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Introduction: Germline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer., Methods: We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing., Results: We identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and an EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), white (86.4%), had a family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%). Among the 18 with advanced-stage NSCLC, 12 patients (66.7%) were treated with first-line osimertinib, demonstrating a median progression-free survival (PFS) of 16.9 months (95% confidence interval [CI]: 6.3-not reached [NR]). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), median PFS was 20.4 months (95% CI: 6.3-NR) and median overall survival was 82.0 months (95% CI: 28.4-NR)., Conclusions: Based on our institutional cohort, NSCLC driven by EGFR germline mutations occurs more frequently in non-smoking, white females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC., Competing Interests: Disclosure Dr. Elamin reports receiving research support from AstraZeneca, Spectrum Pharmaceuticals, and Takeda Pharmaceuticals; and has served on scientific advisory Boards for AstraZeneca, Eli Lilly, Novartis, Spectrum Pharmaceuticals, Sanofi, Takeda Pharmaceuticals, Turning Point Therapeutics, and Bristol-Myers Squibb. Dr. Zhang reports serving on the consulting/advisory board of Bristol-Myers Squibb, AstraZeneca, Novartis, Johnson & Johnson, GenePlus, Innovent, Varian, and Catalyst; receiving research grants to the institution from Merck, Novartis, and Johnson & Johnson. Dr. Negrao reports receiving research funding to institution from Mirati, Novartis, Checkmate, Alaunos, AstraZeneca, Pfizer, Genentech, and Navire; serving on the consultant/advisory board of Mirati, Merck/Merck Sharp & Dohme, Novartis, and Genentech; and receiving other support from Ziopharm Oncology, Apothecom, and Ashfield Healthcare. Dr. Altan reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, Gilead, Lyell, and Insightec and speaker fees from AstraZeneca, Nektar Therapeutics, SITC, and ASTRO, as well as participation on the safety review committee for the Nanobiotix-MDA Alliance, and is on the Hengenix Advisory Board for GlaxoSmithKline, Shattuck Lab, Bristol Myers Squibb, and AstraZeneca. Dr. Skoulidis reports receiving research grants to the institution from Revolution Medicines, Mirati Therapeutics, Pfizer, Merck, Amgen, and Novartis; serving on the consulting/advisory board of AstraZeneca, Amgen, Novartis, BeiGene, Guardant Health, Bergen Bio, Navire Pharma, Tango Therapeutics, Calithera Biosciences, Intellisphere LLC, and Medscape LLC; receiving honoraria from VSPO Mc Gill Universite de Montreal and RV Mais Promocao Eventos LTDS; receiving meeting support/travel grant from Amgen, Tango Therapeutics, and Dava Oncology; and having stock from Moderna and BioNTech SE. Dr. Tsao reports receiving research funding to the institution from Ariad, Bristol-Myers Squibb, Eli Lilly, Genentech, Millennium, Polaris, AstraZeneca, Boehringer Ingelheim, Epizyme, Merck, Novartis, and Seattle Genetics; serving on the consulting/advisory board of Ariad, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, EMD Serono, GlaxoSmithKline, Novartis, and Roche. Dr. Cascone reports receiving speaker fees/honoraria from Society for Immunotherapy of Cancer (SITC), Mark Foundation for Cancer Research, Bristol-Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians' Education Resource LLC (PER), OncLive, and PeerView; having consulting/advisory role from MedImmune/AstraZeneca, Bristol-Myers Squibb, Merck, Genentech, Arrowhead Pharmaceuticals, Pfizer Inc., and Regeneron; receiving travel, food, and beverage expenses from Physicians' Education Resource LLC (PER), Dava Oncology, SITC, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, IDEOlogy Health, OncLive, MedImmune/AstraZeneca, and Bristol-Myers Squibb; and receiving research funding to institution from MedImmune/AstraZeneca, Bristol-Myers Squibb, and EMD Serono. Dr. Heymach reports having stock and other ownership interests from Cardinal Spine and Bio-Tree; having consulting or advisory roles from AstraZeneca, Bristol-Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Lilly, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Catalyst Biotech, Foundation medicine, Novartis, Mirati Therapeutics, BrightPath Biotherapeutics, Janssen, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, and Leads Biolabs; receiving research funding to institution from AstraZeneca (Inst), Spectrum Pharmaceuticals, and GlaxoSmithKline; having patents, royalties, and other intellectual property on licensing agreement between Spectrum and MD Anderson (including Dr. Heymach himself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations. Dr. Ostrin reports consulting/ travel fees from GeneSystems, participation on the scientific advisory board of Grail, and receiving an honorarium from the Texas Association of Family Practitioners. Dr. Le reports consulting/advisory fees from Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, and AbbVie, research funding to Institution from Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim, and Travel Support from EMD Serono, Janssen, and Spectrum Pharmaceutics. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objectives : Patients with type 2 diabetes (T2D) have a high prevalence of non-alcoholic fatty liver disease (NAFLD) (55%) and are at increased risk for developing non-alcoholic steatohepatitis, a severe form of NAFLD. Early detection of advanced fibrosis in patients with T2D and NAFLD is crucial and can prevent progression to chronic liver disease, cirrhosis, and hepatocellular carcinoma. However, screening for liver disease and risk-stratification pathways are not established in patients with T2D. We evaluated the efficacy of using the automated fibrosis-4 (FIB-4) index in routine clinical settings to identify patients requiring further specialist evaluation. Materials and Methods : In this prospective cohort study, individuals diagnosed with T2D were recruited from diabetes clinics at a tertiary university hospital. Demographic, clinical, and laboratory data were comprehensively collected. The FIB-4 index was automatically calculated and integrated into the hospital's electronic medical records (EMRs), which were then stratified by age. Patients with advanced fibrosis (FIB-4 index ≥ 1.3) were referred to a specialist. Student's t -test or the Mann-Whitney U test was used to analyze variables associated with advanced fibrosis. Logistic regression was used to identify predictors of advanced fibrosis. Results : Among the 318 patients with T2D, 9.7% had advanced fibrosis. The majority were females (54.7%) and Saudi nationals (89.6%). Several factors, including age, platelet count, total bilirubin, serum albumin, total cholesterol, low-density lipoprotein, transaminases, and gamma-glutamyl transferase (GGT), showed significant associations with advanced fibrosis (all p < 0.05). Older age, elevated total bilirubin and GGT levels, and prolonged international normalized ratio emerged as independent predictors of advanced fibrosis. Conclusions : Integrating the FIB-4 index into the EMR during the routine care of patients with T2D proved to be a valuable tool in effectively identifying individuals at risk of advanced fibrosis. Our findings emphasize the need for further research to refine screening strategies in this high-risk population.

Introduction: NSCLC transformation to SCLC has been best characterized with EGFR -mutant NSCLC, with emerging case reports seen in ALK , RET , and KRAS -altered NSCLC. Previous reports revealed transformed SCLC from EGFR -mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed TP53 and RB1 loss of function increase the risk of SCLC transformation. Little has been reported on the detailed clinicogenomic characteristics and potential therapeutic targets for this patient population., Methods: In this study, we conducted a single-center retrospective analysis of clinical and genomic characteristics of patients with EGFR -mutant NSCLC transformed to SCLC. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. Kaplan-Meier analyses were used to estimate survival outcomes. Next generation sequencing-based assays was used to identify EGFR and co-occurring genetic alterations in tissue or plasma before and after SCLC transformation. Single-cell RNA sequencing (scRNA-seq) was performed on a patient-derived-xenograft model generated from a patient with EGFR-NSCLC transformed SCLC tumor., Results: A total of 34 patients were identified in our study. Median age at initial diagnosis was 58, and median time to SCLC transformation was 24.2 months. 68% were female and 82% were never smokers. 79% of patients were diagnosed as stage IV disease, and over half had brain metastases at baseline. Median overall survival of the entire cohort was 38.3 months from initial diagnoses and 12.4 months from time of SCLC transformation. Most patients harbored EGFR exon19 deletions as opposed to exon21 L858R alteration. Continuing EGFR tyrosine kinase inhibitor post-transformation did not improve overall survival compared with those patients where tyrosine kinase inhibitor was stopped in our cohort. In the 20 paired pretransformed and post-transformed patient samples, statistically significant enrichment was seen with PIK3CA alterations (p = 0.04) post-transformation. Profiling of longitudinal liquid biopsy samples suggest emergence of SCLC genetic alterations before biopsy-proven SCLC, as shown by increasing variant allele frequency of TP53, RB1, PIK3CA alterations. ScRNA-seq revealed potential therapeutic targets including DLL3, CD276 (B7-H3) and PTK7 were widely expressed in transformed SCLC., Conclusions: SCLC transformation is a potential treatment resistance mechanism in driver-mutant NSCLC. In our cohort of 34 EGFR -mutant NSCLC, poor prognosis was observed after SCLC transformation. Clinicogenomic analyses of paired and longitudinal samples identified genomic alterations emerging post-transformation and scRNA-seq reveal potential therapeutic targets in this population. Further studies are needed to rigorously validate biomarkers and therapeutic targets for this patient population., (© 2024 by the International Association for the Study of Lung Cancer.)

Previous evidence has shown an association between serum ferritin and bilirubin levels in the development of type 2 diabetes mellitus (T2DM) and glycemic control. However, the evidence is scarce in Saudi Arabia. In this study, we aimed to evaluate the association between serum ferritin and bilirubin levels with glycemic control in patients with T2DM. This was a cross-sectional study that involved 153 patients with T2DM recruited from outpatient diabetes clinics. Participants were categorized into two groups: well-controlled and uncontrolled T2DM, based on their glycemic status. We focused on comparing the iron profile and bilirubin levels between these two groups and examining the influence of antidiabetic medications on these parameters. A total of 153 patients with T2DM were included (58.2% women and 41.8% men). In both univariate and multivariate analyses, ferritin levels did not have a statistically significant association with glycemic control. However, patients with well-controlled T2DM had a significantly higher median level of total bilirubin and direct bilirubin than those with uncontrolled T2DM. Only direct bilirubin showed a statistically significant association with FBG less than 130 mg/dl and HbA1c level less than 7.0%. Ferritin level was not associated with glycemic control in patients with T2DM. On the other hand, direct bilirubin level was an independent predictor of better glycemic control. Monitoring direct bilirubin levels could aid in predicting glycemic control in T2DM and could be a potential target for developing antidiabetic medications., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s).)

Purpose: We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC)., Patients and Methods: Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary end point was objective response rate (ORR) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Simon's optimal two-stage design tested the null hypothesis of ORR ≤5% versus ORR ≥20% at 6 months; ≥4 responses in 29 patients would reject the null hypothesis., Results: Forty patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (six screen failures; six evaluable for safety only). The confirmed ORR was 18% (95% CI, 6.1 to 36.9); there was one unconfirmed partial response (PR). Two patients achieved PR after 6 months; thus, the ORR at 6 months was 14%. The median follow-up time for surviving patients was 22 months (95% CI, 16.6 to 39.1 months). The median PFS was 7.3 months (95% CI, 3.7 to 11.2 months), 6-month PFS rate was 57% (95% CI, 41 to 78), and median OS was 16.6 months (95% CI, 12.4 to not reached months). Most common treatment-related adverse events (TRAEs) included fatigue (62%), hypertension (32%), and diarrhea (32%). Ten (29%) patients had serious TRAEs, all grade 3; four patients (12%) discontinued avelumab, and nine patients (26%) underwent axitinib dose reduction., Conclusion: The study reached its primary end point with ≥4 PRs in 28 evaluable patients (confirmed ORR of 18%). The potential added benefit of avelumab to axitinib in ACC requires further investigation.

Background: Obstructive sleep apnea (OSA) is a prevalent disease that is associated with an increased incidence of type II diabetes mellitus (DM) if left untreated. We aimed to determine the association between glycosylated hemoglobin (HbA1c) levels and both nocturnal hypoxemia and apnea-hypopnea index (AHI) among a Saudi patients with OSA., Methods: A cross-sectional study that enrolled 103 adult patients diagnosed with DM and confirmed to have OSA by full night attended polysomnography between 2018 and 2021. Those who presented with acute illness, chronic obstructive pulmonary disease (COPD)/restrictive lung diseases causing sleep-related hypoxemia, or no available HbA1c level within 6 months before polysomnography were excluded from the study. Univariate and multivariate linear regression analyses between HbA1c levels and parameters of interest were tested., Results: Sixty-seven (65%) of the studied population had uncontrolled DM (HbA1c ≥7%). In univariate regression analysis, there was a significant positive association between HbA1c, and sleep time spent with an oxygen saturation below 90% (T90), female gender, and body mass index (BMI) (p<0.05) but not AHI, or associated comorbidities (p>0.05). In the multivariate analysis, HbA1c was positively associated with increasing T90 (p<0.05), and ODI (p<0.05), but not with AHI (p>0.05)., Conclusion: Nocturnal hypoxemia could be an important factor affecting glycemic control in patients with OSA suffering from DM irrespective of the severity of both diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mahmoud, Alotaibi, Almusally, Shafiek, Elamin, Alhaj, AlBaker, Elfaki, Qutub, Albahrani, Alabdrabalnabi, Al Saeed, Al Argan, Al.Rubaish, Alqurashi, Jatoi, Alharmaly, Almubarak, Al Said and Albahrani.)

Purpose: Local consolidative therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment paradigm. We investigated whether the biologically effective dose (BED) of consolidative radiation therapy (RT) to the primary tumor predicted for improved local control, progression-free survival (PFS), and overall survival (OS) among NSCLC patients presenting with oligometastatic disease., Materials and Methods: Patients presenting to a single institution (2000-2017) with stage IV NSCLC, ≤3 synchronous metastatic lesions at diagnosis, and treated with RT to the primary tumor were identified. Univariate and multivariable Cox proportional-hazards regression modeling were performed to identify factors associated with local recurrence-free survival (LRFS), PFS, and OS., Results: One hundred twenty-four patients were identified meeting our inclusion criteria. With a median follow-up of 55.1 months, median PFS and OS for the entire cohort were 11.0 months and 25.3 months, respectively. The median BED (α/β = 10) of RT to the primary tumor was 74.3 Gy. On univariate analysis, increased BED to the primary tumor predicted for improved PFS (p < 0.001) and LRFS (p = 0.01), with a median PFS of 8.5 vs 12.8 months and median LRFS of 23.4 vs 58.4 months between patients treated with BED < 75 Gy and ≥75 Gy, respectively. Increased BED to the primary tumor was also associated with significantly improved OS (p = 0.02); patients treated with a BED of <75 Gy demonstrated a median OS of 22.9 months vs 27.5 months if treated with BED ≥ 75 Gy. On multivariable analysis, primary site BED remained a significant predictor of OS (p = 0.02) and PFS (p = 0.002)., Conclusions: We found that delivery of >75 Gy BED RT regimens to the primary lesion in patients with synchronous oligometastatic NSCLC is associated with improved local control, PFS, and OS. These data support results of recent prospective trials and other ongoing prospective efforts to characterize therapeutic benefits associated with this management strategy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives : The main aim of the present study was to assess the use of androgenic-anabolic steroids (AAS) and to investigate its potentially unfavorable effects among gym members attending gym fitness facilities in Eastern Province, Saudi Arabia. Materials and Methods : A cross-sectional questionnaire-based study was carried out during the summer of 2017. Male gym users in the Eastern Province region of Saudi Arabia were the respondents. Information on socio-demographics, use of AAS, knowledge, and awareness about its side effects were collected using a self-administered questionnaire. Results: The prevalence of AAS consumption among trainees in Eastern Province was 21.3%. The percentage was highest among those 26-30 years of age (31.9%), followed by the 21-25 (27.4%) ( p = 0.003) age group. Participants in the study were not aware of the potential adverse effects of AAS use. Adverse effects experienced by 77% of AAS users include psychiatric problems (47%), acne (32.7%), hair loss (14.2%), and sexual dysfunction (10.7%). Moreover, it appears that trainers and friends are major sources (75.20%) for obtaining AAS. Conclusion: AAS abuse is a real problem among gym members, along with a lack of knowledge regarding its adverse effects. Health education and awareness programs are needed not only for trainees, but also for trainers and gym owners as they are reportedly some of the primary sources of AAS.

Background: Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear., Methods: Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies., Results: Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05)., Conclusions: PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood., Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response., Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth., Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The treatment of patients with EGFR-mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides a greater benefit than EGFR inhibition alone, suggesting that EGFR mutation status may define a patient subgroup with greater benefit from VEGF blockade. The mechanisms driving this potentially enhanced VEGF dependence are unknown., Methods: We analyzed the effect of EGFR inhibition on VEGF and HIF-1α in NSCLC models in vitro and in vivo. We determined the efficacy of VEGF inhibition in xenografts and analyzed the impact of acquired EGFR inhibitor resistance on VEGF and HIF-1α., Results: NSCLC cells with EGFR-activating mutations exhibited altered regulation of VEGF compared with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of HIF-1α and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and a combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, whereas VEGF remained overexpressed, the hypoxia-independent expression of HIF-1α was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1α or VEGF expression., Conclusions: In EGFR-mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1α and VEGF in a hypoxia-independent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1α and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFR-mutant tumors in the EGFR inhibitor-naive and refractory settings., (Copyright © 2020. Published by Elsevier Inc.)

Selpercatinib, a novel, highly selective and potent, inhibitor of RET , demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Background: The main goal of management in patients with non-small cell lung cancer (NSCLC) and malignant pleural effusion (MPE) is palliation. Patients with MPE and actionable mutations, because their disease is expected to respond quickly and markedly to targeted therapy, are less likely than those without actionable mutations to receive definitive MPE management. Whether such management is indicated in these patients is unclear., Research Questions: What is the time to ipsilateral MPE recurrence requiring intervention in patients with metastatic NSCLC by mutation status? What are the risk factors for MPE recurrence?, Study Design and Methods: Retrospective cohort study of consecutive patients who underwent initial thoracentesis for MPE. We used a Fine-Gray subdistribution hazard model to calculate the time to ipsilateral MPE recurrence requiring intervention within 100 days of initial thoracentesis and to identify variables associated with time to pleural fluid recurrence., Results: A total of 396 patients, comprising 295 (74.5%) without and 101 (25.5%) with actionable mutations, were included. Most patients with actionable mutations (90%) were receiving targeted treatment within 30 days of initial thoracentesis. On univariate analysis, patients with actionable mutations showed a significantly higher hazard of MPE recurrence. On multivariate analysis, this difference was not significant. Larger pleural effusion size on chest radiography (P < .001), higher pleural fluid lactate dehydrogenase (P < .001), and positive cytologic examination results (P = .008) were associated with an increased hazard of recurrence., Interpretation: Our findings indicate that patients with actionable mutations have a similar risk of MPE recurrence when compared with patients without mutations and would benefit from a similar definitive management approach to MPE., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance., Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development., Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors., Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

Purpose: To test the hypothesis that the US Food and Drug Administration approval of vismodegib in early 2012 has reduced the prevalence of orbital exenteration for locally advanced periocular basal cell carcinoma (BCC)., Methods: Following institutional review board approval, the authors reviewed clinical and pathological data of patients with locally advanced periocular BCC (T4 per the eyelid carcinoma classification in the 8th edition of the AJCC Cancer Staging Manual) treated by the senior author during 2006-2018. Patients were grouped into those who were treated before February 2012 ("before vismodegib approval") and those who presented later ("after vismodegib approval")., Results: Forty-two patients with locally advanced periocular BCC were treated during the study period, of whom 31 were men. The median age at presentation was 66 years (range, 43-90). Twenty-two patients had T4a and 20 had T4b tumors. Thirteen patients were treated before and 29 were treated after vismodegib approval. The 2 groups did not differ in age distribution (p = 0.164), sex distribution (p = 0.270), prevalence of recurrent tumor at presentation (p = 0.317), or duration of treatment with vismodegib (p = 0.605). Orbital exenteration was significantly more prevalent in patients treated before vismodegib approval than after (46% vs. 10%, p = 0.016), and vismodegib treatment was significantly more prevalent in patients treated after vismodegib approval than before (when vismodegib was given in clinical trials; 69% vs. 23%, p = 0.008). There was a trend toward more patients retaining their eyes at last follow-up in patients treated after vismodegib approval (83% vs. 54%, p = 0.066)., Conclusions: The prevalence of orbital exenteration as a necessary surgical procedure in patients with a locally advanced periocular BCC has fallen since the Food and Drug Administration approval of vismodegib. Although vismodegib is not specifically approved for organ-sparing, it has changed the authors' practice and enabled eye preservation in patients with locally advanced periocular BCC, who would otherwise require an orbital exenteration.

Purpose: Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR -mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described., Experimental Design: Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients., Results: In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02)., Conclusions: Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients. See related commentary by Devarakonda and Govindan, p. 6112 ., (©2018 American Association for Cancer Research.)