Targeted therapies for resectable lung adenocarcinoma: ADAURA opens for thoracic oncologic surgeons.
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ABSTRACT:
SUBMITTER: Jones DR
PROVIDER: S-EPMC8519337 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
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Targeted therapies for resectable lung adenocarcinoma: ADAURA opens for thoracic oncologic surgeons.
Jones David R DR Wu Yi-Long YL Tsuboi Masahiro M Herbst Roy S RS
The Journal of thoracic and cardiovascular surgery 20210209 1
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Project description:BackgroundCardiopulmonary assessment for lung resection is important for risk stratification, and the American College of Chest Physicians (ACCP) guidelines provide decision support. We ascertained the cardiopulmonary assessment practices of thoracic surgeons and determined whether they are guideline concordant.MethodsAn anonymous survey was emailed to 846 thoracic surgeons who participate in The Society of Thoracic Surgeons General Thoracic Surgery Database. We analyzed survey responses by practice type (general thoracic [GT] versus cardiothoracic [CT]) and years in practice (0-9, 10-19, and ≥20) with the use of contingency tables. We compared adherence of survey responses with the guidelines.ResultsThe response rate was 24.0% (n = 203). Most surgeons (n = 121, 59.6%) cited a predicted postoperative forced expiratory volume in 1 second or diffusing capacity of lung for carbon monoxide threshold of 40% for further evaluation. Experienced surgeons (≥20 years) were more likely to have a threshold that varies by surgical approach (31.3% versus 23.5% with 10-19 years of experience and 15.9% for 0-9 years of experience, P = .007). Overall, 52.2% refer patients with cardiovascular risk factors to cardiology and 42.9% refer patients with abnormal stress testing. CT surgeons were more likely to refer all patients to cardiology than GT surgeons (17.6% versus 2.4%, P < .001). Only one respondent (0.5%) was 100% adherent to the ACCP guidelines, and 4.4% and 45.8% were 75% and 50% adherent, respectively.ConclusionsAmong thoracic surgeons, there is variation in preoperative cardiopulmonary assessment practices, with differences by practice type and years in practice, and marked discordance with the ACCP guidelines. Further study of guideline adherence linked to postoperative morbidity and mortality is warranted to determine whether adherence affects outcomes.
| S-EPMC11329212 | biostudies-literature
Project description:Gastroesophageal cancer (GEC) remains a major cause of cancer-related mortality worldwide. Although the incidence of distal gastric adenocarcinoma (GC) is declining in the United States, proximal esophagogastric junction adenocarcinoma (EGJ) incidence is rising. GC and EGJ, together, are treated uniformly in the metastatic setting as GEC. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to date-only first-line anti-HER2 therapy for ERBB2 amplification and second-line anti-VEGFR2 therapy. This article reviews aberrations in epidermal growth factor receptor, MET, and ERBB2, their therapeutic implications, and future directions in targeting these pathways.
| S-EPMC5446061 | biostudies-literature
Project description:BackgroundSmoking is a risk factor for complications after lung resection. Our primary aim was to ascertain thoracic surgeons' beliefs and practices on smoking cessation before lung resection.MethodsAn anonymous survey was emailed to 846 thoracic surgeons who participate in The Society of Thoracic Surgeons General Thoracic Surgery Database.ResultsThe response rate was 23.6% (n = 200). Surgeons were divided when asked whether it is ethical to require that patients quit smoking (yes, n = 96 [48%]) and whether it is fair to have their outcomes affected by patients who do not quit (yes, n = 87 [43.5%]). Most do not require smoking cessation (n = 120 [60%]). Of those who require it, the most common required period of cessation is 2 weeks or more. Most believe that patient factors are the main barrier to quitting (n = 160 [80%]). Risk of disease progression (39% vs 17.5%, p = 0.02) and alienating patients (17.5% vs 8.8%, p = 0.04) were very important considerations of those who do not require smoking cessation versus those who do. Only 19 (9.5%) always refer to a smoking cessation program and prescribe nicotine replacement therapy and even fewer, 9 (4.5%), always refer to a program and prescribe medical therapy.ConclusionsThoracic surgeons are divided on their beliefs and practices regarding smoking cessation before lung resection. Most believe patient factors are the main barrier to quitting and have concerns about disease progression while awaiting cessation. Very few surgeons refer to a smoking cessation program and prescribe nicotine replacement therapy or medical therapy.
| S-EPMC11292109 | biostudies-literature
Project description:PurposePatient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.Experimental designEighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.ResultsPDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non-small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions.ConclusionsWe demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
| S-EPMC9401503 | biostudies-literature
Project description:Gastroesophageal adenocarcinomas (GEA) are devastating diseases with stark global presence. Over the past 10 years, there have been minimal improvements in treatment approach despite numerous clinical trials. Here, we review recent progress toward understanding the molecular features of these cancers and the diagnostic and therapeutic challenges posed by their intrinsic genomic instability and heterogeneity. We highlight the potential of genomic heterogeneity to influence clinical trial outcomes for targeted therapies and emphasize the need for comprehensive molecular profiling to guide treatment selection and adapt treatment to resistance and genomic evolution. Revising our clinical approach to GEA by leveraging genomic advances will be integral to the success of current and future treatments, especially as novel targets become therapeutically tractable. SIGNIFICANCE: GEAs are deadly cancers with few treatment options. Characterization of the genomic landscape of these cancers has revealed considerable genetic diversity and spatial heterogeneity. Understanding these fundamental properties of GEA will be critical for overcoming barriers to the development of novel, more effective therapeutic strategies.
| S-EPMC7232941 | biostudies-literature
Project description:Immunotherapy, targeted therapy, and adoptive T-cell therapy have been revolutionary advancements in cancer research. Some of these therapies have become the standard of care for lung cancer and replaced older treatment algorithms; some continue to be studied in clinical trials. This article discusses the current state of novel treatment options for non-small cell lung cancer patients with metastatic and locoregional disease, with focus on immunotherapy, targeted therapy, and adoptive T-cell therapy.
| S-EPMC7388816 | biostudies-literature
Project description:ObjectiveAlthough minimally invasive techniques have led to shorter hospitalizations, discharge on postoperative day 1 is still uncommon. We hypothesized that day 1 discharge could be performed safely and that there might be significant variation in day 1 discharge rates between hospitals.MethodsWe identified patients with lung cancer who underwent lobectomy and segmentectomy in the Society of Thoracic Surgeons Database from 2012 to 2017. The 10% longest hospital stay outliers were excluded. A multivariable regression model was created to assess for factors associated with day 1 discharge and readmission.ResultsA total of 46,325 patients were examined, and 1821 patients (3.9%) were discharged on day 1. This rate increased from 3.4% to 5.3% over the course of the study (P < .0001). In multivariable analysis, factors associated with day 1 discharge included age, Zubrod score, body mass index greater than 25, forced expiration value at 1 second, middle or upper lobectomy, minimally invasive technique, and procedure time. Outpatient 30-day mortality was similar (0.3% vs 0.4%, P = .472). Patients discharged on day 1 were not at increased risk of readmission. Readmission after day 1 discharge was associated with male sex, coronary artery disease, chronic obstructive pulmonary disease, and longer procedure time. There was substantial variation in day 1 discharge rate between institutions, with 11 centers (4.0%) discharging more than 20% of their patients on day 1, whereas 102 centers (36.7%) had no day 1 discharges.ConclusionsDay 1 discharge after anatomic lung resection is uncommon but is becoming more common. Carefully selected patients may be discharged on day 1 without an increased risk of readmission or death.
| S-EPMC7890415 | biostudies-literature
Project description:Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ?1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696-713. ©2018 AACR.See related commentary by Strickler, p. 679This article is highlighted in the In This Issue feature, p. 663.
| S-EPMC5984701 | biostudies-literature
Project description:BackgroundThe objective of this study was to create a simple preoperative tool to assess the risk of prolonged air leak (PAL) using The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD).MethodsThe STS GTSD was queried for patients who underwent elective lung cancer resection between 2009 and 2016. Exclusion criteria included pneumonectomy, sleeve lobectomy, chest wall resection, bilateral procedures, and patients with incomplete data sets. The primary outcome was PAL exceeding 5 days. Multivariable logistic regression was used to identify risk factors for a PAL. Model coefficients were used to generate a PAL score (PALS). The approach was cross-validated in 100 replications of a training set consisting of two-thirds of the cohort that was randomly selected and a validation set of remaining patients.ResultsA total of 52,198 patients from the STS GTSD met inclusion criteria, with an overall rate of PAL of 10.4% (n = 5453). Final variables incorporated into the PALS included body mass index of 25 kg/m2 or less (7 points), lobectomy or bilobectomy (6 points), forced expiratory volume in 1 second of 70% predicted or less (5 points), male sex (4 points), and right upper lobe procedure (3 points). A cumulative PALS exceeding 17 points stratified patients as high-risk or low-risk for PAL (19.6% vs 9% rate of PAL) with a cross-validated mean negative predictive value of 91%, positive predictive value of 19%, sensitivity of 30%, specificity of 85%, and correctly classifies 79% of patients.ConclusionsThe PALS is a simple preoperative clinical tool that can reliably risk-stratify patients for PAL who are undergoing lung cancer resection.
| S-EPMC8693718 | biostudies-literature
Project description:Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major health burden due to its increasing incidence and poor prognosis. PDAC is characterized by a low tumor mutational burden, and its molecular pathogenesis is driven by Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Response to DNA damage through homologous repair is defective in 15% of tumors. Chemotherapy using FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) or gemcitabine-nab-paclitaxel significantly improves life expectancy, but the median overall survival remains <1 year. Targeted therapies are not efficient in the overall population of patients with metastatic PDAC. Improvements in overall survival or progression-free survival, however, have been demonstrated in subgroups carrying certain mutations. Maintenance therapy with poly-ADP-ribose polymerase (PARP) inhibitors increases progression-free survival in patients with germline mutations in BRCA1/2. Sotorasib shows signs of efficacy against tumors carrying the KRAS G12C mutation, and targeted therapies may also benefit patients with KRAS-wild-type PDAC. Combining targeted therapies with chemotherapy holds promise because of potential synergistic effects. These associations, however, have not yet demonstrated clinical benefit. Checkpoint inhibitors are not effective against metastatic PDAC. Combined immunotherapies attempt to restore their efficacy but have not succeeded yet. Other immunotherapies are emerging such as therapeutic vaccines or chimeric antigen receptor (CAR) T cells, but these strategies remain to be evaluated in large trials. In the future, treatment personalization based on tumor-derived organoids could potentially further improve treatment efficiency.
| S-EPMC9674888 | biostudies-literature