tbuckley/cabot-search huggingface dataset:
The prevalence of cognitive impairment in older Indian persons with cancer and brain metastases.
Authors: Aditya Dhanawat, Vanita Noronha, Anant Ramaswamy, Shreya Gattani, Renita Castelino, Ratan Dhekle, Sarika Mahajan, Vijay Maruti Patil, Nandini Menon, Anuradha Daptardar, Vikram Gota, Kumar Prabhash
Journal: Journal of Clinical Oncology (2021)

e24019 Background: Normal aging is associated with a decline in neurocognitive abilities. Regardless of age, 42% to 91% of persons with cancer and brain metastases are reported to have neurocognitive impairment. There are no data regarding the prevalence of cognitive impairment in older persons with cancer and brain metastasis. Methods: This retrospective analysis was performed on a prospectively collected dataset of patients who attended the geriatric oncology clinic at the Tata Memorial Hospital, a tertiary-care comprehensive cancer center in India from June 2018 to February 2021. Patient aged 60 years and over with malignancy were included. Cognition was assessed with the mini-mental status examination (MMSE); the Hindi MMSE was used for illiterate patients. A score of &lt; 23 on the MMSE was considered abnormal. Correlation between the presence of cognitive impairment and brain metastases was tested using the chi-square test. Results: A total of 401 patients were included, of which 318 (79.3%) were males. The median age was 70 years (range: 60-100 years). All patients had solid tumors; 162 (40.4%) had lung, 139 (34.7%) had gastrointestinal and 48 (12%) had head and neck malignancies. Twenty-five (6.2%) patients had brain metastases, of which 5 (20%) had solitary, 19 (76%) had multiple lesions, and 1 (4%) had leptomeningeal metastases. Cognitive impairment was noted in 4 (16%) of the 25 patients with brain metastases and 61 (16.2%) out of 376 patients without brain metastases. There was no significant correlation between the presence of brain metastases and cognitive impairment, p = 0.57. Conclusions: Older persons with cancer and brain metastases do not have a higher incidence of cognitive impairment than those without brain metastases. The next step is to understand whether older persons with brain metastases are more at risk for cognitive decline as a result of therapeutic interventions such as cranial radiotherapy and chemotherapy.
Concordance of blood and tissue TMB from NGS testing in real-world settings and their ability to predict response to immunotherapy.
Authors: Emma Sturgill, Amanda Misch, Carissa Jones, Daniel Luckett, Xiaotong Fu, Suzanne Fields Jones, Howard A. Burris III, David R. Spigel, Andrew Jacob McKenzie
Journal: Journal of Clinical Oncology (2021)

2540 Background: Tumor mutational burden (TMB) detected by tissue-based Next Generation Sequencing (NGS) is a biomarker for immunotherapy (IO) response. Plasma-based NGS vendors have developed methods for quantifying TMB from circulating tumor DNA; however, the concordance of blood-TMB (bTMB) and tissue-TMB (tTMB) in real-world settings has not been examined. In this study, we analyzed paired bTMB-tTMB values from cancer patients in community oncology clinics who underwent both plasma- and tissue-based NGS testing to determine whether bTMB predicts response to IO equal to tTMB. Methods: We analyzed 112 patient-matched bTMB-tTMB pairs from 102 unique patients in community oncology settings who received both plasma- and tissue-based NGS profiling at any point in care. NGS results were reported by Foundation Medicine (n = 28 plasma, n = 66 tissue), Guardant Health (n = 78 plasma), and Caris Life Sciences (n = 42 tissue). NGS results were linked with electronic medical records in Genospace, Sarah Cannon’s precision medicine platform. Pearson’s correlation (r) and Lin’s concordance (ρ) coefficients were used for statistical analysis. Results: bTMB exceeded the patient-matched tTMB by an average 2.4-fold; therefore, while the two values showed a positive linear correlation (r 2 = 0.62, p = 0.01e-27) their concordance was only moderate (ρ = 0.58, n = 112). Gastrointestinal cancers exhibited the lowest correlation (r 2 = 0.01, p = 0.5) and concordance (ρ = 0.03, n = 35). The discordance between bTMB and tTMB was not an outcome of the specimens being collected on different dates, as the bTMB/tTMB ratio did not correlate with the time between plasma and tissue specimen collection (r 2 = 0.003, p = 0.84, n = 112). While a majority of bTMB-tTMB pairs had agreement in high vs. low status (High ≥ 10 mut/Mb; Low &lt; 10 mut/Mb), a considerable portion were bTMB-High/tTMB-Low (see table). Strikingly, the bTMB-High/tTMB-Low patients who received IO had an average time to treatment failure (TTF) that surpassed that of the bTMB-High/tTMB-High cohort (see table). Considering bTMB alone, patients with a high status outperformed those with a low status on IO (bTMB-High: TTF = 200 days, n = 21; bTMB-Low: TTF = 125 days, n = 12). Conclusions: In real-world settings where tissue- and plasma-based NGS panels are ordered as standard of care, bTMB values are consistently higher than tTMB values. This discrepancy leads to plasma-based tests resulting a TMB-High designation more frequently than tissue-based NGS tests. Patients who are TMB-High by plasma perform relatively well on IO, indicating that bTMB may be a particularly effective biomarker of IO sensitivity.[Table: see text]
A phase I/IIa study to evaluate the safety and efficacy of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin.
Authors: Ahmed Idbaih, Francois Ducray, Roger Stupp, Nathalie Baize, Olivier L. Chinot, John Frederick De Groot, Jacques Guyotat, Adam M. Sonabend, Philippe Menei, Henry Dufour, Jeffrey Weinberg, Carole Desseaux, Michael Canney, Charlotte Schmitt, Alexandre Carpentier
Journal: Journal of Clinical Oncology (2021)

2049 Background: Low intensity pulsed ultrasound (LIPU) in conjunction with intravenous microbubbles can transiently and reversibly disrupt the blood-brain barrier (BBB), allowing for an increase in the tissue concentration of chemotherapy agents in the brain. Mass spectrometry data from preclinical models (mouse, swine) showed a &gt; 5x enhancement in carboplatin brain concentrations, which correlated well with the spatial distribution of a Gadolinium (Gd) contrast agent used for magnetic resonance imaging (MRI). Methods: The primary objective of this phase I/IIa study (NCT03744026) was to demonstrate the safety of BBB disruption using LIPU in patients with recurrent glioblastoma. This study was a 3+3 design using escalating numbers (3, 6, 9) of activated 1 MHz ultrasound emitters. Nine patients were treated in the escalation phase and another 12 patients were treated with 9 emitters in the expansion phase. Eligibility included recurrent GBM (any recurrence) with a maximum tumor size of &lt; 70 mm. The SonoCloud-9 device (CarThera, Paris, France) was implanted during tumor debulking/resection surgery and replaced the bone flap, with the device targeting the tumor and surrounding peritumoral brain. The device was activated every four weeks for a duration of 270 seconds, concomitantly with IV DEFINITY microbubbles (10 ml/kg), to disrupt the BBB prior to administration of carboplatin (AUC 4-6). MRI was performed to verify safety and evaluate efficacy of BBB disruption with Gd enhancement. Results: No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with two transient, manageable grade 3 wound infections and one grade 1 acquired meningocele event considered as probably related to the overall procedure. The most frequent neurologic adverse events were grade 1 blurred vision (5%) and dizziness (5%). Conclusions: Significant Gd enhancement was observed after more than 90% of sonication sessions, suggesting effective BBB disruption and carboplatin enhancement. Clinical trial information: NCT03744026.
Effect of continuing osimertinib with chemotherapy in the post-progression setting on progression-free survival among patients with metastatic epidermal growth factor receptor (EGFR) positive non-small cell lung cancer.
Authors: Tejas Patil, David Chun Cheong Tsui, Andrew Nicklawsky, Erin Lynn Schenk, William T. Purcell, Paul A. Bunn, Jose Maria Pacheco, D. Ross Camidge
Journal: Journal of Clinical Oncology (2021)

9124 Background: Continuing a 1st generation EGFR TKI with chemotherapy upon TKI progression was not shown to be beneficial in the IMPRESS trial. However, the validity of this approach with osimertinib remains under explored. We attempted to characterize the efficacy of continuing osimertinib with chemotherapy in the post-progression setting. Methods: A single-center retrospective review of patients with metastatic EGFR mutant NSCLC who had progressed on osimertinib was performed. Clinical characteristics and treatment outcomes were noted. Progression free survival (PFS), duration of treatment (DOT), overall survival (OS) and rates of intracranial progression were captured. ANOVA or a Fisher exact test were used to identify associations between cohort characteristics and treatment outcomes. Differences in PFS, DOT and OS were assessed using a log-rank test. A Cox proportional hazard model was used to adjust for potential confounders. Results: 73 patients with EGFR mutant NSCLC with post-osimertinib treatment outcomes were identified. Cohort characteristics are summarized in Table. Median duration of follow up was 41 months. Upon progression, osimertinib was discontinued in 34 patients (Cohort A) and continued with next line of therapy in 39 patients (Cohort B). Survival analyses were adjusted for prior lines of therapy, use of platinum doublet chemotherapy, and use of immune checkpoint inhibitors in the post-progression setting. After adjusting for covariates, continuing osimertinib post-progression was associated with an improved PFS (7 vs 4 months; HR 0.58; 95% CI 0.34 – 1.00; p = 0.003) and DOT (7 vs 4 months; HR 0.52; 95% CI 0.31 – 0.87; p = 0.006). There was no difference in OS between Group A and B (52 vs 41 months; HR 0.73; 95% CI 0.43 – 1.24; p = 0.234). Rates of intracranial progression were similar between Group A and B (28% vs 23%; p = 0.649). Conclusions: After adjusting for covariates, continuing osimertinib with chemotherapy in the post-progression setting was associated with a significant difference in PFS and DOT, but with no differences in OS. Continuing osimertinib does not appear to influence the rate of subsequent intracranial progression. Prospective studies are needed to identify the optimal practice pattern.[Table: see text]
Outcomes with COVID-19 in patients with hematopoietic stem cell transplant and cellular therapy: A systemic review and meta-analysis.
Authors: Sibgha Gull Chaudhary, Muhammad Usman Zafar, Maha Awaiz Hassan, Moazzam Shahzad, Ali Hussain, Fatima Ali, Yumna Riaz, Fatima Khalid, Sharad Khurana, Ramesh Balusu, Nausheen Ahmed, Anurag K Singh, Faiz Anwer, Sunil H. Abhyankar, Joseph McGuirk, Muhammad Umair Mushtaq
Journal: Journal of Clinical Oncology (2021)

e18611 Background: Coronavirus Disease 2019 (COVID-19) was declared a pandemic on March 11, 2020. COVID-19 has caused over 100 million infections and over 2 million deaths globally. Patients who have received a hematogenic stem cell transplant or cellular therapy (HCT) have a high risk of mortality and morbidity with COVID-19 due to severe immune dysregulation. We conducted a systematic review and meta-analysis aimed to evaluate the outcomes of COVID-19 in HCT patients. Methods: A literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) guidelines was performed on 3 databases (PubMed, Cochrane, and Clinical trials.gov) from the date of inception to Jan 2021. MeSH terms included ‘hematological malignancies’, ‘hematopoietic stem cell transplantation’, ‘SARS-CoV-2’, and ‘COVID 19’. We screened 99 articles and 6 studies (4 retrospective studies, 2 prospective) were included after excluding review, duplicate, and non-relevant articles. Quality evaluation was done using the NIH quality assessment tool. The Inter-study heterogeneity among the studies was assessed using the Q statistic proposed by Cochrane and the I 2 index introduced by Higgins and Thompson. Pooled analysis was done using the ‘metaXL’, and the random effects model was used to estimate the pooled prevalence with 95% CI. Results: Of 1619 patients in 6studies, 646 HCT patients were analyzed (Table ). The median age of patients was 63 years and 59% were males. Median days since HCT for autologous (auto) HCT and allogeneic (allo) HCT patients were 690 and 450 days respectively. The average follow-up duration after COVID-19 was 24 days. COVID-19 mortality in HCT patients was 20% (95%CI 0.17 to 0.23, I 2 =0). Roedl et al (n=6) reported a mortality of 83% and was excluded from the pooled analysis. The mortality rate was 19% (95% CI 0.15 to 0.24, I 2 =0%) in auto HCT patients and 21% (95% CI 0.17 to 0.25, I 2 =0%) in allo HCT patients. Conclusions: The HCT patients are at significant risk of increased mortality and morbidity due to COVID-19. There is a need to prioritize HCT patients for COVID-19 vaccination, close surveillance, and aggressive management.[Table: see text]
Preliminary safety and efficacy of PBCAR0191, an allogeneic, off-the-shelf CD19-targeting CAR-T product, in relapsed/refractory (r/r) CD19+ NHL.
Authors: Bijal D. Shah, Caron A. Jacobson, Scott Solomon, Nitin Jain, Monika Vainorius, Christopher Ryan Heery, Fiona C. He, Ran Reshef, Alex Francisco Herrera, Luke Paul Akard, Craig Steven Sauter
Journal: Journal of Clinical Oncology (2021)

7516 Background: Although autologous CD19-directed CAR T products have demonstrated unprecedented efficacy in chemorefractory patients, manufacturing failure or delays remain important barriers to care, limiting utility for those with more rapidly growing disease and/or impaired T cell fitness. Here, we present an update to preliminary safety, efficacy, and correlative data for the subjects dosed with at least 3 x 10 6 CAR-T+ cells/kg, or equivalent, of PBCAR0191, an off-the-shelf allogeneic CAR T product. Methods: Subjects were required to have evaluable CD19+ r/r NHL, adequate organ function, 2+ prior treatment regimens, and no active GvHD, CNS disease, infections or active medical issues. Prior stem cell transplant and/or CAR-T therapy were allowed. All subjects were lymphodepleted prior to administration of PBCAR0191with either standard (sLD; 30/500mg/m2/day x 3 days fludarbine/cyclophosphamide) or enhanced (eLD; 30 x 4 days and 1000mg/m2/day x 3 days flu/cy) lymphodepletion. Correlative laboratory samples were taken at baseline and while patients remained on study for CAR T cell expansion, persistence, response to treatment and safety assessments. Results: As of February 2021, 13 subjects were evaluable meeting these criteria. Demographics, baseline disease characteristics, and prior therapy data are presented in the table. Median time from eligibility confirmation to PBCAR0191 infusion was 6.5 days (1 day to start LD). To date, most adverse events (AE) reported were mild, with no cases of GvHD or Grade ≥3 CRS/ ICANS. PBCAR0191 related serious AEs were reported for 31% (4/13) of the subjects and 1 subject (9%) died of Febrile neutropenia on day 42 after treatment. Infections and cytokine release related AEs occurred at higher frequency in the eLD group. Efficacy of PBCAR0191 in 13 NHL subjects with available 28 day follow up is presented in the table. Peak PBCAR0191 expansion was increased 56-fold and was associated with CR rate of 71% in eLD group versus 33% in sLD group. Duration of response assessment is ongoing. Conclusions: PBCAR0191 has demonstrated dose and LD-dependent cell expansion kinetics with encouraging anti-tumor activity. Host-versus-graft rejection may have a role in depth and durability of response. CR rates with PBCAR0191 are preliminarily comparable to those observed with autologous CAR T in this population. Updated response durability assessment will be presented at the time of the meeting. Clinical trial information: NCT03666000. [Table: see text]
Analysis of the MOSAIC correlative cancer database integrating molecular cancer classification and tumor profiling to identify targeted treatment options for metastatic cancer.
Authors: Li Ma, Kai Treuner, Jenna Wong, David R. Spigel, Catherine A. Schnabel, F Anthony Greco
Journal: Journal of Clinical Oncology (2021)

3121 Background: Unless tumor type and genetic alterations can be identified, metastatic cancer patients with unknown or uncertain diagnoses may be limited to empiric chemotherapy. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for patients with cancer of unknown primary (CUP) or ambiguous diagnoses. Multimodal molecular biomarker testing by next-generation sequencing (NGS), tumor mutational burden (TMB), fluorescent in situ hybridization (FISH), microsatellite instability (MSI), and immunohistochemistry (IHC) can identify genetic targets. A database integrating tumor typing with biomarker analysis in metastatic cases was utilized to identify the most prevalent genetic alterations by tumor type. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved database of cases with CancerTYPE ID testing plus multimodal biomarker testing. The current study determined molecular tumor type followed by molecular profiling by NGS for up to 323 genes, (NeoTYPE profiles, Neogenomics). Results: Tumor type was determined in 1992 of 2151 cases (92.7%), comprised of 27 different tumor types. 72% of cases were comprised of the 7 tumor types shown in the table,which also shows the frequency of the 10 most commonly mutated genes by tumor type. Bolded are genes with actionable genetic mutations for which FDA-approved therapies are not currently indicated in the identified tumor type. Conclusions: Precise targeted treatment for many patients with CUP or ambiguous diagnoses requires accurate diagnosis of the cancer origin combined with multimodal molecular testing to identify actionable genetic alterations in the appropriate cellular context. Future studies will evaluate additional biomarker profiles, including TMB, FISH, MSI, and IHC for cases in the MOSAIC database.[Table: see text]
Incidence of <i>ERBB</i> gene fusions (<i>EGFR</i>, <i>ERBB2</i>, <i>ERBB4</i>) across tumor types.
Authors: Laura Schubert, Andrew Elliott, Robert Charles Doebele, Emil Lou, Hossein Borghaei, Michael J. Demeure, Razelle Kurzrock, Anh T. Le, Joshua E. Reuss, Sai-Hong Ignatius Ou, David R. Braxton, Christian A. Thomas, Sourat Darabi, Wolfgang Michael Korn, Wafik S. El-Deiry, Stephen V. Liu
Journal: Journal of Clinical Oncology (2021)

3091 Background: Gene fusions often represent critical therapeutic targets across cancer subtypes. Fusions within the ErbB family of receptor tyrosine kinases, including EGFR, ERBB2 ( HER2) and ERBB4 ( HER4), have been previously described and represent potentially actionable alterations. Here, we report the relative incidence and functional characterization of these rare genomic events. Methods: Tumor samples (n = 64,354; representing &gt; 40 tumors types) submitted to Caris Life Sciences (Phoenix, AZ) were molecularly profiled by next-generation sequencing of DNA (NextSeq, 592-gene panel; or NovaSeq, whole exome) and RNA (whole transcriptome). Gene fusion partners, in/out-of-frame status, retention of ERBB kinase domain, and topology of fusion breakpoints were characterized for each ERBB fusion transcript detected. Fusion prevalence was further examined in public data sets (TCGA, MSK-IMPACT and AACR GENIE). Results: From the Caris database, a total of 64 EGFR fusion isoforms were detected in 59 tumors (incidence 0.09%); 83% were in-frame and 91% retained the EGFR kinase domain. 206 ERBB2 fusion isoforms were detected in 114 tumors (0.18%); 37% were in-frame and 34% retained the ERBB2 kinase domain. 131 ERBB4 fusion isoforms were detected in 108 tumors (0.17%); 62% were in-frame and 51% retained the kinase domain. All fusions were detected at low incidence across all tumor types. EGFR fusions were most common in high grade glioma (1.7%, n = 35), largely driven by recurrent EGFR-SEPT14 fusions (n = 20). ERBB2 fusions were most common in esophageal/gastroesophageal junction carcinoma (1.1%, n = 20), with recurrent fusion to PGAP3 observed in multiple tumor types (n = 37). ERBB4 fusions were most common in ovarian (0.7%, n = 40) and bladder (0.7%, n = 15) cancers, which often resulted from recurrent fusion with IKZF2 (n = 36). EGFR and ERBB2 fusions were generated predominantly (44-48%) from inversion events, while ERBB4 fusions arose more frequently and at similar rates (27-32%) from deletions, duplications, or translocations. Mining of public data sets corroborated the prevalence of ERBB gene fusions: the frequency of EGFR fusions was 0.63%, ERBB2 was 0.14% and ERBB4 was 0.04%. TP53 mutations frequently co-occurred with ERBB2 and ERBB4 fusions ( &gt; 60% average across public data sets), with higher co-mutation rates ( &gt; 70%) observed for samples in the Caris database. Conclusions: ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer. Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.