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 |
REPOSITORIES: biostudies-literature
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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.
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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.
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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: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: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:The Society of Thoracic Surgeons (STS) creates risk-adjustment models for common cardiothoracic operations for quality improvement purposes. Our aim was to update the lung cancer resection risk model utilizing the STS General Thoracic Surgery Database (GTSD) with a larger and more contemporary cohort.We queried the STS GTSD for all surgical resections of lung cancers from January 1, 2012, through December 31, 2014. Logistic regression was used to create three risk models for adverse events: operative mortality, major morbidity, and composite mortality and major morbidity.In all, 27,844 lung cancer resections were performed at 231 centers; 62% (n = 17,153) were performed by thoracoscopy. The mortality rate was 1.4% (n = 401), major morbidity rate was 9.1% (n = 2,545), and the composite rate was 9.5% (n = 2,654). Predictors of mortality included age, being male, forced expiratory volume in 1 second, body mass index, cerebrovascular disease, steroids, coronary artery disease, peripheral vascular disease, renal dysfunction, Zubrod score, American Society of Anesthesiologists rating, thoracotomy approach, induction therapy, reoperation, tumor stage, and greater extent of resection (all p < 0.05). For major morbidity and the composite measure, cigarette smoking becomes a risk factor whereas stage, renal dysfunction, congestive heart failure, and cerebrovascular disease lose significance.Operative mortality and complication rates are low for lung cancer resection among surgeons participating in the GTSD. Risk factors from the prior lung cancer resection model are refined, and new risk factors such as prior thoracic surgery are identified. The GTSD risk models continue to evolve as more centers report and data are audited for quality assurance.
| S-EPMC5016798 | biostudies-literature
Project description:The role of surgical resection in patients with clinical stage IIIA-N2 positive (cIIIA-N2) lung cancer is controversial, partly because of the variability in short- and long-term outcomes. The objective of this study was to characterize the management of cIIIA-N2 lung cancer in The Society of Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD).The STS-GTSD was queried for patients who underwent operations for cIIIA-N2 lung cancer between 2002 and 2012. A subset of patients aged older than 65 years was linked to Medicare data.Identified were 3,319 surgically managed, cIIIA-N2 patients, including 1,784 (54%) treated with upfront resection (treatment naïve upfront surgery group, and 1,535 (46%) with induction therapy. A positron emission tomography scan was documented in 93% of patients, and 51% of patients were coded in STS-GTSD as having undergone invasive mediastinal staging. Nodal overstaging (cN2?pN0/N1) was observed in 43% of upfront surgery patients. Lobectomy was performed in 69% of patients and pneumonectomy in 11%. Operative mortality was similar between patients treated with upfront surgery (1.9%) and induction therapy (2.5%, p = .2583). The unadjusted Kaplan-Meier estimate of 5-year survival of cIII-N2 patients treated with induction therapy then resection was 35%.STS surgeons achieve excellent short- and long-term results treating predominantly lobectomy-amenable cIIIA-N2 lung cancer. However, prevalent overstaging and abstention from induction therapy suggest "overcoding" of false positives on imaging or variable compliance with current guidelines for cIIIA-N2 lung cancer. Efforts are needed to improve clinical stage determination and guideline compliance in the GTSD for this cohort.
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Project description:Orai3 channel has emerged as important player in malignant transformation. Indeed, its expression is increased in cancer and favors cell proliferation and survival by permitting calcium influx. In this study, Orai3 was overexpressed in lung adenocarcinoma as compared to their matched non-tumour samples and was associated with tumoural aggressiveness. Moreover, its expression was associated with estrogen receptor alpha (ER?) expression and visceral pleural invasion in multivariate analysis. Furthermore, both the overall survival (OS) median and the metastasis free survival (MFS) median of tumors with high Orai3 expression were lower than in low Orai3 expression regardless of cancer stage (35.01 months vs. 51.11 months for OS and 46.01 months vs. 62.04 months for MFS). In conclusion, Orai3 protein level constitutes an independent prognostic marker in lung adenocarcinoma, and a novel prognostic marker that could help selecting the patients with worst prognosis to be treated with adjuvant chemotherapy in resectable stage.
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Project description:Until recently, the majority of genomic cancer research has been in discovery and validation; however, as our knowledge of tumor molecular profiling improves, the idea of genomic application in the clinic becomes increasingly tangible, paralleled with the drug development of newer targeted therapies. A number of profiling methodologies exist to identify biomarkers found within the patient (germ-line DNA) and tumor (somatic DNA). Subsequently, commercially available clinical assays to test for both germ-line and somatic alterations that are prognostic and/or predictive of disease outcome, toxicity or treatment response have significantly increased. This review aims to summarize clinically relevant cancer biomarkers that serve as targets for therapy and their potential relationship to lung cancer. In order to realize the full potential of genomic cancer medicine, it is imperative that clinicians understand these intricate molecular pathways, the therapeutic implication of mutations within these pathways, and the availability of clinical assays to identify such biomarkers.
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