The International Association for the Study of Lung Cancer (IASLC) has proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, the efficacy of this grading system in predicting distant metastases in patients with LUAD remains unexplored. This study aims to assess the potential of the IASLC grading system in predicting the occurrence of brain and bone metastases in patients with resectable LUAD, thereby identifying individuals at high risk of post-surgery distant metastasis.
Abstract Introduction: The FDA’s approval of immune checkpoint inhibitors (ICI) in 2015 drastically changed the survival of late-stage non-small cell lung cancer (NSCLC) patients. However, only about 30% of NSCLC patients respond to treatment, while the other 70% are immune resistant. Through an analysis of 424 NSCLC patients at Atrium Wake Forest, we have identified a loss-of-function mutation in Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) as a biomarker for response to ICI. We hypothesize that by treating wild-type immune-resistant tumors with Entrectinib, we can mimic the effect of the mutation in NTRK1 and induce immune responses. Methods: To identify biomarkers, we collected genomic sequencing data and comprehensive clinical characteristics on 424 NSCLC patients who received ICI or chemo-ICI treatment at Atrium Health Wake Forest Baptist. To determine the role of NTRK1 in vivo, we implanted LL/2-scramble (wild-type NTRK1) or LL/2-shNTRK1, which diminished NTRK1, into C57/B6 mice. The animals were injected with either IgG or Anti-PD1. To determine if we could mimic the effect of a mutation in NTRK1, C57/B6 mice were inoculated with LL2-wildtype NTRK1 and treated with either a) IgG, b) Entrectinib, c) Anti-PD-1, or d) Anti-PD-1 + Entrectinib. All in vivo experiments had tumor growth monitored, and a flow cytometry panel was performed at the endpoint to understand the immune responses. Bulk RNA-Sequencing was performed on cell cultures and tumors. Results: Mice given the LL/2-shNTRK1 responded to Anti-PD-1 treatment and had a significant increase in CD4+ stem-like effector T cells in the spleen and tumor-draining lymph nodes. Animals that were inoculated with the LL/2 cell lines and treated with Anti-PD-1 + Entrectinib also responded. Mice treated with Anti-PD-1 + Entrectinib were found to have a significant increase in CD4+ stem-like effector T cells as well. RNA-Sequencing revealed that in the mutant cell line LL/2-shNTRK1 and LL/2 tumors treated with Anti-PD-1 + Entrectinib, there was a significant upregulation of C3 production. Conclusion: Our studies demonstrate that the loss of NTRK1 function, through either genetic ablation or enzymatic inhibition combined with Anti-PD-1, provides a potent treatment for immune-resistant NSCLC tumors. Citation Format: Margaret R Smith, Yuezhu Wang, Caroline B. Dixon, Ralph D'Agostino, Yin Liu, George C. Oliver, Lance D Miller, Umit Topaloglu, Michael D Chan, Micahel Farris, Jing Su, Kathryn F Mileham, Wencheng Li, Jason M. Grayson, Thomas Lycan, Fei Xing. Enhancing immune checkpoint inhibitor efficacy by targeting neurotrophic receptor tyrosine kinase 1 signaling in immune resistant non-small cell lung cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A050.
Vasculitic immune checkpoint inhibitor-related adverse events (irAEs) are rare, with limited data to guide their management. Here, we present a case of a 67-year-old female with stage IV cutaneous melanoma who received first-line pembrolizumab. She had completed 21 cycles of pembrolizumab dosed at 200 mg every 21 days over 15 months when she developed fatigue, chills, decreased appetite, night sweats, nausea, diarrhea, dry cough, and chest pain. A routine, staging positron emission tomography (PET) scan revealed aortitis of the transverse aortic arch. An extensive workup was unremarkable for other causes, so her condition was labeled a grade III immune-related vasculitis. Based on this diagnosis, we started high-dose prednisone and discontinued pembrolizumab. After two months of high-dose prednisone, she developed bothersome weight gain and insomnia, leading to a switch from prednisone to tocilizumab as a steroid-sparing agent. The selection of tocilizumab was based on its routine use for giant cell arteritis which can have extracranial symptoms including thoracic aortitis. Her symptoms resolved, and subsequent PET scans showed resolution of the aortitis and no evidence of metastatic melanoma. As the indications for immunotherapy expand, rare complications are becoming more prevalent, and more data will be needed to guide their management. While there is evidence for tocilizumab use as a steroid-sparing treatment for large-vessel vasculitides due to other conditions, this is the first case of its use to treat an aortitis irAE to our knowledge. In this case, it was an effective means of treating the patient while sparing them from prolonged corticosteroids.
Abstract Background Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy‐induced peripheral neuropathy (CIPN), the dose‐limiting toxicity of this agent. Methods This cross‐sectional study of breast cancer patients with taxane CIPN measured nerve cross‐sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). Results A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm 2 smaller than healthy controls ( P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm 2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R 2 0.30; P = .04). Conclusions These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.
Describe the incidence, spectrum, management and long-term outcomes of neurological immune related adverse events (IRAEs) of immune checkpoint inhibitors (ICIs).
Abstract Introduction:Stage is the most important prognostic factor for survival in non-small cell lung cancer (NSCLC). The current TNM (Tumor, Node, Metastasis) staging system for NSCLC uses physical exam, histology, imaging, and surgical findings to define the extent and spread of a patient’s cancer. Despite advances in molecular testing which can impact treatment and prognosis for NSCLC patients, the current system does not incorporate molecular data into staging. We proposed a novel predictive model for survival analysis which integrates molecular analysis of liquid biopsies (B) into the TNM staging system (1). In this study, we tested this new staging system and our predictive model shows TNM + B (TNMB) provides a better predictive model for survival compared to TNM alone. Methods:176 patients were identified at Atrium Health Wake Forest Baptist with Guardant 360 liquid biopsies sent at diagnosis for NSCLC. Clinical data was obtained through retrospective chart review. Molecular analysis was performed on 81 genes across all Guardant 360 liquid biopsies. Using Cox proportional hazards model, we identified significant gene mutations or genes with significant magnitude of variant allele frequency (VAF) that improved survival prediction. We then designed a novel staging system incorporating whether a patient had a positive liquid biopsy test (B1), defined by the presence of these impact gene variables, to TNM stage. Results: Three impact genes STK11 (p=0.0253), NFE2L2 (p = 0.0025), TP53 (p=0.0129) and one gene with a magnitude of VAF, ARID1A (p=0.0082) was identified which significantly improved the predictive model for survival. Patients with negative liquid biopsy test, B0, had improved survival compared to patients with a positive liquid biopsy test, B1 (p<0.005). In our cohort, TNM staging alone did not show a significant survival difference between stage II and III (p = 0.19). Whereas TNMB staging showed a significant survival difference between stage II, III and IV. Conclusions: While TNM stage remains a major prognostic factor for NSCLC patients, it fails to incorporate molecular data which has a critical impact on management and prognosis. We designed a novel method to analyze molecular data obtained by liquid biopsy to identify significant gene mutations and gene magnitude of VAF that impacts survival prediction. In our cohort, we showed 4 impact genes which we used to create a new TNMB staging system which led to improved survival prediction compared to TNM alone. Acknowledgments: Research partly supported by NIH T32 Grant (T32CA247819) and Cancer Center Support Grant (P30CA012197) Reference: (1) Yang M, Forbes ME, Bitting RL, O'Neill SS, Chou PC, Topaloglu U, Miller LD, Hawkins GA, Grant SC, DeYoung BR, Petty WJ, Chen K, Pasche BC, Zhang W. Incorporating Blood-based Liquid Biopsy Information into Cancer Staging: Time for a TNMB System? Ann Oncol. 2018 Feb 1;29(2):311-323. Citation Format: Lauren Schmalz, Cetin Urtis, Liang Liu, Elizabeth Forbes, Fang-Chi Hsu, Nury Steuerwald, Alberto de Hoyos, Thomas Lycan, Jimmy Ruiz, William Petty, Wei Zhang. Integrating blood based liquid biopsies with TNM stage improves survival prediction model for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5065.
e14701 Background: Medical providers often describe concerns about a patient’s functional status in routine clinical documentation (e.g., hard of hearing, recent falls, difficulty with home medication). These clinician-documented pretreatment functional variables (PFVs) may be predictive of outcomes among patients receiving immunotherapy. The goal of this retrospective study is to check for an association between the documentation of PFVs with overall survival (OS), progression-free survival (PFS), and the incidence of immune-related adverse events (irAEs). Methods: We created a retrospective registry of all patients who received at least one dose of an immune checkpoint inhibitor for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center. The investigators created a validated REDCap registry; clinical research specialist at Vasta Global captured most data. PFVs were collected by review of routine clinical documentation 30 days before or after the first dose. Patients were stratified by their number of PFVs (0,1, or 2+) and by their age (≥ or <65 years). PFVs assessed function, nutritional status and social support and were dichotomized to indicate impaired vs not with ten total categories. We used Cox proportional hazard modeling for survival analyses between the three PFV groups, calculated from the first dose of immunotherapy to disease progression, death, and last known follow-up controlling for age, BMI, smoking, and disease type with a two-sided alpha of 0.05. Results: From the overall cohort (n = 3,101), 35% had no PFVs, 32% had one PFV, and 32% had two or more PFVs; 52.5% were considered younger, and 47.5% geriatric-aged (≥65yo). PFVs were more common among the geriatric-aged population (mean 1.43 vs 0.89). The most common cancer types were lung cancer (45%), melanoma (14%), and kidney (6%). The most noted PFVs were visual impairment (26%), unintentional weight loss (22%), inability to walk a quarter block (17%), living alone (16%), and falls (14%). In the overall population, an increasing number of PFVs was associated with shorter OS. When stratified by age, the number of PFVs was associated with shorter progression-free survival (p <0.01) and overall survival (p <0.01) among the geriatric and non-geriatric populations (Table). There was no association between increasing PFVs and incidence of irAEs. Conclusions: Although often considered to be signs of aging, documentation of multiple PFVs was associated with worse OS and PFS among geriatric-aged and non-geriatric-aged populations. This study highlights the utility of routine clinical documentation on health status, including function, nutrition, and social support, to estimate survival regardless of chronologic age. [Table: see text]
