Browsing by Subject "Non-small-cell lung carcinoma"

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    Association of Allostatic Load With Overall Mortality Among Patients With Metastatic Non-Small Cell Lung Cancer
    (American Medical Association, 2022-07-01) Obeng-Gyasi, Samilia; Li, Yaming; Carson, William E.; Reisenger, Sarah; Presley, Carolyn J.; Shields, Peter G.; Carbone, David P.; Ceppa, DuyKhanh P.; Carlos, Ruth C.; Andersen, Barbara L.; Surgery, School of Medicine
    Importance: Adverse social determinants of health (SDHs) (eg, poverty) are associated with poor oncologic outcomes among patients with lung cancer. However, no studies have evaluated biological correlates of adverse SDHs, operationalized as allostatic load (AL), with mortality due to lung cancer. Objective: To examine the association among AL, SDHs, and mortality among patients with metastatic non-small cell lung cancer (NSCLC). Design, setting, and participants: This cross-sectional study of an observational cohort was performed at a National Cancer Institute-designated comprehensive cancer center with data accrued from June 1, 2017, to August 31, 2019. Patients with metastatic (stage IV) NSCLC enrolled at diagnosis into a prospective observational cohort study were included in the present analysis if they had all the biomarkers to calculate an AL score (N = 143). Follow-up was completed on August 31, 2021, and data were analyzed from July 1 to September 30, 2021. Exposures: Social determinants of health. Main outcomes and measures: Overall mortality and AL. Results: A total of 143 patients met the study criteria with a median age of 63 (IQR, 55-71) years (89 men [62.2%] and 54 women [37.8%]). In terms of race and ethnicity, 1 patient (0.7%) was Asian, 7 (4.9%) were Black, 117 (81.8%) were White, 17 (11.9%) were of multiple races, and 1 (0.7%) was of other race or ethnicity. The mean (SD) AL was 2.90 (1.37). Elevated AL covaried with lower educational level (r = -0.26; P = .002), male sex (r = 0.19; P = .02), limited mobility (r = 0.19; P = .04), worsening self-care (r = 0.30; P < .001), problems engaging in usual activities (r = 0.21; P = .01), depressive symptoms (r = 0.23; P = .005), and a high number of stressful life events (r = 0.30; P < .001). Multivariable analysis found only increasing difficulty with mobility (r = 0.37 [95% CI, 0.13-0.60]; P = .002) and male sex (r = 0.63 [95% CI, 0.19-1.08]; P = .005) associated with higher AL. On adjusted analysis, elevated AL (hazard ratio, 1.43 [95% CI, 1.16-1.79]; P = .001) and low educational level (hazard ratio, 2.11 [95% CI, 1.03-4.34]; P = .04) were associated with worse overall mortality. Conclusions and relevance: The findings of this cross-sectional study suggest that higher AL was associated with adverse SDHs and worse overall mortality among patients with advanced NSCLC. These results provide a framework for replication and further studies of AL as a biological correlate for SDH and future prognostic marker.
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    Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy
    (American Association for Cancer Research, 2021) Hellmann, Matthew D.; Jänne, Pasi A.; Opyrchal, Mateusz; Hafez, Navid; Raez, Luis E.; Gabrilovich, Dmitry; Wang, Fang; Trepel, Jane B.; Lee, Min-Jung; Yuno, Akira; Lee, Sunmin; Brouwer, Susan; Sankoh, Serap; Wang, Lei; Tamang, David; Schmidt, Emmett; Meyers, Michael L.; Ramalingam, Suresh S.; Shum, Elaine; Ordentlich, Peter; Medicine, School of Medicine
    Purpose: New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1) blockade to overcome resistance. We report outcomes in patients with anti-programmed cell death ligand-1 [PD-(L)1]-resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601. Patients and methods: The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described. Results: Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST-assessed ORR was 9.2% [95% confidence interval (CI): 3.8-18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9-not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5-4.1), and median overall survival was 11.7 months (95% CI: 7.6-13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγ gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients. Conclusions: In anti-PD-(L)1-experienced patients with NSCLC, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit, with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.
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    OMRT-9. Effect of Pre-Operative Stereotactic Radiosurgery on Brain Metastasis: Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694
    (Oxford University Press, 2021-07) Shireman, Jack; Huff, Wei; Monaco, Gina; Agrawal, Namita; Watson, Gordon; Dey, Mahua; Neurological Surgery, School of Medicine
    Background: With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient’s overall survival (OS). Treatment varies based on presentation, however, for patients with <4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1–4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor. Methods: Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing. Conclusions: Our initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways (p <.001, p<.01). These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment.
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    Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review)
    (Spandidos Publications, 2023) Zhang, Joshua; Darman, Lily; Hassan, Md Sazzad; Von Holzen, Urs; Awasthi, Niranjan; Surgery, School of Medicine
    Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in solid tumors. More than 90% of pancreatic ductal adenocarcinoma (PDAC) are driven by mutations in the KRAS gene, suggesting the importance of targeting this oncogene in PDAC. Initial efforts to target KRAS have been unsuccessful due to its small size, high affinity for guanosine triphosphate/guanosine diphosphate, and lack of distinct drug‑binding pockets. Therefore, much of the focus has been directed at inhibiting the activation of major signaling pathways downstream of KRAS, most notably the PI3K/AKT and RAF/MAPK pathways, using tyrosine kinase inhibitors and monoclonal antibodies. While preclinical studies showed promising results, clinical data using the inhibitors alone and in combination with other standard therapies have shown limited practicality, largely due to the lack of efficacy and dose‑limiting toxicities. Recent therapeutic approaches for KRAS‑driven tumors focus on mutation‑specific drugs such as selective KRASG12C inhibitors and son of sevenless 1 pan‑KRAS inhibitors. While KRASG12C inhibitors showed great promise against patients with non‑small cell lung cancer (NSCLC) harboring KRASG12C mutations, they were not efficacious in PDAC largely because the major KRAS mutant isoforms in PDAC are G12D, G12V, and G12R. As a result, KRASG12D and pan‑KRAS inhibitors are currently under investigation as potential therapeutic options for PDAC. The present review summarized the importance of KRAS oncogenic signaling, challenges in its targeting, and preclinical and clinical targeted agents including recent direct KRAS inhibitors for blocking KRAS signaling in PDAC.