tbuckley/cabot-search huggingface dataset:
Clinical relevance of comprehensive genomic profiling for advanced cancers in India.
Authors: Serena Elizabeth Joseph, Aju Mathew, Senthill J. Rajappa, Nitesh Rohatgi, Bhawna Sirohi, Reetu Jain, Vivek Agarwala, Deepak Kumar Shukla, Anurag Mehta, Raja Pramanik, Vineet Talwar, Vinayak Maka, Nirmal Vivek Raut
Journal: Journal of Clinical Oncology (2021)

e18718 Background: Comprehensive genomic profiling (CGP) assay, a next-generation sequencing (NGS) based technique generates a large amount of genomic information about a cancer. While CGP is increasingly used in low-middle income countries (LMIC), little is known about the extent to which these benefits patients. Here we describe the proportion of patients with advanced cancer in India who eventually receive targeted therapy for an actionable genetic alteration identified on CGP assays. Methods: This was a multicenter, retrospective cohort study in adult patients with advanced non-hematological malignancies who underwent a CGP test. We excluded patients who were identified to have a genetic alteration that has a well-validated targeted standard-of-care therapy (e.g.; EGFR exon 18, 19, 21 mutations for lung cancer, HER2 amplification for breast cancer). Participating oncologists provided anonymized information of consecutive CGP test reports through an online data capture form. Descriptive statistics were used to describe the proportion of patients with subsequent targeted therapy. Results: During 2019-20, 12 medical oncologists provided CGP reports for 297 patients; 235 met the inclusion criteria. Fourteen different testing panels were used by the oncologists. Among the study cohort, 45% were male. Eighty nine percent underwent tumor tissue biopsy and 11% had liquid biopsy. The most common cancers were lung (19%), breast (18%), pancreatobiliary (9%) and colorectal (6%). Patients received a median of 2 lines (range: 0-5) of prior systemic therapy. Based on the CGP assay, 35 patients (15%) received targeted therapy. Among them, 29% was for HER2 amplification (non-breast cancer), 26% for PIK3CA mutation, 11% for HER2 or EGFR exon 20 insertion mutation (lung cancer), 5% each for BRAF mutation (non-melanoma), EGFR mutation (non-lung cancer) and MET mutation. Conclusions: In a LMIC setting, 15% patients received a targeted therapy based on CGP assay. This is comparable to reports from high income countries. Considering the limited access to new drugs and clinical trials, this finding requires further analysis.
Predictors of home death and the quality of end-of-life care at a cancer center in Brazil.
Authors: Sarah Gomes, Danielle Silva, Júlia Sá, Thais Passarini, Matheus Viana, Marcela de Paula, Bruna Silva, Clarissa Vieira, Alexandre A. Jácome, Bruno Lemos Ferrari
Journal: Journal of Clinical Oncology (2021)

e24004 Background: Early palliative care has shown an improvement in the quality of life of cancer patients by reducing overtreatment at the end of life and improving symptomatic control. Little is known about the quality of death in developing countries. End-of-life cancer care varies widely, and very few centers evaluate it systematically. The aim of the present study is to analyze the impact of follow-up of cancer patients by an outpatient palliative care team (OPCT) on the end-of-life outcomes at a Cancer Center in Brazil. Methods: We retrospectively retrieved data from electronic medical records of cancer patients who were treated at a Cancer Center in Brazil and who died from cancer or associated complications during the year of 2020. They were divided into two groups: OPCT and No-OPCT. OPCT group was followed-up by a multidisciplinary team composed of physician, nurse, physiotherapist, psychologist, nutritionist, social worker, speech-language therapist, and pharmacist, who regularly evaluated cancer patients during their treatments at outpatient setting. During COVID-19 pandemic, some patients were evaluated by telemedicine appointments. No-OPCT group was followed-up by cancer physicians exclusively. We performed univariate comparisons and multivariate analysis by Cox proportional hazards model. p &lt; 0.05 was deemed as statistically significant. Results: A total of 315 patients were included in the study: OPCT (N=122) and No-OPCT (N=193). The groups were well balanced in relation to median age (61yo vs 63yo), gender (women: 51% vs 54%), and TNM stage (stage IV: 69% vs 65%). Gastrointestinal and breast cancers were the most prevalent. The rate of home death was 44% in the OPCT group, compared to 16% in the No-OPCT group (p&lt;0.001). The rate of admission in intensive care unit in the last 30 days of life (ICU30) was 13% vs 10%, respectively (p=0.413). Likewise, the rate of patients treated with chemotherapy in the last 30 days of life (CT30) was 42% vs 51% (p=0.146). In multivariate analysis, follow-up by the OPCT was the strongest independent predictor of home death (Table). In contrast, ICU30 and CT30 were inversely correlated with this outcome. Age, gender, and TNM stage did not have influence on the place of death. Conclusions: Follow-up by an OPCT had a strong positive impact on end-of-life care of cancer patients in a country which does not have Hospice culture. The OPCT was able to offer home death to a greater number of patients, with proximity to caregivers, and respect to their beliefs and values. Our data highlight the importance of early conversations about goals of care, prognostic awareness, and end-of-life preferences, while also reinforcing the need of early referral to a palliative care team.[Table: see text]
Transcriptomic profiling of peripheral blood mononuclear cells in patients with multiple primary melanoma.
Authors: Lilit Karapetyan, Xi Yang, Min Mo, Hong Wang, Arivarasan Karunamurthy, Cindy Sander, Walter Storkus, John M. Kirkwood
Journal: Journal of Clinical Oncology (2021)

e21558 Background: Patients (PTs) with cutaneous melanoma (MEL) are at increased risk of developing subsequent MEL. The primary objective of the present study was to determine whether the peripheral blood gene expression profile (GEP) of PTs with multiple primary melanoma (MPM) differs from that of patients with single primary melanoma (SPM) and healthy controls (HCs). A secondary objective is to assess if the peripheral blood immune transcriptional profile varies in relation with clinical and immunopathological characteristics of MEL. Methods: Cases with MPM, SPM and HCs were retrieved from the University of Pittsburgh Human Biological Sample and Nevus Image Banking and Analysis Repository. NanoString PanCancer Immune Profiling of 770-immune related genes was used to define GEP in peripheral blood mononuclear cells (PBMCs). Quality control (QC), data normalization, and differential expression analyses were performed using the ROSALIND Analysis System. Genes with fold change ≥1.5 and p-value &lt; 0.05 were considered as differentially-expressed between cohorts. Results: In total, 47 PTs including 10 with SPM, 40 with MPM, and 10 HCs, were included. GEP data from 3 cases did not meet QC requirements and were discarded. The majority of PTs had stage I/II disease (87.2%). The median Breslow thickness was 1 mm, ulceration was present in 6 (12.2%) MELs. Tumor-infiltrating lymphocytes (TILs) were absent, non-brisk, and brisk in 20%, 65%, 15% of cases, respectively. The expression of IFIT1, MX1, ISG15 was decreased in PTs with MPM in comparison to HCs. In comparison to SPMs, PTs with MPM demonstrated downregulation of B-cell receptor signaling pathway genes (CD19, CD22, CD79A, BLK). 14 genes involved in TNF-alpha effects on cytokine activity, cell motility, and apoptosis, and 12 genes in the IL18 signaling pathway were differentially expressed in PTs with Breslow thickness of &gt;1mm vs ≤1mm. The top downregulated genes in &gt;1mm thick MELs were CD83, VEGFA and CXCL3. Ulcerated MEL had decreased expression of CCL2, CCL3, CCL3L1, CCL4. Stage III MEL had decreased expression of GZMH, MHC Class II genes HLA-DMB, HLA-DRB3, lectin receptor family genes KLRC2 and KLRD1, as well as Type-1 immune-associated biomarkers IRF1, SYK, TBX21 in comparison to Stage I/II cases. Tumors deficient in TILs exhibited decreased expression of Granzyme A and B, T-box 21, and IL18RAP (enhances IL18R-mediated signaling) in peripheral blood. Tumors with brisk TILs had increased expression of the B-cell associated transcripts CD19, CD22, CD79A in peripheral blood. Conclusions: The GEP of PBMC's from PTs with MPM was similar overall to that of PTs with SPM/HC, with only a subset of genes exhibiting differentially expression in PTs with MPM vs. PTs with SPM and HCs. GEP varied in relation to Breslow thickness, stage, ulceration, and TIL content in MELs.
Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials.
Authors: Li Zhang
Journal: Journal of Clinical Oncology (2021)

e14505 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.
Phase I study of transarterial chemoembolization of lung metastases.
Authors: Franz Edward Boas, Nancy E. Kemeny, Constantinos T. Sofocleous, Randy Yeh, Vanessa R Thompson, Meier Hsu, Chaya S. Moskowitz, Etay Ziv, Hooman Yarmohammadi, Achiude Bendet, Stephen Barnett Solomon
Journal: Journal of Clinical Oncology (2021)

3602 Background: Lung chemoembolization (via the bronchial or pulmonary artery) is a new treatment option for unresectable and unablatable lung metastases. Methods: 10 patients with unresectable and unablatable lung, endobronchial, or mediastinal metastases, who failed systemic chemotherapy, were enrolled in this single center, single arm, phase I trial. Pulmonary and bronchial angiography was performed in all patients, to determine the blood supply to the lung metastases. Based on the angiographic findings, bronchial or pulmonary artery chemoembolization was performed, using a lipiodol / mitomycin emulsion, followed by spherical particles. Technical success, safety, efficacy, and pharmacokinetics were evaluated. Wilcoxon signed-rank test was used to compare change in size of treated versus untreated tumors. Results: On angiography, all patients had lung metastases that were hypervascular compared to normal lung. 90% of patients had lung metastases supplied by the bronchial artery, and 10% were supplied by the pulmonary artery. Technical success rate of intra-tumoral drug delivery was 100% (95% CI: 76-100%). There were no severe adverse events, and all patients met criteria for discharge 4 hours post procedure. Response rate of treated lesions was 10% by RECIST and 40% by PERCIST. Treated tumors were mostly stable to decreased in size after chemoembolization (median change in size: 0%; IQR: -11% to 2%; mean: -4%), and untreated tumors were mostly increased in size (median change in size: 10%; IQR: 0% to 17%; mean 9%; p= 0.02). Intra-tumoral lipiodol retention at 4-6 weeks was correlated with decreased tumor size and metabolic activity. Pharmacokinetics showed that 45% of the mitomycin dose underwent burst release in 2 minutes, and 55% of the dose was retained intratumorally with a half-life &gt; 5 hours. Initial tumor-to-plasma ratio of mitomycin concentration was 380. Half-life of intratumoral lipiodol retention was 16 days. In vitro experiments showed 50% emulsion separation in 6.2 days, and 50% drug release in 7.1 hours. Conclusions: Lung chemoembolization can safely treat lung, mediastinal, and endobronchial metastases, with minimal systemic toxicity. High intratumoral drug concentrations after chemoembolization can overcome chemoresistance. Clinical trial information: NCT04200417.
A pan-cancer profiling of somatic mutations and tumor microenvironment to reveal mutation dependent immunophenotypic signature differences in KRAS.
Authors: Lee McDaniel, Charles Abbott, Rachel Pyke, Eric Levy, Simo V. Zhang, Jing Wang, Rena McClory, Richard Chen, Sean Michael Boyle
Journal: Journal of Clinical Oncology (2021)

e14526 Background: The ubiquity of tumor genotyping has identified hundreds of clinically actionable somatic mutations such as KRAS mutations predicting anti-EGFR response in colorectal cancer. Here, we describe an integrative pan-cancer study leveraging the Personalis NeXT Platform across 13 tumor types to reveal a broad portrait of clinically relevant mutations across 36 genes. Given the ascendance of tumor immunotherapy, there is an urgent need to better elucidate associations between clinically relevant gene mutations, patient demographics, and tumor immunobiology. Methods: Paired tumor-normals (n &gt; 450) were sequenced on the Personalis NeXT Platform, a diagnostic platform which simultaneously profiles tumor and immune microenvironments via exome and transcriptome sequencing. Samples were evaluated for the presence of KRAS variants at the G12, G13, and Q61 positions, requiring a minor allele frequency of more than 2%. Additionally, more than 200 clinically relevant amino acid changes were considered across 36 genes. DNA sequencing data was harnessed to profile MSI status, oncovirus status, HLA allele-specific LOH, SNVs, and neoantigens. RNA sequencing data furnished profiles for gene expression, TILs, TCR, BCR, and immune signatures. Statistical tests compared both the presence of clinically relevant mutations, and specific amino acid changes, to each of these DNA and RNA derived features. Results: Immunogenomic analysis with the Personalis NeXT Platform identified KRAS mutations at the G12, G13, and Q61 positions in 6 of the 13 tumor types, including bladder, CRC, liver, NSCLC, pancreatic, and uterine cancers, consistent with known KRAS allelic incidence. 11 different KRAS amino acid substitutions were identified in this cohort, including G12(A/C/D/R/S/V), G13(C/D), and Q61(H/K/L), with 14% of samples positive for KRAS variants across our pan-cancer cohort, including malignancies not associated with KRAS. Immune signatures, including TCRB clones, mutational burden, and TILs signatures demonstrated variability in a KRAS allele-dependent manner. Pancreatic cancers demonstrated a statistically significant increase in macrophage enrichment score (p &lt; 0.001) in KRAS-mutant tumors. Conclusions: Utilizing the Personalis NeXT Platform, our analysis characterized the tumor microenvironment of over 460 samples across 13 tumor types, 36 genes, and over 200 clinically relevant amino acid substitutions. This comprehensive characterization demonstrated significant differences in immune cell signatures in pancreatic cancer, suggestive of an association between the presence of KRAS mutations and immune cell infiltrate composition.
Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study
Authors: Vivek Subbiah, Mimi I Hu, Lori J Wirth, Martin Schuler, Aaron S Mansfield, Giuseppe Curigliano, Marcia S Brose, Viola W Zhu, Sophie Leboulleux, Daniel W Bowles, Christina S Baik, Douglas Adkins, Bhumsuk Keam, Ignacio Matos, Elena Garralda, Justin F Gainor, Gilberto Lopes, Chia-Chi Lin, Yann Godbert, Debashis Sarker, Stephen G Miller, Corinne Clifford, Hui Zhang, Christopher D Turner, Matthew H Taylor
Journal: The Lancet Diabetes & Endocrinology (2021)
Rural-Urban Disparity in Mortality in the US From 1999 to 2019
Authors: Sarah H. Cross, Robert M. Califf, Haider J. Warraich
Journal: JAMA (2021)

The economic, social, and political challenges facing rural areas in the US have implications for the entire country.Even though rural-urban disparities in mortality from such diseases as chronic lung disease and cardiovascular disease have been described, 1,2 less is known about recent trends in ruralurban differences in age-adjusted mortality rates (AAMRs) overall in the US. Methods |We analyzed all deaths occurring in the US using the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from 1999 to 2019.We used the National Center for Health Statistics Urban-Rural Classification Scheme to create the following population categories per the 2013 US Census classification: large metropolitan area (≥1 million), small-or medium-sized metropolitan area (50 000-999 999), and rural area (<50 000). 3 The AAMRs per 100 000 population were calculated by multiplying the age-specific death rate for each age group by the corresponding weight from the 2000 standard US population, summing across all age groups, and then multiplying by 100 000.We stratified the results by age, sex, and race/ ethnicity.We also analyzed these subgroups among individuals aged 25 to 64 years.We estimated the annual percentage change (APC) in AAMR using Poisson regression with log-link and robust standard errors and included an interaction term to test for differences in time trends.We performed all analyses using Stata version 16 (StataCorp), considering a 2-tailed P < .05 as statistically significant.The data were publicly available and deidentified and therefore informed consent was not applicable per HHS regulation 45 CFR 46.101(c).Results | From 1999 to 2019, rural areas had the highest AAMRs.The overall AAMR in large metropolitan areas decreased from 861.5/100 000 to 664.5/100 000 and in rural areas it decreased from 923.8/100 000 to 834.0/100 000 (P < .001for time trend) (Figure andTable).The absolute difference in the AAMRs between large metropolitan areas and rural areas increased from 62.3/100 000 (95% CI, 59.2/100 000-65.4/ 100 000) in 1999 to 169.5/100 000 (95% CI, 167.0/100 000-172.1/100000) in 2019, which was an increase of 172%.From 1999 to 2019, the AAMRs declined for all ages except for rural residents aged 25 to 64 years, in whom the AAMR increased from 398.7/100 000 to 447.0/100 000 (APC, 0.6%; 95% CI, 0.4%-0.7%).Across areas, men had greater AAMRs than women (P < .001);however, men experienced a greater APC reduction in the AAMRs.Among men, the AAMR in large metropolitan areas decreased from 1044.
Overall and progression-free survival in young breast cancer patients with low muscle mass and density.
Authors: Rebecca Sheaff Greiner, Matthew Flores, Danielle Boselli, Taylor Stone, Lejla Hadzikadic-Gusic, Anna Hecksher, Chasse Margot Bailey-Dorton, Eric Wang, Declan Walsh
Journal: Journal of Clinical Oncology (2021)

12052 Background: Low muscle mass (skeletal muscle index, SMI) and density (skeletal muscle density, SMD) are associated with chemotherapy toxicity and shorter survival in women with breast cancer. This has not been studied specifically in women ≤ 40 years at diagnosis. They have different body compositions and more aggressive cancers than older women. We compared pre-treatment muscle measures in survivors and non-survivors and investigated their association with overall survival (OS) and progression-free survival (PFS). Methods: This case-control study included 112 women aged ≤ 40 years at diagnosis. Women with pre-treatment CT scans from 2009-2018 were identified; non-survivors were matched with survivors by age, year of diagnosis and disease characteristics. Body composition was determined by CT analysis. Measures were compared between the groups using Kruskal-Wallis tests. Kaplan-Meier methods summarized OS and PFS and the associations of muscle characteristics with OS and PFS were examined by univariate Cox proportional hazard models. Results: Median age was 35 years; median follow-up was 8.2 years. 75% had Stage II or III disease and 21% Stage IV disease. 33% were sarcopenic (SMI &lt; 40) and 16% had low SMD (HU &lt;37.8). Non-survivors had more intermuscular fat (IMAT), reduced SMD, and reduced skeletal muscle gauge (SMG). Sarcopenia was not associated with OS; however, sarcopenia was associated with shorter PFS. The median skeletal muscle gauge was 1973; low skeletal muscle gauge (SMG &lt;1973) was associated with both shorter OS and PFS. Median IMAT was 1.6, and high IMAT (≥1.6) was associated with shorter OS and PFS. Conclusions: Low muscle mass (sarcopenia) at breast cancer diagnosis was associated with shorter PFS and low muscle density (low SMG and higher IMAT) was associated with shorter OS and PFS in women ≤ 40 years. These sub-optimal muscle characteristics may indicate an overall reduced state of health and/or decreased ability to tolerate treatment, thus reducing survival. Future research should determine the significance of muscle changes throughout treatment and establish standards for improved muscle health.[Table: see text]