tbuckley/cabot-search huggingface dataset:
Perceptions of non-disclosure of results in clinical trial designs for multicancer detection tests.
Authors: Goli Samimi, Sarah M. Temkin, Carol J. Weil, Paul KJ Han, Elyse LeeVan, Wendy S. Rubinstein, Tessa Swigart, Sarah Caban, Katherine Dent, Lori M. Minasian
Journal: Journal of Clinical Oncology (2024)

10546 Background: Multi-cancer detection tests (MCDs) are blood-based tests designed to detect multiple cancers. The National Cancer Institute (NCI) is planning a pilot study to ascertain the feasibility of recruitment and the necessary infrastructure, clinical workflow, and diagnostic pathways for conducting a large clinical trial to assess whether cancer screening using MCDs reduces cancer mortality. In preparation for these activities, the NCI conducted a qualitative focus group study with primary care physicians (PCPs) and laypersons to explore the acceptability of alternative MCD trial designs, including the disclosure vs. non-disclosure of MCD test results to study participants. Methods: Focus groups were conducted with convenience samples of PCPs (6 groups, N=45) and laypersons (4 groups, N=88) by a consumer research firm. Interviews used both open-ended questions and specific prompts to explore participants’ perceptions of alternative clinical trial designs. Interviews were audio-recorded and transcribed, and qualitative thematic analysis of interview transcripts was conducted to identify emergent themes. Results: In general, PCPs and laypersons reported a willingness to refer or participate in an MCD trial regardless of design, with the understanding that clear and transparent information would be provided in the consent process. However, both groups expressed concern with a trial design in which patients in the control arm would not receive their MCD test results—a design that would allow a marked reduction in sample size and time necessary to assess a mortality endpoint. PCPs noted that although this design might be ethically acceptable due to current clinical equipoise about MCD testing, they expressed concern about mistrust among patients and medical-legal liability. Laypersons had difficulty understanding the rationale for non-disclosure of MCD test results during a trial, and concerns about the ethics of non-disclosure. Some participants felt more comfortable if return of value with other information was included as part of routine study procedures. Participants were more comfortable with an alternative design involving delayed testing of stored blood samples from the control group after trial completion. PCPs also expressed concern about increased workloads if their patients enrolled. Conclusions: PCPs and laypersons had generally positive reactions to a trial to investigate diagnostic performance, pathways, and outcomes of MCDs. Concerns about study designs involving non-disclosure of results might be managed through return of value strategies, careful education, and clear communication of the benefits and risks of MCDs.
Targeted treatment in inflammatory myofibroblastic tumors in children.
Authors: Rejin Kebudi, Ulku Miray Miray Yildirim, Osman Bulent Zulfikar
Journal: Journal of Clinical Oncology (2024)

10046 Background: Inflammatory myofibroblastic tumors (IMTs) and epithelioid inflammatory myofibroblastic sarcoma (EIMS)-a variant of IMT, are rare mesenchymal neoplasms in children. Surgical resection has been the mainstay of treatment, however it may cause morbidities due to the size, location, invasiveness of the tumor. With the identification of targetable molecular alterations, targeted treatment has begun to be used in inoperable/relapsed/refractory cases. Methods: Files of children with IMT diagnosed and treated between 1990-2023 were retrospectively evaluated for demographic, clinical, molecular characteristics, treatment and outcome. Results: The mean age of 8 patients (5 male, 3 female) at diagnosis was 9 years (8 months-17 years). Six had IMT and two EMS. Tumor localization was intestine, retroperitoneum, lower extremity in two patients each; liver and back in one each. None had metastatic at diagnosis. Three of the six patients (one EMS) who underwent only surgical resection had negative surgical margins (one after re-resection) and are under follow-up with no evidence of disease (NED). Molecular analysis was performed in six patients. ALK was positive in the tumor tissue of five patients. One patient with an inoperable local recurrence received chemotherapy, had a life-threatening infection and resistant hypercalcemia. The molecular analysis by next-generation sequencing revealed a YWHAE-ROS fusion and she was treated by ceritinib, after which a significant (&gt;90%) tumor shrinkage occurred and hypercalcemia resolved. She is currently in remission and continuing treatment. The patient with a positive surgical margin experienced local and metastatic (lung, liver) recurrences during follow-up and was treated with chemotherapy containing vincristine, actinomycin-D, and cyclophosphamide, the patient died due to progressive disease. In a patient with an unresectable tumor and ALK positivity, crizotinib treatment was initiated. After a treatment duration of seven months with crizotinib, the tumor completely regressed and treatment was stopped. On follow-up, local recurrence was detected after two months of cessation of crizotinib, crizotinib was restarted, considering the infiltrative appearance of the tumor and possible morbidities if operated. Two months after readministering crizotinib, complete response was achieved once again. The patient is continuing treatment with crizotinib. Thus, 7/8 patients are alive with NED for a median of 99 (9-174) months. Conclusions: Inflammatory myofibroblastic tumor and epithelioid inflammatory myofibroblastic sarcoma are rare in children. Surgery is the mainstay of treatment. The effectiveness of chemotherapy is yet unclear despite its use in inoperable cases. Molecular analysis of tumor tissue is highly recommended as targets such as ALK rearrangements or ROS fusions may enable the use of targeted treatments with fewer side effects.
Germline sequence variation in Rwandan patients with breast and prostate cancer.
Authors: Achille Van Christ Manirakiza, Temidayo Fadelu, Shakuntala Baichoo, Annette Uwineza, Francois Uwinkindi, Damas Dukundane, Edouard Ngendahayo, Fidel Rubagumya, Emmanuel Muhawenimana, Nicaise Nsabimana, Jeffrey Besada, Sarah M. Nielsen, Brianna A. Bucknor, Diane R. Koeller, Caroline Andrews, Timothy Rebbeck
Journal: Journal of Clinical Oncology (2024)

10591 Background: Clinically relevant cancer genetic data from Sub-Saharan Africa (SSA) are limited, despite the observation that cancers in this region are frequently diagnosed at an early age and follow an aggressive course. A prospective pilot study was undertaken to explore the feasibility of implementing germline genetic testing (GGT) and counseling in breast and prostate cancer patients in Rwanda. Methods: Consecutive female breast (FBC), male breast (MBC) and prostate (PC) cancer patients from hospitals in Rwanda underwent GGT. Demographic, disease, and treatment information were collected. A commercial 84-gene multi-cancer panel (Invitae Corp.) was used to identify pathogenic variants (PV) and variants of uncertain significance (VUS). Descriptive statistics were utilized. Results: 342 total patients underwent GGT: PV were observed in 32/175 (18.3%) FBC, 7/161 (4.3%) PC, and 1/6 (16.7%) MBC patients. PV were most frequently identified in BRCA2: FBC (n=14), MBC (n=1), PC (n=2). BRCA1 was almost common in FBC (n=11). The majority of PV in FBC cases were in established breast cancer susceptibility genes (94%), while 43% of PV in PC involved PC susceptibility genes. Notably, of 40 total PV identified, 35 (88%) were in DNA damage repair (DDR) genes. 224 patients (65%) had &gt; 1 VUS in the absence of a PV finding, including 109 (68%) in PC and 115 (64%) in FBC/MBC combined. Recurrent PV were observed in BRCA1, BRCA2, or ATM in apparently unrelated FBC cases. Conclusions: The high proportion of PV, observed in these Rwandan breast and prostate cancer cases, particularly in DDR genes, suggest that GGT should be more routinely implemented into cancer care and prevention strategies in this population. More widespread GGT may also help to resolve the high VUS rates. The recurrent variants identified warrant further investigation into founder effects. [Table: see text]
Tracking uncertainty in germline genetic testing for hereditary cancer syndromes: Sources, attributes, and resolution of variants of uncertain significance in over 1 million individuals.
Authors: Brian Reys, Britt Johnson, Elaine Chen, Yuya Kobayashi, Flavia Facio, Yi-Lee E Ting, Sarah M. Nielsen Young, Ed Esplin, Kathryn E. Hatchell, Sienna E Aguillar, Karen E Ouyang, W. Michael Korn, Swaroop E Aradhya, Sara Pirzadeh-Miller
Journal: Journal of Clinical Oncology (2024)

10513 Background: Genetic testing for hereditary cancer syndromes has diagnostic, prognostic and therapeutic implications; however, variant(s) of uncertain significance (VUS) are not clinically actionable. As such, VUS are a challenge to the entire medical community. Additionally, individuals from underrepresented race, ethnicity, and ancestry (REA) groups are disproportionately impacted by VUS. This study reports on the prevalence of VUS in patients referred for genetic testing for hereditary cancer syndromes and the results of reclassification. Methods: Patients were referred for diagnostic multigene panel testing for hereditary cancer from September 2014 to September 2022. Variants were classified as benign (B), likely benign (LB), VUS, likely pathogenic (LP), or pathogenic (P) using Sherloc, a validated system based on guidelines from ACMG/AMP. Both the number of unique VUS (uVUS) and the number of times they were observed in individuals (oVUS) were counted. All-time uVUS were separated as being reclassified and non-reclassified, and the relative contribution of evidence types used for reclassification was analyzed. Results: During this 8-year period, 1,122,444 unrelated individuals were tested for hereditary cancer with a mean number of 53 genes tested per individual. Results showed a mean of 0.45 oVUS per individual; 30.6% of individuals without a P/LP variant had at least 1 oVUS. The rate of oVUS normalized to the number of genes tested was highest in French Canadian and lowest in Ashkenazi Jewish individuals, as the mean number of genes sequenced to observe one VUS was 39.8 and 59.4, respectively. White individuals had a lower oVUS rate of 31.4% than Sephardic Jewish (53.8%), Asian (48.3%), Black (40.5%), Hispanic (37.6%), and additional underrepresented REA groups. In total, 7,542 (7.3%) of 103,767 uVUS were reclassified, affecting 88,877 individuals (7.9%); 5,864 (77.8%) of the reclassified uVUS were downgraded to B/LB, and 1,678 (22.2%) were upgraded to LP/P. Evidence from clinical observation contributed the most for upgrading uVUS (16.0-fold compared to non-reclassified uVUS), while evidence from experimental studies contributed the most to downgrading uVUS (23.9-fold). Conclusions: Experimental studies and clinical evidence were the most impactful types of evidence for reclassifications. This highlights the partnership among researchers, clinicians, and laboratories to resolve VUS. Further representation of diverse REA groups in genomic databases is needed to address the disparities in VUS rates, and additional research is needed into methods that could expedite the resolution of VUS so that patients can make more informed decisions.
CINSARC score use in pediatric non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in the Children’s Oncology Group (COG) studies ARST0332 and ARST1321.
Authors: Rachel M Hurley, Lei Guo, Donald A. Barkauskas, Lei Yu, Yen-Lin Chen, Lauren Gutstein, Douglas S. Hawkins, Thomas Scharschmidt, Stephen X Skapek, Sheri L. Spunt, Dian Wang, Aaron R. Weiss, Lin Xu, Theodore Willis Laetsch
Journal: Journal of Clinical Oncology (2024)

10013 Background: Despite genomic and histologic heterogeneity, limited risk stratification is used in the treatment of NRSTS (grade, size, presence of metastases, and extent of surgical resection). Genomic signatures including CINSARC score and Genomic Index (GI), both measures of genomic instability, have been shown to be prognostic in retrospective studies, but are not routinely used clinically. Here we evaluated the association of these scores with EFS and OS on two consecutive, prospective COG NRSTS studies, ARST0332 and ARST1321. Methods: All patients enrolled to ARST0332 or ARST1321 with sufficient banked tumor in the COG biospecimen repository were included in this analysis. Whole exome and transcriptome sequencing was performed on DNA and RNA from banked FFPE and flash frozen specimens. Raw WES reads were mapped to hg38 using BWA. The base qualities of the aligned reads were recalibrated and realigned by GATK. RNAseq data was aligned to hg38 by STAR. Differential expression analysis was performed by DESeq2. Stratified log rank and proportional hazards models were used to evaluate the association of CINSARC score and GI above or below the median with EFS and OS. Results: Tumors from 197 patients yielded sufficient DNA and 166 sufficient RNA, of which 177 and 142, respectively, passed sequencing quality metrics and were included. Demographics of these patients were generally representative of overall trial enrollment with most patients between ages 10-17 years (53%) with localized disease (77-80%). The most common histologic diagnoses were synovial sarcoma (35-37%) and MPNST (9-12%). Median follow-up was 6 years. CINSARC high vs low was associated with worse EFS (5-year 52.1% vs 74.6%, p &lt; 0.01) and OS (5-year 66.2% vs 83.6%, p &lt; 0.01). Accounting for sex and presence of metastatic disease, the hazard ratio for CINSARC high was 2.4 for EFS and 2.7 for OS (p &lt; 0.01). CINSARC maintained the association with EFS among patients with non-metastatic disease (p = 0.017), and with OS among patients with metastatic disease (p = 0.031). GI analysis is ongoing and will be reported. Conclusions: In this analysis from the largest prospective North American pediatric NRSTS studies to date, CINSARC score was prognostic for EFS and OS. Further analysis including additional clinical prognostic factors (tumor size, grade, and extent of resection) is ongoing and will be reported. Use of CINSARC score for risk stratification should be considered on future NRSTS clinical trials. Clinical trial information: NCT00346164 , NCT02180867 .
Trends in human papilloma virus vaccination uptake by sex and race/ethnicity among US adolescents and young adults, 2011-2020.
Authors: Jacqueline Nguyen, Arthur S Hong, Allan Zhang, Danh Nguyen
Journal: Journal of Clinical Oncology (2024)

10519 Background: High-risk strains of human papillomavirus (HPV) are associated with a variety of oral and anogenital cancers, many of which are preventable through HPV vaccination. In the US, completion of an HPV vaccination series is recommended for all individuals from age 9 through 26; however, national trends in HPV vaccination uptake across sex and racial/ethnic groups over the past decade are not well described. Methods: We analyzed data from the National Health and Nutrition Examination Survey across 4 survey cycles spanning January 2011 to March 2020. We used univariate logistic regression to evaluate temporal trends in HPV vaccination uptake across sex and racial/ethnic strata, with the midpoint of each survey cycle modeled as a continuous independent variable. Vaccination uptake was defined as self/parent-reported receipt of ≥ 1 dose of an HPV vaccine series (estimates for 2 and 3 doses were unreliable due to recall bias and missing data). All estimates incorporated appropriate survey weights to be representative of the US population. Results: We identified 10,927 participants representing 70,066,252 individuals: mean age 17.4 years, 48.8% male, 54.9% White. Between 2011-March 2020, overall HPV vaccination uptake steadily increased from 23.3% to 43.0% ( P trend &lt; 0.001; Table). HPV vaccination rates improved from 37.7% to 49.4% among females ( P trend &lt; 0.001) and from 7.8% to 36.4% among males ( P trend &lt; 0.001). HPV vaccination uptake increased similarly across all racial/ethnic strata by approximately 20%, with White individuals achieving the greatest vaccination uptake (45.5%) by March 2020. Conclusions: Among US adolescents and young adults, HPV vaccination uptake rose by ~20% overall and across all racial/ethnic groups. HPV vaccination uptake accelerated the most among males but still lags behind females, perhaps because routine vaccination wasn’t recommended for males until 2011, 5 years after it had been recommended for females. [Table: see text]
Institutional review of pediatric oncology patients participating in early phase clinical trials.
Authors: Avina Rami, Kira Bona, Suzanne Shusterman, Karen D. Wright, Andrew E. Place, Puja J Umaretiya, Ketki Bhushan, Steven G. DuBois, Kevin Campbell
Journal: Journal of Clinical Oncology (2024)

10042 Background: Phase 1 or phase 1/2 trials are a first step in pediatric cancer drug development with a primary objective of evaluating safety and dosing of new therapies or new combinations. They most commonly enroll patients with relapsed/refractory or very rare cancers and currently there is a paucity of information regarding outcomes for pediatric patients enrolled on phase 1/2 trials. Thus, we sought to describe clinical outcomes of pediatric patients enrolled in phase 1 clinical trials over a 9-year period at a single institution. Methods: We queried our clinical trials management system to generate a list of all pediatric patients who were enrolled and treated on phase 1 or phase 1/2 trials from 2011-2019. We reviewed the electronic medical record to collect baseline demographic and clinical data. We also collected key efficacy and safety endpoints post-enrollment including: time to death (if applicable); objective response to trial therapy; duration on therapy; need for dose modification; and occurrence of DLT. Overall survival was calculated using Kaplan-Meier methods. Results: A total of 224 unique patients accounted for 258 enrollments and 253 episodes of treatment on trial. The median age at trial enrollment was 11 years (range 0-27 years) and 56.2% were male. The majority of patients were white (85.7%) and non-Hispanic (88.2%). English was the primary language for 86.3% of patients and 65.8% of patients had private insurance. Solid tumors were the most common malignancy at 41.0%, followed by brain tumors (34.1%), and hematologic malignancies (24.9%). The majority of patients (60%) had metastatic disease at time of first enrollment. Among episodes of treatment, 51.4% received targeted monotherapy. Median overall survival from first enrollment for 210 patients treated with available vital status was 12.8 months. Among episodes of treatment, 25.2% of patients had an objective response to trial therapy. Stratified by disease type, objective response was documented for 52.9% of patients with hematologic malignancies, 20.5% of patients with CNS tumors, and 15.8% of patients with solid tumors. Patients on trials with cytotoxic-only treatment had the highest objective response (47.5%), while patients treated with cytotoxic plus targeted therapies combinations had the lowest rate (18.9%). The median duration of therapy was 1.5 months. Twenty-seven patients (11.0%) required dose modification and 22 patients (9.0%) had DLT. Conclusions: We present clinical outcomes for a recent cohort of pediatric patients treated on early phase clinical trials. We identified differential response rates to phase 1 therapy by disease and trial-type in a single-center cohort treated over the past decade. These data are immediately informative to discussions between providers and patients/parents regarding expected phase 1 trial outcomes.
Preclinical efficacy of BRG1/BRM ATPase inhibitor in B lymphoblastic leukemia.
Authors: Isela Garcia, Farzane Sivandzade, Matthew Wither, Rachel Rau
Journal: Journal of Clinical Oncology (2024)

10030 Background: Acute lymphoblastic leukemia (ALL) is the most common blood cancer in children and young adults. While ALL has a high cure rate, approximately 20% of patients who initially respond to treatment relapse and prognosis post relapse remains poor. New therapeutic treatments are needed to reduce relapse rates in B-ALL pediatric patients and to minimize the toxic side effects seen with current therapies. We and others have previously shown that BRG1/BRM ATPase inhibitors have efficacy in targeting acute myeloid leukemia (AML) and one, FHD-286, is currently being evaluated for its use in AML in an ongoing clinical trial (NCT04891757). BRG1 and BRM are the ATP-dependent catalytic subunits of the SWI/SNF chromatin remodeling complex which has a critical role in controlling gene expression, cell growth and survival of AML cells. Our prior work revealed that BRG1/BRM ATPase inhibition leads to selective transient reduction of normal B cells. Further, data from Depmap also nominates SMARCA4, the gene encoding BRG1, as a dependency in B-ALL cell lines, leading us to hypothesize that BRG1/BRM inhibition may be an effective therapy for B-ALL. Methods: We treated B-ALL cell lines with varying genetic lesions ( KMT2A-rearranged: RS4;11, KOPN-8, SEM; ETV6::RUNX1 fusion: REH and DUX4-rearranged: Nalm6) with dose titrations of FHD-286 and measured cell growth over the course of six days. In addition, at 48- and 72-hours post-treatment, we assayed cells for viability, cell cycle kinetics, and apoptosis induction via flow cytometry to provide insight into FHD-286’s mechanism of action in B-ALL. Results: We found that FHD-286 treatment resulted in decreased cell growth in a dose-dependent manner across all B-ALL cell lines. While all cell lines were displayed reduced proliferation at nanomolar doses, sensitivity varied. Nalm6, REH and SEM cells were the most sensitive with low nanomolar IC50s (2-7nM). In contrast, two of the KMT2Ar B-ALL lines, RS4;11 and KOPN-8, required higher doses to achieve growth inhibition (40-70nM). To better understand the mechanism by which FHD-286 is affecting cell growth, we evaluate whether FHD-286 is targeting cell growth through the apoptotic pathway or through cell cycle arrest. Our preliminary data indicates cell growth inhibition is only slightly attributable to cell cycle arrest and apoptosis induction, leading us to explore terminal differentiation as a mechanism of slowed proliferation. Conclusions: Our results show FHD-286 can strongly inhibit B-ALL cell growth in vitro, indicating FHD-286 as a potential therapeutic agent to treat B-ALL. In vivo validation is ongoing. Further directions include defining the effect of FHD-286 on chromatin remodeling, gene expression, and exploring efficacy in combination therapy, which has been shown to increase FHD-286 efficacy against AML. Our data may ultimately justify inclusion of B-ALL patients in clinical studies of BRG1/BRM inhibitors.