المؤلفون: Negrao, Marcelo, Araujo, Haniel, Lamberti, Giuseppe, Cooper, Alissa, Akhave, Neal, Zhou, Teng, Delasos, Lukas, Hicks, J, Aldea, Mihaela, Minuti, Gabriele, Hines, Jacobi, Aredo, Jacqueline, Dennis, Michael, Scott, Susan, Bironzo, Paolo, Scheffler, Matthias, Christopoulos, Petros, Stenzinger, Albrecht, Riess, Jonathan, Kim, So, Goldberg, Sarah, Li, Mingjia, Wang, Qi, Qing, Yun, Ni, Ying, Do, Minh, Lee, Richard, Ricciuti, Biagio, Alessi, Joao, Wang, Jing, Resuli, Blerina, Landi, Lorenza, Tseng, Shu-Chi, Nishino, Mizuki, Digumarthy, Subba, Rinsurongkawong, Waree, Rinsurongkawong, Vadeerat, Vaporciyan, Ara, Blumenschein, George, Zhang, Jianjun, Owen, Dwight, Mountzios, Giannis, Shu, Catherine, Bestvina, Christine, Garassino, Marina, Marrone, Kristen, Gray, Jhanelle, Patel, Sandip, Cummings, Amy, Wakelee, Heather, Wolf, Juergen, Scagliotti, Giorgio, Cappuzzo, Federico, Barlesi, Fabrice, Patil, Pradnya, Drusbosky, Leylah, Gibbons, Don, Meric-Bernstam, Funda, Lee, J, Heymach, John, Hong, David, Heist, Rebecca, Awad, Mark, Skoulidis, Ferdinandos, Blakely, Collin, Chakrabarti, Turja

المصدر: Cancer Discovery. 13(7)

مصطلحات موضوعية: Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Kelch-Like ECH-Associated Protein 1, Phosphatidylinositol 3-Kinases, Mutation, NF-E2-Related Factor 2, DNA Helicases, Nuclear Proteins, Transcription Factors

الوصف: UNLABELLED: Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9224f2jcTest

المؤلفون: Tompkins, William, Grady, Connor B., Hwang, Wei-Ting, Chandrasekhara, Krishna, McCoach, Caroline, Sun, Fangdi, Liu, Geoffrey, Patel, Devalben, Nieva, Jorge, Herrmann, Amanda, Marrone, Kristen, Lam, Vincent K., Velcheti, Vamsi, Liu, Stephen V., Bravo Montenegro, Gabriela Liliana, Patil, Tejas, Weiss, Jared, Miller, Kelsey Leigh, Schwartzman, William, Dowell, Jonathan E., Shaverdashvili, Khvaramze, Villaruz, Liza, Cass, Amanda, Iams, Wade, Aisner, Dara, Aggarwal, Charu, Camidge, D. Ross, Marmarelis, Melina E., Sun, Lova

المساهمون: AstraZeneca, LUNGevity Foundation, AACR

المصدر: JTO Clinical and Research Reports ; page 100669 ; ISSN 2666-3643

مصطلحات موضوعية: Pulmonary and Respiratory Medicine, Oncology

الإتاحة: https://doi.org/10.1016/j.jtocrr.2024.100669Test
https://api.elsevier.com/content/article/PII:S2666364324000390?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2666364324000390?httpAccept=text/plainTest

المؤلفون: Marrone, Kristen A, Landon, Blair V, Topper, Michael J, Tsai, Hua-Ling, Balan, Archana, Niknafs, Noushin, Cherry, Christopher, White, James, Hu, Chen, Riemer, Joanne, Fitzpatrick, Margaret, Forde, Patrick, Hann, Christine, Kelly, Ronan, Ettinger, David, Levy, Benjamin, Nieva, Jorge, Herman, James, Velculescu, Victor, Anagnostou, Valsamo, Baylin, Stephen, Brahmer, Julie

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0604Test

المؤلفون: Phallen, Jillian, Leal, Alessandro, Woodward, Brian D, Forde, Patrick M, Naidoo, Jarushka, Marrone, Kristen A, Brahmer, Julie R, Fiksel, Jacob, Medina, Jamie E, Cristiano, Stephen, Palsgrove, Doreen N, Gocke, Christopher D, Bruhm, Daniel C, Keshavarzian, Parissa, Adleff, Vilmos, Weihe, Elizabeth, Anagnostou, Valsamo, Scharpf, Robert B, Velculescu, Victor E, Husain, Hatim

المصدر: Cancer Research. 79(6)

مصطلحات موضوعية: Biotechnology, Cancer, Lung, Biomedical Imaging, Lung Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Adenocarcinoma, Aged, Aged, 80 and over, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Circulating Tumor DNA, DNA, Neoplasm, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Mutation, Prognosis, Protein Kinase Inhibitors, Survival Rate, Tumor Burden, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.Significance: Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.See related commentary by Zou and Meyerson, p. 1038.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5v10b8jxTest

المؤلفون: Kim, Dong-Wan, Kim, Sang-We, Camidge, D. Ross, Shu, Catherine A., Marrone, Kristen A., Le, Xiuning, Blakely, Collin M., Park, Keunchil, Chang, Gee-Chen, Patel, Sandip Pravin, Kar, Gozde, Cooper, Zachary A., Samadani, Ramin, Pluta, Michael, Kumar, Rakesh, Ramalingam, Suresh

المساهمون: Kim, Dong-Wan

مصطلحات موضوعية: CD73, EGFR TKI resistance, Non–small-cell lung cancer, T790M-negative

الوصف: Introduction: CD73 is overexpressed in EGFR-mutated NSCLC and may promote immune evasion, suggesting potential for combining CD73 blockers with EGFR tyrosine kinase inhibitors (TKIs). This phase 1b-2 study (NCT03381274) evaluated the anti-CD73 antibody oleclumab plus the third-generation EGFR TKI osimertinib in advanced EGFR-mutated NSCLC. Methods: Patients had tissue T790M-negative NSCLC with TKI-sensitive EGFR mutations after progression on a first- or second-generation EGFR TKI and were osimertinib naive. They received osimertinib 80 mg orally once daily plus oleclumab 1500 mg (dose level 1 [DL1]) or 3000 mg (DL2) intravenously every 2 weeks. Primary end points included safety and objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1. Results: By July 9, 2021, five patients received DL1 and 21 received DL2. Of these patients, 60.0% and 85.7% had any-grade treatment-related adverse events (TRAEs) and 20.0% and 14.3% had grade 3 TRAEs, respectively. No dose-limiting toxicities, serious TRAEs, or deaths occurred. Four patients were T790M positive on retrospective circulating tumor DNA (ctDNA) testing; three had objective partial responses. In patients who were T790M negative in tumor and ctDNA, objective response rate was 25.0% at DL1 and 11.8% at DL2 (all partial responses); response durations at DL2 were 14.8 and 16.6 months. In patients receiving DL2, excluding those who were T790M positive by ctDNA, median progression-free survival was 7.4 months, and median overall survival was 24.8 months. DL2 was the recommended phase 2 dose. Conclusions: Oleclumab plus osimertinib was found to have moderate activity with acceptable tolerability in previously treated patients with advanced EGFR-mutated NSCLC. ; Y ; 1

العلاقة: Journal of Thoracic Oncology, Vol.18 No.5, pp.650-656; https://hdl.handle.net/10371/192261Test; 000984821300001; 2-s2.0-85147560675; 181623

الإتاحة: https://doi.org/10.1016/j.jtho.2022.12.021Test
https://hdl.handle.net/10371/192261Test

المؤلفون: Niknafs, Noushin, Balan, Archana, Cherry, Christopher, Hummelink, Karlijn, Monkhorst, Kim, Shao, Xiaoshan M., Belcaid, Zineb, Marrone, Kristen A., Murray, Joseph, Smith, Kellie N., Levy, Benjamin, Feliciano, Josephine, Hann, Christine L., Lam, Vincent, Pardoll, Drew M., Karchin, Rachel, Seiwert, Tanguy Y., Brahmer, Julie R., Forde, Patrick M., Velculescu, Victor E., Anagnostou, Valsamo

المساهمون: U.S. Department of Health & Human Services | National Institutes of Health, U.S. Department of Defense, V Foundation for Cancer Research, LUNGevity Foundation

المصدر: Nature Medicine ; volume 29, issue 2, page 440-449 ; ISSN 1078-8956 1546-170X

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology, General Medicine

الوصف: Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types ( n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer ( n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.

الإتاحة: https://doi.org/10.1038/s41591-022-02163-wTest
https://www.nature.com/articles/s41591-022-02163-w.pdfTest
https://www.nature.com/articles/s41591-022-02163-wTest

المؤلفون: Kamson, David Olayinka, Cheunkarndee, Tia, Marrone, Kristen, Murray, Joseph, Feliciano, Joy, Hann, Christine, Ettinger, David, Anagnostou, Valsamo, Forde, Patrick, Brahmer, Julie, Levy, Benjamin, Scott, Susan, Lam, Vincent

المصدر: Neuro-Oncology Advances ; volume 5, issue Supplement_3, page iii9-iii9 ; ISSN 2632-2498

مصطلحات موضوعية: Surgery, Oncology, Neurology (clinical)

الوصف: Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) is known to have a high propensity to form brain metastases (BrM), with over 50% of ALK+ lung cancer patients developing BrM despite effective ALK tyrosine kinase inhibitor (TKI) therapy with central nervous system (CNS) activity. Pharmacokinetic (PK) data from other CNS-active lung cancer TKIs have suggested that there may be differences in drug concentration between white and gray matter in the brain, which may play a role in BrM formation patterns and response. In this study, we aimed to compare the size and distribution of ALK+ NSCLC BrMs at diagnosis in a TKI-naïve and TKI-exposed cohort. Brain MRI data from patients with ALK+ NSCLC were retrospectively reviewed, and each tumor was marked in a standard space brain model using 3D Slicer-4.11. FreeSurfer white-gray matter atlases were used to assess BrM distribution. We found that TKI-exposed patients had significantly smaller BrM diameters than TKI-naïve patients (6.1±3.8 vs. 10.2±5.5mm, p=0.02) and were more likely to have white matter-exclusive (3.5±4.4 vs. 1.4±2.0, p=0.05) and deep white matter metastases (3.2±4.3 vs. 1.3±2.0, p=0.06). The metastatic burden was similar between the groups, while the mean number of BrM per patient was numerically higher in the TKI-exposed group (10.6±11.9 vs. 6.2±9.5; p=0.22). These findings suggest that TKI therapy may result in smaller individual lesions that are more likely to be exclusive to the white matter, where drug concentrations may be significantly lower. This suboptimal CNS distribution of TKIs in the white matter may contribute to the progression of brain metastases in ALK+ patients despite TKI therapy. Further analyses are ongoing to evaluate ALK TKIs of varying CNS penetrance and later disease time points in more granular anatomic regions.

الإتاحة: https://doi.org/10.1093/noajnl/vdad070.033Test
https://academic.oup.com/noa/article-pdf/5/Supplement_3/iii9/51037783/vdad070.033.pdfTest

المؤلفون: Ghanem, Paola, Murray, Joseph C, Marrone, Kristen A, Scott, Susan C, Feliciano, Josephine L, Lam, Vincent K, Hann, Christine L, Ettinger, David S, Levy, Benjamin P, Forde, Patrick M, Shah, Ami A, Mecoli, Christopher, Brahmer, Julie, Cappelli, Laura C

المساهمون: Jerome L Greene Foundation, NIAMS, Bill and Melinda Gates Foundation

المصدر: RMD Open ; volume 9, issue 4, page e003471 ; ISSN 2056-5933

مصطلحات موضوعية: Immunology, Immunology and Allergy, Rheumatology

الوصف: Purpose Concomitant autoimmune rheumatic diseases (ARD) can add morbidity and complicate treatment decisions for patients with lung cancer. We evaluated the tumour characteristics at diagnosis and clinical outcomes in lung cancer patients with or without ARD. Methods This retrospective cohort study included 10 963 patients with lung cancer, treated at Johns Hopkins. Clinical data including tumour characteristics and outcomes were extracted from the cancer registry. Data on patients’ history of 20 ARD were extracted from the electronic medical record. Logistic regression was used to compare tumour characteristics between those with and without ARD; Kaplan-Meier curves and Cox proportional hazards models were performed to compare survival outcomes. Results ARD was present in 3.6% of patients (n=454). The mean age at diagnosis was 69 (SD 10) and 68 (SD 12) in patients with and without ARD (p=0.02). Female sex and smoking history were significantly associated with a history of ARD (OR: 1.75, OR: 1.46, p<0.05). Patients with ARD were more likely to be diagnosed with stage 1 lung cancer (36.8% vs 26.9%, p<0.001) and with smaller tumour size (OR: 0.76, p=0.01), controlling for sex, race and histology. Notably, lung cancer patients with ARD had a significantly prolonged median overall survival (OS) (7.11 years vs 1.7 years, p<0.001), independent of stage. Conclusion Patients with ARD and lung cancer had better OS compared with their counterparts, independent of cancer stage and treatments and were less likely to have advanced stage lung cancer at diagnosis. Additional studies are needed to investigate the differential immunological anti-tumour immune activity and genomic variations in patients with and without ARD.

الإتاحة: https://doi.org/10.1136/rmdopen-2023-003471Test

المؤلفون: Ghanem, Paola, Fatteh, Maria, Kamson, David Olayinka, Balan, Archana, Chang, Michael, Tao, Jessica, Blakeley, Jaishri, Canzoniero, Jenna, Grossman, Stuart A., Marrone, Kristen, Schreck, Karisa C., Anagnostou, Valsamo

المصدر: Frontiers in Medicine ; volume 10 ; ISSN 2296-858X

مصطلحات موضوعية: General Medicine

الوصف: Background Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Methods Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Results Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC 50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and ...

الإتاحة: https://doi.org/10.3389/fmed.2023.1254955Test

المؤلفون: Topper, Michael J., Anagnostou, Valsamo, Marrone, Kristen A., Velculescu, Victor E., Jones, Peter A., Brahmer, Julie R., Baylin, Stephen B., Hostetter, Galen H.

المصدر: iScience ; volume 26, issue 7, page 107095 ; ISSN 2589-0042

مصطلحات موضوعية: Multidisciplinary

الإتاحة: https://doi.org/10.1016/j.isci.2023.107095Test
https://api.elsevier.com/content/article/PII:S2589004223011720?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2589004223011720?httpAccept=text/plainTest