on phase 2 study is in progress (NCT04049669).
DNA methylome reveals cellular origin of cell-free DNA in spent medium of human preimplantation embryos
Authors: Yidong Chen, Yuan Gao, Jialin Jia, Liang Chang, Ping Liu, Jie Qiao, Fuchou Tang, Lu Wen, Jin Huang
Journal: Journal of Clinical Investigation (2021)

The discovery of embryonic cell–free DNA (cfDNA) in spent embryo culture media (SECM) has brought hope for noninvasive preimplantation genetic testing. However, the cellular origins of SECM cfDNA are not sufficiently understood, and methods for determining maternal DNA contamination are limited. Here, we performed whole-genome DNA methylation sequencing for SECM cfDNA. Our results demonstrated that SECM cfDNA was derived from blastocysts, cumulus cells, and polar bodies. We identified the cumulus-specific differentially methylated regions (DMRs) and oocyte/polar body–specific DMRs, and established an algorithm for deducing the cumulus, polar body, and net maternal DNA contamination ratios in SECM. We showed that DNA methylation sequencing accurately detected chromosome aneuploidy in SECM and distinguished SECM samples with low and high false negative rates and gender discordance rates, after integrating the origin analysis. Our work provides insights into the characterization of embryonic DNA in SECM and provides a perspective for noninvasive preimplantation genetic testing in reproductive medicine.
A morphological subset of circulating tumor cells in advanced prostate cancer reveals a potential biomarker for clinical outcomes.
Authors: Jasmine Jiemei Wang, Karen Angelica Cavassani, Pai-Chi Teng, Jie-Fu Chen, Yu Jen Jan, Gina Chia-Yi Chu, Yi-Te Lee, Allen Gao, Dolores Di Vizio, Leland WK Chung, Sungyong You, Yazhen Zhu, Michael Freeman, Andre Rogatko, Ju Dong Yang, Hsian-Rong Tseng, Edwin Melencio Posadas
Journal: Journal of Clinical Oncology (2021)

e17008 Background: A morphological subset of prostate cancer (PCa) circulating tumor cells (CTCs) with particularly small nuclei (&lt; 8.5 μm), named very-small-nuclear CTCs (vsnCTCs), were found to be correlated with the presence of visceral metastases. It is reported that the depletion of nuclear envelope protein emerin promotes PCa metastasis and is associated with nuclear shape instability. In this study, we hypothesize vsnCTCs as prognostic biomarkers in metastatic castration resistant PCa (mCRPC), and aim to investigate the correlation between emerin level and vsnCTCs. Methods: PCa CTCs were enriched using the NanoVelcro CTC Assay from 76 patients with mCRPC. The Kaplan-Meier analysis and log-rank test were used to estimate and compare the overall survival (OS) and progression free survival (PFS) of androgen receptor signaling inhibitor (ARSI), taxanes and other therapy in patients stratified by the presence of vsnCTCs. The correlation between the presence of vsnCTCs and OS and PFS were evaluated using the Cox proportional hazard regression. The expression level of emerin in patients with and without vsnCTC were compared using Mann-Whitney U test, and the correlation between emerin level and CTC nuclear size was tested by Pearson correlation coefficient. Results: Patients with vsnCTC (i.e, vsnCTC+) had significantly shortened OS and PFS compared with those without vsnCTC (i.e, vsnCTC-). The median OS was 34 (vsnCTC+, n= 49) vs. 149 (vsnCTC-, n= 27) weeks (hazard ratio [HR] = 2.6, 95% confidence interval [CI]: 1.5-4.5, P&lt; 0.001). The median PFS was 12 (vsnCTC+, n= 32) vs. 26 (vsnCTC-, n= 18) weeks (HR = 2.2, 95% CI: 1.3 -4.0, P= 0.004). The emerin expression level was significantly higher in vsnCTC+ compared to vsnCTC- ( P= 0.009). In addition, we observed a significantly positive correlation between emerin expression and CTC nuclear size (r = 0.52, P&lt; 0.001). Conclusions: This study casts light on the importance of the vsnCTCs in patients with mCRPC, as vsnCTC+ patients represented a group at risk for faster clinical progression who are at the highest risk for mortality. vsnCTC represents a new hallmark of an aggressive subtype of mCRPC and is related to emerin dysregulation, which promotes lethal progression and metastasis of PCa.
Global tissue stiffness on breast MR elastography: High-risk dense breast patients have higher stiffness compared to average-risk dense breast patients.
Authors: Bhavika K. Patel, Kay Pepin, Kathy R Brandt, Gina L. Mazza, Barbara A. Pockaj, Jun Chen, Yuxiang Zhou, Donald W. Northfelt, Karen Anderson, Brenda Ernst, Patricia Cronin, Sarwat Ahmad, Juliana Kling, Denise Millstine, Heidi Apsey, Celine M Vachon, Ilyse Nelson, Richard Ehman
Journal: Journal of Clinical Oncology (2021)

10541 Background: Biomechanical tissue properties may vary in the breasts of patients at elevated risk for breast cancer. We aim to quantify in vivo biomechanical tissue properties in various breast densities and in both normal risk and high risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association of biomechanical properties of the breast with cancer risk. Methods: In this IRB–approved prospective single-institution study, we recruited two groups of women differing by breast cancer risk to undergo a 3.0 T dynamic contrast enhanced MRI/MRE of the breast. Low-average risk women were defined as having no personal or significant family history of breast cancer, no prior high risk breast biopsies and a negative mammography within 12 months. High-risk breast cancer patients were recruited from those patients who underwent standard of care breast MR. Within each breast density group (non-dense versus dense), two-sample t-tests were used to compare breast stiffness, elasticity, and viscosity across risk groups (low-average vs high). Results: There were 50 low-average risk and 86 high-risk patients recruited to the study. The risk groups were similar on age (mean age = 55.6 and 53.6 years), density (68% vs. 64% dense breasts) and menopausal status (66.0% vs. 69.8%). Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high risk patients ( N = 55) compared to low-average risk patients ( N = 34; all p &lt; 0.001). In the multivariate logistic regression model, breast stiffness remained a significant predictor of risk status (OR=4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, MRI BPE, age, and menopausal status. Similar results were seen for breast elasticity (OR=4.88, 95% CI [2.08, 11.43]) and viscosity (OR=11.49, 95% CI [1.15, 114.89]). Conclusions: Structurally-based, quantitative biomarker of tissue stiffness obtained from global 3D breast MRE is associated with differences in breast cancer risk in dense breasts. As such, tissue stiffness could provide a novel prognostic marker to help identify the subset of high-risk women with dense breasts who would benefit from increased surveillance.[Table: see text]
Corrigendum to “Molecular imaging-guided photothermal/photodynamic therapy against tumor by iRGD-modified indocyanine green nanoparticles” [Journal of Controlled Release 224 (2016) 217–228]
Authors: Fei Yan, Hao Wu, Hongmei Liu, Zhiting Deng, Hong Liu, Wanlu Duan, Xin Liu, Hairong Zheng
Journal: Journal of Controlled Release (2021)
Association of Cumulative Social Risk and Social Support With Receipt of Chemotherapy Among Patients With Advanced Colorectal Cancer
Authors: Rachel E. Davis, Amber W. Trickey, Paul Abrahamse, Ikuko Kato, Kevin Ward, Arden M. Morris
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Approximately 38% of patients with advanced colorectal cancer do not receive chemotherapy. <h3>Objective</h3> To determine whether cumulative social risk (ie, multiple co-occurring sociodemographic risk factors) is associated with lower receipt of chemotherapy among patients with advanced colorectal cancer and whether social support would moderate this association. <h3>Design, Setting, and Participants</h3> This cross-sectional, population-based, mailed survey study was conducted from 2012 to 2014. Participants were recruited between 2011 and 2014 from all adults within 1 year after diagnosis of stage III colorectal cancer in the Detroit, Michigan, and State of Georgia Surveillance, Epidemiology, End-Results cancer registries. Patients were eligible if they were aged 18 years or older, had undergone surgery 4 or more months ago, did not have stage IV cancer, and resided in the registry catchment areas. Data analyses were conducted from March 2017 to April 2021. <h3>Main Outcomes and Measures</h3> The primary outcome was receipt of chemotherapy. Cumulative social risk represented a sum of 8 risk factors with the potential to drain resources from participants' cancer treatment (marital status, employment, annual income, health insurance, comorbidities, health literacy, adult caregiving, and perceived discrimination). Social support was operationalized as emotional support related to colorectal cancer diagnosis. <h3>Results</h3> Surveys were mailed to 1909 eligible patients; 1301 completed the survey (response rate, 68%). A total of 1087 participants with complete data for key variables were included in the sample (503 women [46%]; mean [SD] age, 64 [13] years). Participants with 3 or more risk factors were less likely to receive chemotherapy than participants with 0 risk factors (3 factors, odds ratio [OR], 0.48 [95% CI, 0.26-0.87]; 4 factors, OR, 0.41 [95% CI, 0.21-0.78]; 5 factors, OR, 0.42 [95% CI, 0.20-0.87]; ≥6 factors, OR, 0.22 [95% CI, 0.09-0.55]). Participants with 2 or more support sources had higher odds of undergoing chemotherapy than those without social support (2 sources, OR, 3.05 [95% CI, 1.36-6.85]; 3 sources, OR, 3.24 [95% CI, 1.48-7.08]; 4 sources, OR, 3.69 [95% CI, 1.71-7.97]; 5 sources, OR, 4.40 [95% CI, 1.98-9.75]; ≥6 sources, OR 5.95 [95% CI, 2.58-13.74]). Within each social support level, participants were less likely to receive chemotherapy as cumulative social risk increased. <h3>Conclusions and Relevance</h3> Cumulative social risk was associated with reduced receipt of chemotherapy. These associations were mitigated by social support. Assessing cumulative social risk may identify patients with colorectal cancer who are at higher risk for omitting chemotherapy who can be targeted for support programs to address social disadvantage and increase social support.
RARE-15. THE MOLECULAR PROFILE OF SECONDARY MENINGIOMAS IN SURVIVORS OF CHILDHOOD NON-CENTRAL NERVOUS SYSTEM CANCERS
Authors: Catherine Corriveau-Bourque, Derek Wong, Frank van Landeghem, Matija Snuderl, Maria Spavor, Stephen Yip, David Eisenstat
Journal: Neuro-Oncology (2021)

Abstract Introduction Cranial irradiation remains part of childhood cancer therapy and secondary meningiomas are a late effect. Secondary meningiomas are reported in patients who received low and high dose cranial irradiation and arise ~ 20 years post exposure. The molecular and genetic profile of primary meningiomas has been well studied; however, only a few studies describe these in radiation-induced meningiomas (RIM). Methods We identified patients followed at the Childhood Cancer Survivor Clinic, Stollery Children’s Hospital who had a history of non-central nervous system malignancies and received cranial irradiation who developed meningiomas between clinic inception in 1971 and June 2013. Whole exome sequencing (WES) as well as DNA methylation profiling were performed for patients where tumor and germline DNA were available. Results Of 96 patients who received cranial irradiation, 16 (16.7%) developed symptomatic meningiomas. This patient cohort is unique; all 16 patients received 2000–2400 cGy, suggesting a threshold dose. 9/16 (56%) had WHO Grade 2 meningiomas or greater and 7/16 (44%) were infiltrative. Post-surgical recurrences occurred in 43%. Patients experienced considerable morbidities directly attributable to the meningiomas or their treatment. 14 patients had samples suitable for further analysis. Preliminary results revealed that NF2 mutations were the most common (5). Other meningioma related genes with mutations identified in our patient cohort include TRAF7, AKT3, MSH4 (2), KMT2C (2), TET1 (2), KDM6A, and MLH3. Copy number alternations were noted with increased frequency on chromosomes 1p, 22q, 19q. 850k methylation analysis did not conclusively show any clustering. Ongoing studies include assessment of tumor mutation burden, RNAseq, and the mutational profile. Conclusions This study examined RIM in patients who received similar doses of radiation for their childhood cancer. To date, our findings are consistent with previously described primary and RIM mutations. Enhanced knowledge in secondary meningiomas is crucial for accurate patient counseling, prognostication, and treatment.