tbuckley/cabot-search huggingface dataset:
Interplay of cachexia progression on the efficacy and toxicity of immune checkpoint inhibitors in patients with esophageal squamous cell cancer (ESCC): A longitudinal perspective.
Authors: Haoqian Li, Butuo Li, Huan Zhang, Chunni Wang, Bingjie Fan, Linlin Wang
Journal: Journal of Clinical Oncology (2024)

e14629 Background: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with advanced esophageal squamous cell cancer (ESCC), however, the benefit of ICIs was limited to a few patients. It is vital to comprehend the factors influencing the response in order to identify patients who might benefit from ICIs. Cachexia, an intricate multifaceted syndrome characterized by the loss of skeletal muscle and substantial weight reduction, might impact on the immune response and efficacy of ICIs in cancer patients. The purpose of this study is to explore the impact of longitudinal dynamics of cachexia on the efficacy and adverse effect of ICIs for advanced ESCC patients. Methods: Advanced ESCC patients received at least two cycles of ICIs were enrolled from 2017 to 2021. The baseline and longitudinal changes of cachexia during ICI treatment were collected. Based on the longitudinal weight changes during ICI treatment, patients exhibiting cachexia at baseline were categorized into "reversible cachexia" and "irreversible cachexia" group, and patients without cachexia at baseline were also divided into "latent cachexia" and "cachexia-free" group. Kaplan-Meier curves and Cox regression analysis were performed to explore the impact of cachexia on the efficacy ICIs for ESCC patients. And chi-square test was used to evaluate the correlation between cachexia and immune-related adverse effects (irAEs). Results: A total of 278 individuals who had either received or were presently undergoing ICI treatment were enrolled, with the median progression free survival (PFS) of 5.8 months and overall survival (OS) of 8.3 months. Patients with cachexia before treatment had notably poorer outcomes, with median PFS of 7.9 vs 5.3 months (P=0.001), median time to progression (TTP) of 10.9 vs 6.1 months (P&lt;0.001), and median OS of 14.3 vs 9.2 months (P=0.001). In terms of the longitudinal dynamics of cachexia, significantly inferior outcomes were observed for patients in irreversible cachexia compared to reversible cachexia, with the PFS of 4.4 months and 9 months (P&lt;0.001), the TTP of 4.9 months and 9 months (P=0.006), and the OS of 7.8 months and 15 months, respectively (P=0.003). Although patients in latent cachexia group had inferior survival compared to cachexia-free group, no statistical difference was observed, with the PFS of 10.0 and 7.9 months and OS of 13.9 and 16.2 months. Besides, neither baseline nor longitudinal changes of cachexia was associated with irAEs for ESCC patients. Conclusions: This study indicated the impact of baseline and longitudinal cachexia on the efficacy of ICIs for advanced ESCC patients with ICIs. Dynamic monitoring and management of cachexia was recommended during the ICI treatment of ESCC patients.
The prognostic impact of transforming growth factor beta 2 (TGFB2) mRNA levels, in conjunction with interferon-gamma receptor activation of interferon regulatory factor 5 (IRF5) and expression of CD276/B7-H3 in low-grade gliomas.
Authors: Vuong N. Trieu, Anthony Ernest Maida, Sanjive Qazi
Journal: Journal of Clinical Oncology (2024)

e14564 Background: Low-grade glioma (LGG) tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. Methods: We analyzed mRNA expression datasets from the UCSC Xena web platform to compare normal brain tissue with LGG tumor samples to screen for upregulated genes. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Results: Tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (P&lt;0.0001), 8.9-fold (P&lt;0.0001), and 15.6-fold increases in mRNA expression levels, respectively in LGG tumors. Both TGFB1 (4.1-fold increase, P&lt;0.0001) and TGFB2 (2.2-fold increase, P&lt;0.0001) were upregulated in brain tumors, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive TME. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. A tumor-associated antigen, CD276/B7-H3, mRNA expression showed a significant (P&lt;0.0001) 4.03-fold increase in tumor tissue. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25 percentile cut-off) of TGFB2 high was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2 high HR (95% CI) = 4.07 (2.35-7.06), 6 (3.62-10.11), 4.38 (2.67-7.17), and 4.48 (2.82-7.12) for models with IFNGR2, STAT1, IRF1, or IRF5 respectively). Patients with high levels of TGFB2 were overrepresented by LGG patients with IDH wild-type mutation status. The prognostic impact of TGFB2 high and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05-3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9-10.4)) were independent predictors of survival requiring risk stratification of patients identify LGG patients with IDH wild-type and TGFB2 high in the design of clinical trials. The ratio of TGFB1:TGFB2 expression levels was also a prognostic indicator for OS, whereby patients who exhibited a 2.5-fold greater level of TGFB1 compared to TGFB2 mRNA levels experienced improved survival outcomes. A 1.8-fold higher TGFB2 levels, the mRNA expression corresponded to worse OS. Conclusions: The specific abrogation of TGFB2 and not TGFB1 by OT101, a TGFB2-specific synthetic phosphorothioate antisense oligodeoxynucleotide, is a prerequisite to employing a strategy to target TGFB pathways. IRF5 and CD276/B7-H3 as prognostic markers are potential targets for combination therapies with TGFB2 inhibitors.
The influence of access to care on radiation therapy utilization among older women with breast cancer.
Authors: Jane MeLampy, Mu-Hsun Chen, Madhu Mazumdar, Paula Klein, Andrea Marcadis, Jennifer L Marti
Journal: Journal of Clinical Oncology (2024)

1539 Background: In 2004, the Cancer and Leukemia Group B (CALGB) C9343 trial compared outcomes among women aged ≥ 70 who had stage I, estrogen-receptor positive (ER+) breast cancer (BC) who received a lumpectomy and hormonal therapy, treated with and without radiation therapy (RT). While the trial found that overall survival was not different between groups, RT use did not significantly decline after its publication. We investigated regional variation in RT utilization in the United States (US) and its association to access to healthcare among women aged ≥ 70 diagnosed with localized ER+ BC after partial mastectomy (PM) between 2004–2020. We hypothesize that women with greater access to health care will more often receive RT. Methods: To examine regional variation in the use of RT and its association with access to healthcare, we extracted data from the Surveillance, Epidemiology, and End Results 17 registry. From 2004 – 2020, 105,694 women aged ≥ 70 years who received a PM for localized ER+ BC across 199 US counties with a population &gt; 50,000 were identified. Access to healthcare was measured using six socioeconomic (SES) variables: median household income, % with high school education, % of families above poverty line, % with bachelor’s degree, % speaking English, and % employed, measured from 2015-2019. A multivariable linear regression model tested for association between each variable and RT use. A composite SES score was calculated as the sum of z-scores across all six variables and we identified the top 20 and bottom 20 scoring counties. SES score was used as a surrogate for access to healthcare and was correlated to RT use using a linear regression model. Results: The percentage of women aged ≥ 70 receiving RT after PM for localized ER+ BC varied across counties from 19.0% to 84.6%. In 2004, receipt of RT was similar between the top 20 and bottom 20 counties (67.8% vs 65.2%, respectively). This decreased after publication of CALGB C9343; by 2020 receipt of RT was 58.7% for the top 20 and 49.2% for the bottom 20 SES counties (Table). In linear regression analysis, SES was significantly associated with RT use (p&lt;0.0001). In multivariable linear regression analysis, only % above high school education was significantly associated with RT use (p=0.0205). Conclusions: Among women aged ≥ 70 with localized ER+ BC who underwent PM and who were candidates for omission of RT, those who lived in higher SES counties were more likely to receive RT from 2004 – 2020. Since the CALGB C9343 trial in 2004, RT use has declined; however, the decline was less among those with higher SES and therefore likely less among those with greater access to healthcare. These women may experience over treatment, which may result in personal or system wide harms. [Table: see text]
Patterns of screening and access to care in women diagnosed with breast cancer in a safety-net system.
Authors: Shifa Kanjwal, Malcolm Su, Madeleine Hopson, Sarah Kashanian, Chul Ahn, Samira K. Syed, Glenda Maria Delgado Ramos, Nisha Unni, Navid Sadeghi
Journal: Journal of Clinical Oncology (2024)

1531 Background: Screening mammography reduces breast cancer specific mortality by allowing diagnosis at an earlier stage. Inconsistent guidelines and limitations in access to primary care are among factors that affect screening uptake. In this study, we reviewed patient characteristics, access to care, and uptake of screening mammogram (SMMG) prior to a breast cancer diagnosis at a safety-net system. Methods: Parkland Health (PH) is the safety-net system for Dallas County and is affiliated with the University of Texas Southwestern Simmons Comprehensive Cancer Center. Electronic medical records of patients with a new invasive breast cancer diagnosis between 2018 and 2019 at PH were reviewed and data on demographics and clinical presentation were collected. Patients were categorized based on SMMG uptake prior to their cancer diagnosis: never-screened, ever-screened (SMMG &gt; 2 years prior to diagnosis) and recent-screened (SMMG within 2 years of diagnosis). Results: A total of 468 new breast cancer cases were identified (48.7% Hispanic; 32.9% Black). Of these, 12.2% were younger than 40 and 27.8% were 40-49. Payer mix included 64.7% uninsured and 34.8% Medicare/Medicaid. Half of the patients (50.6%) never had SMMG. Never-screened rate was higher among younger patients (98.2% in &lt; 40; 53.8% in 40-49; and 39.4% in &gt;50; p &lt; 0.0001). Only 25.2% (118/468) of the patients had a SMMG within 2 years prior to their diagnosis. Among patients aged &gt;40, 44.0% (181/411) were never-screened and 28.7% (118/411) were recent-screened. Screen-detection rate among patients &gt;40 was 40.1% (165/411), of whom 22 (13.3% of screen-detects) were diagnosed with cancer on their first ever SMMG. Race/ethnicity, insurance status, and positive family history of cancer were not significantly different between never, ever, and recent-screened patients. Screening uptake correlated with nodal status, tumor size and stage at diagnosis. Patients who had a prior encounter at Parkland were more likely to have a SMMG. Patients established with Parkland primary care at diagnosis were more likely to have early-stage disease. In patients &lt; 40, 24.6% presented with stage IV disease at diagnosis and 57.9% did not have a primary care provider. A positive family history of breast/ovarian cancer or any cancer was noted in 38.6% and 57.9% of patients &lt; 40, respectively. Conclusions: In the cohort presented here, 27.8% of patients were between age 40-49, reflecting the impact of a gap in the guideline, which is now addressed in the most recent iteration of USPSTF guidelines. Connecting ED users to primary care, identifying higher risk individuals through family history, and increasing SMMG rate in the primary care setting are among strategies to reduce the rate of late-stage diagnosis of breast cancer, particularly among vulnerable patient populations.
Primary intracranial germ cell tumors in adolescents and adults: Results of an international, multicenter, retrospective cohort study.
Authors: Stefanie Zschaebitz, Clarissa K Heck, Rega Kasim, Christoph Alexander Seidel, Veronika Blum, Pia Paffenholz, Marcus Hentrich, Richard Cathomas, Marinela Augustin, Marco Timmer, Christoph Schäfers, Sophia Schäfer, Semi Harrabi, Dirk Jaeger, Joerg Beyer, Anja Lorch, Sebastian Ochsenreither
Journal: Journal of Clinical Oncology (2024)

2061 Background: Primary Intracranial Germ Cell Tumors (iGCT) are rare. Previous prospective and retrospective studies mainly included pediatric patients (pts) with a median age of 10-14 years. The aim of this retrospective analysis was to evaluate characteristics, treatment and outcome of adolescents and adults with iGCT. Methods: Data were collected from 10 institutions in Germany and Switzerland. Pts aged &gt;/= 16 years at first diagnosis or at relapse with a primary iGCT were included. Objective responses were evaluated by local investigators. Statistics (Cox proportional hazard model, progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method) were performed with SPSS v29. Results: We identified 75 pts (92.0% male) with a median age of 23 years (range 16-60, 94.7% &gt;/= 18 years). At first diagnosis, histology was pure germinoma in 70.7%, pure teratoma in 10.7%, other non-germinomatous GCT (NGGCT) in 13.3%, unknown in 5.3% of pts. Localized, bifocal, and metastatic disease was found in 72.0, 6.7, and 21.3% of pts. As part of their first line (1L) treatment, 69.3%, 80.0%, and 62.7% received surgery, radiotherapy, and chemotherapy, respectively. High dose chemotherapy/ autologous stem cell transplantation (HDCT/ASCT) was part of 1L treatment in n=3 pts with NGGCT. Trimodal and bimodal treatment was performed in 48.0% and 32.0% of pts. Response to 1L therapy was complete remission (CR) in 61.3%, partial remission tumor marker negative (PRm-) in 16.0%, PRm+ in 4.0%, PR with tumor marker status unknown in 4.0%, progressive disease (PD) in 2.7%, and unknown in 12.0%. Relapse occurred in 13/75 pts (17.3%) with unknown histology (n=4), teratoma (n=2), other NGGCT (n=4), and germinoma (n=3). In 2 pts. in whom germinoma was diagnosed at time of first diagnosis, at time of recurrence PNET and Yolk sac tumor were histologically proven. Median time to relapse was 19.0 months (mo.; range 3-223). HDCT/ASCT as salvage treatment was performed in 5 pts with NGGCT and in one pt with germinoma as 2L (n=5) or 3L (n=1). NGGCT histology was associated with increased risk for recurrence or death (p=0.012 and 0.039).3-year PFS was 90.7% (germinoma: 98.1%, NGGCT: 73.9%) and 5-year OS was 92.0% (germinoma: 98.1%; NGGCT: 78.3%). Median follow-up time was 60 mo (range 0-339). Conclusions: Disease characteristics, treatment and outcomes of adolescent/ adult iGCT pts are comparable to those reported in pediatric pts. High cure rates are achieved in pts with pure germinoma and current treatment concepts. In pts with NGGCT further investigation is needed to improve survival outcomes.
Large language models to evaluate racial discrepancies in performance status assignment.
Authors: Arda Demirci, Julian C. Hong, Travis Zack
Journal: Journal of Clinical Oncology (2024)

1561 Background: Oncologic treatment eligibility relies heavily on “Performance Status” (PS), a subjective gauge of a patient's overall health. Despite frameworks aimed at quantifying PS, these assessments remain prone to potential bias. A systematic evaluation of discrepancies in language between ECOG PS and race has yet to be conducted. Large language models (LLMs) have the ability to synthesize text and may enable an assessment of the relationship between race, note text, and physician-documented PS. We hypothesize that LLMs can quantify these relationships to understand potential inconsistencies in ECOG PS. Methods: In our single-institution cohort study, we examined patients from medical or radiation oncology clinics between January 2012 to December 2023 with documented ECOG PS. PS was extracted from clinical notes and redacted from downstream analyses. Notes were categorized by patient-reported race (Asian, Black, White, Other). 1,500 matched subjective assessments (from oncologist clinical notes) and PS were randomly sampled for each race, except for Black patients, where only 640 entries were available. We divided training and test sets using an 80-20 ratio across each race. Using the training cohort, we trained race-specific models to assign ECOG PS based on subjective assessment, using two LLMs: UCSFBERT (BERT pretrained on UCSF data) and RoBERTa. In the hold-out test sets, we applied each model across all races to assign ECOG PS based on subjective assessments. These were evaluated by micro-F1 (model accuracy) and Multiway ANOVA to compute model-specific p-values. Results: 13.6% of patients had a documented ECOG 2+, with variation across races (Asian: 16.1%, Black: 17.7%, White: 7.7%, Other: 15.3%). Models tended to assign Black patients with ECOG 0-1 with worse performance status (ECOG 2+). Other than RoBERTa models trained on Asian and White cohorts, all models trained on a specific race showed disparate classification results when applied to other races (out-of-domain), highlighting potential biases in LLM models trained where a specific race predominates (Table; ANOVA). Conclusions: This study demonstrates a novel way to use LLM to assess discordance within physician documentation and performance status assignment. It underscores the need for incorporating diverse demographic data when using LLM in medical contexts. This research has potential to dissect how bias may be propagated within physician practice and provide insight into known disparities in clinical trial enrollment and standard of care implementation.[Table: see text]
Primary treatment modification strategies among older adults with advanced cancer.
Authors: Mostafa Refaat Mohamed, David Rich, Jennifer Leigh Lund, Christopher Seplaki, Marie Anne Flannery, Kah Poh Loh, Eva Culakova, Rachael Tylock, Allison Magnuson, Richard Francis Dunne, Erika E. Ramsdale, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2024)

1512 Background: Primary treatment modification (PTM; any change in dose or agents of the planned chemotherapy regimen from the standard guidelines) is a common therapeutic approach among older adults with advanced cancer due to their geriatric vulnerabilities. However, strategies to employ these modifications are understudied. This study compares a PTM strategy based on Geriatric Assessment (PTM-GA) intervention vs. usual care strategy based on oncologist’s impression (PTM-UC) on treatment tolerability in older adults with advanced cancer starting new chemotherapy regimens. Methods: In this subgroup analysis of the GAP 70+ study (NCT02054741; PI: Mohile), we included patients aged ≥ 70 with incurable solid tumors who initiated a chemotherapy course with PTM (n=298). For the first (PTM-GA) group, PTM was guided by GA results and recommendations while for the second (PTM-UC) group, PTM was guided by the treating oncologist's estimate only. Tolerability outcomes were assessed within 3 months of treatment and included: 1) any grade 3-5 clinician-rated toxicity according to National Cancer Institute Common Toxicity Criteria; 2) subsequent dose reduction; 3) Activity of Daily Living (ADL) decline; 4) unplanned hospitalization. We used multivariable, cluster-weighted generalized estimating equations models to examine the association of PTM-GA vs. PTM-UC and outcomes adjusting for confounders. Results: Mean age was 77 years. The most common cancer types were gastrointestinal (37%) followed by lung cancer (26%). PTM-GA versus PTM-UC was associated with reduced risk of grade 3-5 toxicity (relative risk (RR)= 0.77, 95% CI, 0.61- 0.90) and subsequent dose reduction (RR, 0.46; 95% CI, 0.29-0.73). Point estimates suggest that patients with PTM-GA may have a lower risk of unplanned hospitalization but results did not reach statistical significance (RR, 0.69; 95% CI, 0.46–1.02). PTM-GA vs. PTM-UC was not associated with ADL decline (RR, 1.05; 95% CI, 0.74–1.49). Conclusions: Older patients with advanced cancer who had PTM guided by GA recommendations had improved treatment tolerability compared to those who PTM based on oncologist’s estimate only. Integrating GA into treatment dosing decisions may lead to improved outcomes in this vulnerable population.
Effect of placental circulating T cells expressing CD16 on multiple hematological and solid tumor cancers through combination with various monoclonal antibodies.
Authors: Kathy Karasiewicz-Mendez, Kristina Tess, Mansour Djedaini, Chenfei Huang, Joseph Gleason, Shengchen Lin, Natalia Ruggeri Barbaro, John Fitzgerald, Shuyang He, Robert Hariri, Adrian Kilcoyne
Journal: Journal of Clinical Oncology (2024)

2554 Background: PT-CD16VS is an allogeneic cell therapy derived from human postpartum placental circulating T (PT) cells that are genetically modified to express CD16 and endogenous T cell receptor (TCR) knockout. PT-CD16VS cells can be combined with various monoclonal antibodies to engage in anti-tumor antibody-dependent cellular cytotoxicity (ADCC) against diverse cancers with a “universal receptor” approach. Here we report the characterization and preclinical evaluation of PT-CD16VS in combination with monoclonal antibodies against both hematological and solid tumor cancers. Methods: PT cells were activated, transduced with a lentiviral vector containing a construct expressing a high affinity CD16 variant, CD16VS, and transfected to knock out the TCR. In vitro,functional activity of PT-CD16VS cells in combination with monoclonal antibodies was assessed in cytotoxicity, cytokine release, and proliferation assays. Invivo, PT-CD16VS was combined with Rituximab in a Raji xenograft model in NSG mice, and with Trastuzumab in a subcutaneous NCI-N87 xenograft model in NSG mice in which tumor volume was measured and tumor samples were evaluated for PT-CD16VS infiltration. Results: In vitro, PT-CD16VS exhibited potent ADCC and cytokine release when combined with Rituximab against CD20+ Burkitt's lymphoma (Daudi and Raji), with Trastuzumab against HER2+ gastric carcinoma (NCI-N87), with Trastuzumab or Avelumab against HER2+/PDL-1+ non-small cell lung carcinoma (NCI-H1975) and Trastuzumab-resistant metastatic mammary adenocarcinoma (JIMT-1), and with Cetuximab against EGFR+ triple negative metastatic mammary adenocarcinoma (MDA-MB-231). Moreover, examples of PT-CD16VS antigen-specific proliferation were demonstrated against Raji and NCI-N87 when cells were combined with Rituximab and Trastuzumab, respectively. In vivo, in combination with Rituximab in the Raji mouse model, PT-CD16VS exhibited significant survival benefit compared to vehicle and Rituximab alone treated groups. In the subcutaneous NCI-N87 solid tumor model, PT-CD16VS with Trastuzumab demonstrated significant reduction in tumor volume compared to vehicle, Trastuzumab, and Enhertu groups. In addition, PT-CD16VS infiltration into the tumor was shown to be Trastuzumab dependent, with infiltrating cells expressing high levels of CD16 and Ki67. Conclusions: Our results show that PT-CD16VS have potent in vitro and in vivo ADCC activity, and a single drug product has the potential to be combined with various monoclonal antibodies to target multiple cancers across hematological and solid tumor indications. This “universal receptor” with antibody-dependent targeting approach, together with the benefits of an allogeneic cell platform, may democratize accessibility of such therapies for patients.