Faculty Bibliography

Spread through air spaces (STAS) is reportedly associated with worse prognosis in sublobar resections of lung adenocarcinoma. Recently, it was proposed that STAS detected on frozen sections can be an indication for lobectomy instead of sublobar resection. We undertook this study to evaluate the reliability of STAS assessment on frozen sections compared to permanent sections, as well as the associations among STAS, tumor grade, and recurrence-free survival (RFS) after sublobar resection. A total of 163 stage I lung adenocarcinoma resections with frozen sections were identified retrospectively. For each case, and for frozen and permanent sections separately, the presence or absence of STAS, as well as the tumor grade, were recorded. Compared to permanent sections, STAS detection on frozen sections had low sensitivity (55%), low positive predictive value (48%), and fair agreement (K = 0.34), whereas there was higher specificity (80%) and negative predictive value (85%). Accuracy was 74%. Tumor grade assessment on frozen sections showed higher sensitivity (77%), positive predictive value (90%), agreement (K = 0.72), specificity (94%), and accuracy (87%), and the same negative predictive value (85%). High-grade histology on frozen sections was associated with shorter RFS (p = 0.02), whereas STAS on frozen sections was not (p = 0.47). Our results suggest that the intraoperative detection of STAS has low sensitivity and positive predictive value. False-positive results may lead to overtreatment of patients with lung cancer. The determination of tumor grade on frozen sections offers better sensitivity and specificity, plus it is associated with RFS, whereas STAS on frozen sections is not. Further study is needed to explore the utility of assessing tumor grade on frozen sections.

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

Objective/UNASSIGNED:(AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (INV). We sought to develop and evaluate a quantitative imaging method to determine invasiveness of small, ground-glass lesions on computed tomography (CT) chest scans. Methods/UNASSIGNED:N=162). Results/UNASSIGNED:(AUC=0.909, p<0.001). Conclusions/UNASSIGNED:radiomics to the routine visual assessment of CT scans help better differentiate adenocarcinoma subtypes and can aid in clinical decision making. Further prospective validation in this direction is warranted.

Objectives/UNASSIGNED:To investigate the efficacy and safety of lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) including oligorecurrent and oligoprogressive disease. Methods/UNASSIGNED:Single-institution retrospective analysis of 60 NSCLC patients with 62 discrete lesions treated with SBRT between 2008 and 2017. Patients were stratified into three groups, including early stage, locally recurrent, and oligoprogressive disease. Group 1 included early stage local disease with no prior local therapy. Group 2 included locally recurrent disease after local treatment of a primary lesion, and group 3 included regional or well-controlled distant metastatic disease receiving SBRT for a treatment naive lung lesion (oligoprogressive disease). Patient/tumor characteristics and adverse effects were recorded. Local failure free survival (LFFS), progression free survival (PFS), and overall survival (OS) were estimated using the Kaplan Meier method. Results/UNASSIGNED:At median follow-up of 34 months, 67% of the study population remained alive. The estimated 3-year LFFS for group 1, group 2, and group 3 patients was 95% (95% CI: 86%-100%), 82%(62% - 100%), and 83% (58-100%), respectively. The estimated 3-year PFS was 59% (42-83%), 40% (21%-78%), and 33% (12%-95%), and the estimated 3-year OS was 58% (41-82%), 60% (37-96%), and 58% (31-100%)), respectively for each group. When adjusted for age and size of lesion, no significant difference in OS, LFFS, and PFS emerged between groups (p > 0.05). No patients experienced grade 3 to 5 toxicity. Eighteen patients (29%) experienced grade 1 to 2 toxicity. The most common toxicities reported were cough and fatigue. Conclusions/UNASSIGNED:Our data demonstrates control rates in group 1 patients comparable to historical controls. Our study also reveals comparable clinical results for SBRT in the treatment of NSCLC by demonstrating similar rates of LFFS and OS in group 2 and group 3 patients with locally recurrent and treatment naïve lung lesion with well-controlled distant metastatic disease.

Background: Detection of residual disease post-NA treatment (tx) using ctDNA may indicate response and post-surg relapse risk. We profiled ctDNA and describe ctDNA dynamics in pts with NSCLC pre- and post-NA tx with atezo (anti-PD-L1) and post-surg in the LCMC3 study.
Method(s): Pts (N=181) with stage IB to select IIIB NSCLC received 2 cycles of NA atezo before surg. Tumour tissue-informed, germline-corrected ctDNA was measured pre- and post-atezo and post-surg using the AVENIO Oncology Surveillance Test (ctDNA+ defined as ctDNA detection index <=0.05). We correlated quantitative ctDNA levels and ctDNA presence with major pathologic response (MPR; primary endpoint), pathologic response, change in tumour size and disease-free survival (DFS).
Result(s): 126 pts had sufficient tissue to test, of which 106 (84%) had tumour variants suitable for monitoring. Of these, ctDNA was detected in 72% of pre-atezo (n=101), 56% of post-atezo (n=102) and 10% of post-surg samples (n=49). Median ctDNA levels (range) dropped from 3 (0-4448) mean tumour molecules/mL plasma (mtm/mL) pre-atezo to 0.5 (0-406) mtm/mL post-atezo and 0 (0-35) mtm/mL post-surg (all paired comparisons P<0.01). Greater ctDNA reduction post-atezo was seen in pts with MPR vs non-MPR (median log2 fold change -4.8 vs 0.3, P<0.001). Reduced ctDNA levels post-atezo were also associated with pathologic response (P<0.001, r=0.38) and reduction in radiographic tumour size (P<0.001, r=0.42). 2-yr DFS rate for pts who were ctDNA- vs ctDNA+ post-surg was 75% vs 40% (HR, 3.6; 95% CI: 1.0, 13.1; P=0.054). In 64 pts with non-squamous tumours, higher disease stage was associated with higher rates of pre-atezo ctDNA+ status and ctDNA levels (all P<0.05).
Conclusion(s): >60% of pts with resectable lung cancers had sufficient tissue, trackable tumour variants, and were ctDNA+ pre-atezo. ctDNA reductions post-atezo correlated with pathologic response and reduced radiographic tumour size. 2-yr DFS was better in pts who were ctDNA- post-surg. Combining changes in ctDNA with pathologic and radiographic assessment may provide a thorough measurement of response to NA therapy, and may inform management of early NSCLC pts. Clinical trial identification: NCT02927301. Editorial acknowledgement: Medical writing assistance for this abstract was provided by Derrick Afful, PhD and Christopher Lum, PhD of Health Interactions Inc, and funded by Genentech, Inc. Legal entity responsible for the study: Genentech, Inc.
Funding(s): Genentech, Inc. Disclosure: M.G. Kris: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Editorial Support: Genentech; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Janssen. J.M. Grindheim: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc; Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech. J.E. Chaft: Financial Interests, Personal, Other, editorial/ medical writing assistance: Genentech; Financial Interests, Personal, Other, Consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb; Financial Interests, Personal, Other, Consultant: Genentech; Financial Interests, Personal, Other, Consultant: Merck. J.M. Lee: Financial Interests, Personal, Other, Editorial/ medical writing Support: Novartis; Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Genentech; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting Fees: Genentech; Financial Interests, Personal, Other, Consulting Fees: Novartis; Financial Interests, Personal, Speaker's Bureau: AstraZeneca; Financial Interests, Personal, Speaker's Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker's Bureau: Genentech; Financial Interests, Personal, Speaker's Bureau: Novartis; Financial Interests, Personal, Speaker's Bureau: eCancer; Financial Interests, Personal, Speaker's Bureau: Medscape; Financial Interests, Personal, Other, meeting attendance support: AstraZeneca; Financial Interests, Personal, Other, meeting attendance support: Genentech; Financial Interests, Personal, Leadership Role, Steering or Executive Committee for Clinical Trials: AstraZeneca; Financial Interests, Personal, Leadership Role, Steering or Executive Committee for Clinical Trials: Genentech; Financial Interests, Personal, Leadership Role, Steering or Executive Committee for Clinical Trials: Novartis. B.E. Johnson: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Cannon Medical Systems; Financial Interests, Personal, Advisory Board: Hengrui Therapeutics; Financial Interests, Personal, Advisory Board: Checkpoint Therapeutics; Financial Interests, Personal, Advisory Board: Boston Pharmaceuticals; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Janssen Scientific; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Other, Dana-Farber Cancer Institute: Dana-Farber Cancer Institute. V.W. Rusch: Financial Interests, Institutional, Other, Institutional Clinical Trial: Genelux, Inc.; Financial Interests, Institutional, Other, Institutional clinical trial: Genentech; Financial Interests, Personal, Other, Travel reimbursement for robotic mentoring: Intuitive Surgical; Financial Interests, Personal, Other, Travel and meeting prep reimbursement for Co-Chair of Thoracic Malignancy Staging Committee: NIH/Coordinating Center for Clinical Trials. P.A. Bunn: Financial Interests, Personal, Other, editorial/ medical writing support: Genentech; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Ascentage; Financial Interests, Personal, Other, Consulting fees: CStone; Financial Interests, Personal, Other, Consulting fees: Imidex; Financial Interests, Personal, Other, Consulting fees: Viecure; Financial Interests, Personal, Other, Consulting fees: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Ascentage; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: CStone; Financial Interests, Personal, Advisory Board: Imidex; Financial Interests, Personal, Advisory Board: Viecure; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Leadership Role: Verastem,.H. Pass: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Research Grant: Delfi; Financial Interests, Personal, Research Grant: Micronoma; Financial Interests, Personal, Royalties: NCI (cell lines); Financial Interests, Personal, Speaker's Bureau: PER; Financial Interests, Personal, Speaker's Bureau: RTP; Financial Interests, Personal, Other, Patent: IL8 for Lung Cancer; Financial Interests, Personal, Leadership Role, Steering committee for Skyscaper: Genentech; Financial Interests, Personal, Leadership Role, Steering committee for IMpower: Genentech. E. Schum: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech. J. Carlisle, M. Weyant: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech. A. Nicholas, A. Johnson, D. Shames: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. I. I Wistuba: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Research Grant: Genentech; Financial Interests, Personal, Research Grant: HTG Molecular; Financial Interests, Personal, Research Grant: DepArray; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Medimmune; Financial Interests, Personal, Research Grant: Adaptive; Financial Interests, Personal, Research Grant: Adaptimmune; Financial Interests, Personal, Research Grant: EMD Serono; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Karus; Financial Interests, Personal, Research Grant: Johnson & Johnson; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Iovance; Financial Interests, Personal, Research Grant: 4D; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Akoya; Financial Interests, Personal, Other, Consulting Fees: Genentech/Roche; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Personal, Other, Consulting Fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Other, Consulting Fees: Pfizer; Financial Interests, Personal, Other, Consulting fees: HTG Molecular; Financial Interests, Personal, Other, Consulting fees: Asuragen; Financial Interests, Personal, Other, Consulting Fees: Merck; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Personal, Other, Consultant Fees: Guardant Health; Financial Interests, Personal, Other, Consultant fees: Flame; Financial Interests, Personal, Other, Consultant Fees: Novartis; Financial Interests, Personal, Other, Consutant fees: Sanofi; Financial Interests, Personal, Other, Consultant Fees: Daiichi Sankyo; Financial Interests, Personal, Other, Consultant Fees: Amgen; Financial Interests, Personal, Other, Consultant fees: Oncocyte; Financial Interests, Personal, Other, Consultant fees: MSD; Financial Interests, Personal, Speaker's Bureau: Medscape; Financial Interests, Personal, Speaker's Bureau: MSD; Financial Interests, Personal, Speaker's Bureau: Genentech/Roche; Financial Interests, Personal, Speaker's Bureau: Platform Health; Financial Interests, Personal, Speaker's Bureau: Pfizer; Financial Interests, Personal, Speaker's Bureau: AstraZeneca; Financial Interests, Personal, Speaker's Bureau: Merck. D.P. Carbone: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb KK (Japan); Financial Interests, Personal, Other, Consultant: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Daiichi Sankyo Inc.; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: EMD Serono/Merck; Financial Interests, Personal, Advisory Board: Flame Biosciences; Financial Interests, Personal, Other, Consultant: FENIX; Financial Interests, Personal, Other, Consultant: Genentech/Roche; Financial Interests, Personal, Other, Consultant: GI Therapeutics/ Intellisphere; Financial Interests, Personal, Advisory Board: Glaxo-Smith Kline; Financial Interests, Personal, Other, Consultant: Glaxo-Smith Kline; Financial Interests, Personal, Advisory Board: Gritstone; Financial Interests, Personal, Other, Consultant: Janssen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Other, Consultant: Mirati; Financial Interests, Personal, Other, Consultant: Novocure; Financial Interests, Personal, Other, Consultant: OncoCyte; Financial Interests, Personal, Other, Consultant: OncoHost; Financial Interests, Personal, Other, Consultant: Piper Sandler; Financial Interests, Personal, Other, Consultant: Roche China; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Other, Consultant: Seattle Genetics; Financial Interests, Personal, Other, editorial/ medical writng support: Genentech. K. Schulze: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. D.J. Kwiatkowski: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech.
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