Cell Lung Cancer Patients Research Articles

RNA methyltransferase METTL3 induces intrinsic resistance to gefitinib by combining with MET to regulate PI3K/AKT pathway in lung adenocarcinoma.

Clinical research data show that gefitinib greatly improves the progression‐free survival of patients, so it is used in advanced non‐small cell lung cancer patients with EGFR mutation. However, some patients with EGFR sensitive mutations do not have good effects on initial gefitinib treatment, and this mechanism is rarely studied. METTL3, a part of N6‐adenosine‐methyltransferase, has been reported to play an important role in a variety of tumours. In this study, we found that METTL3 is up‐regulated in gefitinib‐resistant tissues compared to gefitinib‐sensitive tissues. Cell function experiments have proved that under the treatment of gefitinib, METTL3 knockdown promotes apoptosis and inhibits proliferation of lung cancer cells. Mechanistic studies have shown that METTL3 combines with MET and causes the PI3K/AKT signalling pathway to be manipulated, which affects the sensitivity of lung cancer cells to gefitinib. Therefore, our research shows that METTL3 can be used as a molecular marker to predict the efficacy of EGFR‐TKI therapy in patients, and METTL3 may be a potential therapeutic target.

Initial experience of patients treated in a real-world clinical setting with bevacizumab-awwb: The first FDA-approved biosimilar to bevacizumab.

81 Background: Bevacizumab-awwb is the first anti-cancer biosimilar and the first biosimilar to bevacizumab approved by the FDA. It was launched in the United States on July 19, 2019. Bevacizumab-awwb approval was based on a phase 3 study in a pre-determined sensitive population of non-squamous non-small cell lung cancer (NSCLC) patients. This study investigated initial use of bevacizumab-awwb, across its approved indications for advanced cancer management, in real-world US community and academic oncology practices. Methods: This retrospective observational study described demographic and clinical characteristics of patients who received bevacizumab-awwb using structured patient-level data from the nationwide de-identified Oncology Services Comprehensive Electronic Records (OSCER), a Flatiron Health EHR-derived database. The database is longitudinal, demographically and geographically diverse, and includes more than 2.2 million US cancer patients from >280 cancer clinics. This analysis included adult patients who received ≥1 bevacizumab-awwb infusion between July 30, 2019 and April 30, 2020 and focused on describing initial biosimilar uptake in cancer patient populations beyond NSCLC. Results: First use of bevacizumab-awwb was in mCRC and occurred within 10 days of product launch. All bevacizumab-awwb approved cancer indications were represented among 2,422 patients treated with bevacizumab-awwb. Initial use of bevacizumab-awwb across indications: mCRC (68%), NSCLC (14%), brain cancer (11%), cervical cancer (5%), metastatic renal cell carcinoma (1%). Among 1657 mCRC patients treated with bevacizumab-awwb, 55% were male with a median age of 65 years (y). Most patients were white (60%), with ECOG scores of 0/1 (84%), and median body weight was 78 kg. Among mCRC patients, 59% had received the reference product before receiving the biosimilar. Among patients with other tumor types, 42-50% had prior bevacizumab exposure. Among mCRC patients with prior exposure to bevacizumab, 67% received bevacizumab-awwb within 28 days of last infusion of reference product (Table). Demographic and clinical characteristics were comparable between patients with and without prior bevacizumab use. Conclusions: Early evidence suggests physicians are comfortable initiating or transitioning patients to the first FDA-approved biosimilar to bevacizumab, with little evidence that demographic characteristics differ between patients with and without previous treatment with bevacizumab. Future analyses will determine whether these patterns persist across all indications. [Table: see text]

The use of COLD-PCR and pyrosequencing for sensitive detection of EGFR T790M mutation

A sensitive and convenient method for the detection of epidermal growth factor receptor (EGFR) T790M mutation in non-small cell lung cancer (NSCLC) patients with acquired resistance to tyrosine kinase inhibitors (TKIs) would be desirable to guide treatment strategy. Consequently, studies have focused on sensitive characterization of EGFR T790M mutation. Herein, two methods of co-amplification at lower denaturation temperature PCR (COLD-PCR) and pyrosequencing were combined (COLDPCR/ pyrosequencing) for detecting EGFR T790M mutation. Evaluation of mutation-containing dilutions revealed that the sensitivities of COLD-PCR/pyrosequencing and conventional PCR/pyrosequencing assays for the detection of the T790M mutation were 0.1 and 5%, respectively, indicating a 50-fold increase in sensitivity. When the T790M mutation in 20 clinical NSCLC samples who had relapsed under firstgeneration EGFR TKI were further determined using COLD-PCR/pyrosequencing and conventional PCR/pyrosequencing, the detection rates were 35% (7/20) and 25% (5/20), respectively. All patients who were positive for the T790M mutation with conventional PCR/pyrosequencing were also found to be positive with COLD-PCR/pyrosequencing. The discordant cases were 2 samples with no T790M mutation detected with conventional PCR/pyrosequencing, but which were positive with COLD-PCR/pyrosequencing. COLD-PCR/pyrosequencing is a sensitive and cost-effective tool for detecting the T790M mutation which will permit an improvement of therapeutic management.

Effect of Intensity Modulated Radiotherapy (IMRT) on the immunity, physical status and clinical effect of locally advanced NSCLC patients.

Objectives:To evaluate the clinical value of radiotherapy combined with Camrelizumab in treating locally advanced non-small cell lung cancer (NSCLC) patients.Methods:80 locally advanced NSCLC patients were randomly divided into two groups (n=40). The control group was administered with intensity modulated radiation therapy (IMRT), whereas the experimental group with Camrelizumab in addition to IMRT. All the patients underwent clinical efficacy evaluation in terms of adverse drug reaction (ADR), physical status improvement after the treatment, and changes in T lymphocyte subpopulations (incl. CD3+, CD4+, CD8+, CD4+/CD8+).Results:The efficacy was found to be 70% and 47.5 in experimental group and control group, respectively, with the former being significantly better than the latter (p=0.03). The ADR rates were 50% and 37.5% in the experimental group and control group, respectively; but the difference remained insignificant (p=0.26). As for physical status improvement, experimental group evidently excelled the control group (p=0.04). The post-treatment indicators such as CD3+, CD4+, CD8+, CD4+/CD8+ were significantly more improved in the experimental group than the control group (CD3+, p=0.02; CD4+, p=0.00; and CD4+/CD8+, p=0.01). However, the changes in CD8+ were not significant at all (p=0.46).Conclusions:The combined therapy of IMRT with Camrelizumab appeared effective in dealing with the locally advanced NSCLC patients, as such patients presented significantly better immune state and physical status improvement but not increased ADR. The therapy is both safe and effective.

Evaluation of the relationship between the range of radiation-induced lung injury on CT images after IMRT for stage I lung cancer and dosimetric parameters

Background This study evaluated the correlation between radiation-induced lung injury (RILI) and dosimetric parameters on computed tomography (CT) images of stage I non-small cell lung cancer (NSCLC) patients undergoing intensity-modulated radiotherapy (IMRT). Materials and methods Sixty-three stage I NSLC patients who underwent IMRT were enrolled in the study. The patients underwent CT within 6 months (acute phase) and 1.5 years (late phase) after radiotherapy. These were fused with the planned irradiation CT. The range of RILI was measured from 10% to 100%, with an IC in 10% increments. Results The median interval from completion of radiotherapy to acute and late phase CT was 92 and 440 days, respectively. The median RILI ranges of the acute and late phases were in the 80% (20–100%) and 70% dose regions (20–100%), respectively. The significantly narrower range of RILI when lung V20 in the acute phase was less than 19.2% and that of V5 in the late phase was less than 27.6% at the time of treatment planning. Conclusions This study showed that RILI occurred in a localized range in stage I NSCLC patients who underwent IMRT. The range of RILI was correlated with V20 in the acute phase and V5 in the late phase. KEY MESSAGES RILI correlated with V20 in acute and V5 in late phase. The shadow of RILI occurred in 80% dose region in acute and 70% in late phase. No relationship exists between radiographic changes in RILI and PTV volume.

Developing Genomic Predictive Biomarkers for Survival Benefit from Adjuvant Chemotherapy in Early-Stage Lung Cancer Patients for Personalized Medicine

Surgical resection only remains the standard choice for the treatment of early-stage non-small cell lung cancer (NSCLC) patients. Preliminary studies suggest that the application of adjuvant chemotherapy with surgery (ACT) is associated with a better prognosis for more severe NSCLC patients compared to those who only underwent surgical resection. However, at an individual level, not all patients may benefit from ACT. Given the well-known adverse effects and toxicity of ACT, finding the patients that are most likely to benefit from ACT is paramount. Thus, the purpose of this research is to utilize gene expression and clinical data from lung cancer patients to develop a statistical decision support algorithm to find predictive genomic biomarkers and identify subgroups of patients who benefit from ACT. Cox regression models are trained using a randomized controlled trial gene expression data from the National Center for Biotechnology Information (NCBI) utilizing explicit treatment interaction terms. To handle high dimensions inherent in gene expression data, a regularized Cox regression model with lasso penalty is applied to find the most significant interacting markers. Risk scores are estimated from the proposed model and are used to stratify patients into a high risk or low risk group respective to ACT treatment. After applying the model to an independent validation genomic data set, we show that patients who underwent the recommended treatment according to their risk group estimated by our proposed algorithm exhibit a slightly higher survival rate than those who do not.

Survival benefit from immunocheckpoint inhibitors in stage IV non-small cell lung cancer patients with brain metastases: A National Cancer Database propensity-matched analysis.

Immunocheckpoint inhibitors (ICIs) have become a standard pharmacological therapy in non‐small cell lung cancer (NSCLC). Because brain metastases (BMs) have historically been listed as exclusion criteria in previous clinical trials involving ICIs in advanced NSCLC, the survival benefit from ICI in NSCLC patients with BMs remains unclear. The National Cancer Database was queried for stage IV NSCLC patients with or without BMs between 2014 and 2015. Overall survival (OS) of stage IV NSCLC patients who received immunotherapy and that of stage IV NSCLC patients who did not receive immunotherapy were compared according to the presence or absence of BMs. Multivariable logistic analyses identified the clinical characteristics predictive of overall survival. A propensity score analysis was conducted with the aim of adjusting the potential biases arising from the clinical characteristics. This study included 42,512 patients with stage IV NSCLC; 11,810 patients with BMs and 30,702 patients without BMs. In univariate analysis, stage IV NSCLC patients with BMs treated with immunotherapy had a significantly longer OS than those without immunotherapy after propensity score matching (median OS: 12.8 vs 10.1 months, hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.72–0.89, p < 0.0001). Multivariable Cox modeling after propensity score matching confirmed the survival benefit from ICI for stage IV NSCLC patients with BMs (HR: 0.75, 95% CI: 0.67–0.83, p < 0.0001). The HR in NSCLC patients without BMs treated with ICI compared with those without ICI was 0.77 (95% CI: 0.73–0.82, p < 0.0001). Survival in stage IV NSCLC patients with BMs was significantly improved by ICI treatment at levels comparable to those without BMs using a retrospective database. ICI may be one of the promising treatment options for stage IV NSCLC patients with BMs. These findings should be validated in future prospective studies.

First-line treatment with irreversible tyrosine kinase inhibitors associated with longer OS in EGFR mutation-positive non-small cell lung cancer.

BackgroundFew studies have compared the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), afatinib, with that of reversible EGFR‐TKIs. Therefore, this study assessed the effectiveness of afatinib, erlotinib, and gefitinib in terms of OS (overall survival) and progression‐free survival (PFS) in EGFR mutation‐positive advanced non‐small cell lung cancer (NSCLC) patients.MethodsPatients with EGFR mutation‐positive advanced NSCLC who sought treatment from December 2013 to June 2018, at a tertiary referral center were retrospectively analyzed. These patients were treated with afatinib or a reversible EGFR‐TKI (erlotinib or gefitinib) until disease progression, intolerable adverse events, or death. The Kaplan‐Meier and log‐rank tests were then used to compare the OS and PFS of the patients. We further analyzed the survival differences among the subgroup of patients without brain metastases.ResultsOf the 363 patients enrolled, 134 and 229 received first‐line afatinib and first‐line reversible EGFR‐TKI, respectively. Those given afatinib had better OS (39.3 vs. 26.0 months; HR 0.65, P = 0.033) and PFS (14.1 vs.11.2 months; HR 0.58, P < 0.001). Of the 246 patients without brain metastases, 93 and 153 received first‐line afatinib and a first‐line reversible EGFR‐TKI, respectively. Those given afatinib had a better OS (52.6 vs. 24.9 months; HR 0.62, P = 0.0030) and PFS (17.7 vs. 11.1 months; HR 0.51, P < 0.001). The survival benefit was more significant in the subgroup of patients with L858R substitutions.ConclusionsThe results indicated that afatnib resulted in significantly better OS and PFS than gefitnib and erlotinib for EGFR mutation‐positive advanced NSCLC patients without brain metastases.Key points Significant findings of the study Afatnib resulted in significantly better overall survival and progression‐free survival than gefitnib and erlotinib for EGFR mutation‐positive advanced non‐small cell lung cancer patients without brain metastases. What this study adds This study helps fill the gap in our limited understanding of the differences in the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), afatinib, with that of reversible EGFR‐TKIs.

Incorporating the Number of PLN into the AJCC Stage Could Better Predict the Survival for Patients with NSCLC: A Large Population-Based Study

Purpose This study aimed to investigate the application of the number of positive lymph nodes (PLNs) in tumor, node, metastasis (TNM) staging system of non-small cell lung cancer (NSCLC) patients. Patients and Methods. We screened a total of 15820 patients with resected NSCLC between 2004 and 2015 from SEER database. The X-tile model was used to determine the cutoff values of the number of PLNs. Overall survival (OS) curves were plotted using the Kaplan–Meier method, and the differences among the individual groups were defined using the log-rank test. Cox regression model was used to perform univariate and multivariate analyses and to assess the association between the number of PLNs and OS. Results In this study, using the X-tile model, we screened three different cutoff values, including nN0, nN1–3, and nN4-. Survival curves demonstrated that our defined nN stage had a significant predictive value for OS (P < 0.001). In the univariate and multivariate Cox analyses, the result showed that nN stage was a significant prognostic factor of OS for NSCLC patients (P < 0.001). Subsequently, we classified the patients into five subgroups based on the combination of pN and nN stages, including pN0 + nN0, pN1 + nN1-3, pN2 + nN1-3, pN1 + nN4-, and pN2 + nN4-. Moreover, survival curves revealed significant differences among these five groups (P < 0.001). Conclusion A combination of pathological LNs (pN) and the number of LN (nN) involvement in NSCLC patients had a better prognostic value than the current TNM staging system based on only pN stage.

Stereotactic body radiotherapy for early stage non-small cell lung cancer in patients with subclinical interstitial lung disease.

BackgroundFor lung cancer patients with subclinical (untreated and asymptomatic) interstitial lung disease (ILD), there is a lack of relatively safe and effective treatment. Stereotactic body radiation therapy (SBRT) can achieve a high level of tumor control with low toxicity in early-stage non-small cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and toxicity of early stage NSCLC patients with subclinical ILD receiving SBRT.MethodsA total of 109 early stage NSCLC patients receiving SBRT treatment between December 2011 and August 2016 were reviewed in our institutions; patients with clinical ILD were excluded. The median dose of SBRT was 50 Gy in 5 fractions. The median biologically effective dose (BED; α/β=10) was 100 Gy (range, 72–119 Gy). An experienced radiation oncologist and an experienced radiologist reviewed the presence of subclinical ILD in the CT findings before SBRT. The relationships among the efficacy, radiation-induced lung injury (RILI) and subclinical ILD were explored.ResultsIn all, 38 (34.9%) of 109 patients were recognized with subclinical ILD before SBRT, 48 (44.0%) of 109 patients were recognized with grade 2–5 RILI after SBRT, and 18 (47.4%) of 38 patients with subclinical ILD were observed with grade 2–5 RILI. Subclinical ILD was not a significant factor of grade 2–5 RILI (P=0.608); however, 3 patients had extensive RILI, and they all suffered from subclinical ILD. Dosimetric factor of the lungs, such as mean lung dose (MLD) was significantly related with Grade 2–5 RILI in patients with subclinical ILD (P=0.042). The progression-free survival (PFS) rates at 3 years in the subclinical ILD patients and those without ILD were 61.6% and 66.8%, respectively (P=0.266).ConclusionsSubclinical ILD was not a significant factor for RILI or PFS in early stage NSCLC patients receiving SBRT; however, patients with subclinical ILD receiving SBRT may experience uncommon extensive RILI.

Different pathologic responses to neoadjuvant anti-PD-1 in primary squamous lung cancer and regional lymph nodes

Neoadjuvant immunotherapy provides a unique opportunity for understanding therapeutic responses. We analyzed pathologic responses in surgical specimens obtained from 31 squamous non-small cell lung cancer (NSCLC) patients receiving neoadjuvant anti-PD-1 treatment. Fifteen (48.4%) patients achieved pathologic complete response (pCR) or major pathologic response (MPR). Among them, seven (46.7%) were assessed as radiological partial response and eight (53.3%) as stable disease. Among 20 patients with pathologically identified tumor beds in lymph nodes (LNs), 10 and six patients achieved pCR/MPR in primary tumors and paired LNs, respectively. pCR was achieved in 6/19 N1 nodes and 1/7 N2 nodes. Residual viable tumor (RVT) cells in 8/9 MPR specimens had 100% immune-activated phenotype, while a median of 80% of RVT cells in pathologic nonresponse specimens presented immune-excluded/desert phenotype. These findings demonstrated that assessment of pathologic responses in both primary tumor and LNs may be important as a surrogate for assessing neoadjuvant immunotherapeutic efficacy.

54P Impact of comorbidity and venous thromboembolism on outcome in real-life non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibition (ICI)

54P Impact of comorbidity and venous thromboembolism on outcome in real-life non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibition (ICI)

Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients

BackgroundAlthough advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy.MethodsThis study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment.Results Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P < 0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs. 25.0%, P = 0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab.ConclusionsOur study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Abstract IA22: Tracking metabolic compartmentation and epigenetic metabolism in human lung cancer

Abstract Although metabolic reprogramming has been recognized as a hallmark of human cancers, our understanding of metabolic heterogeneities/compartmentation and regulation of epigenetics in human tumors is largely unknown. This is crucial to elucidating metabolic checkpoints and strategizing therapeutic target(s) for human cancer. The slow progress is at least in part due to the lack of relevant models and tools for studying these processes. We have established patient-derived organotypic tissue cultures (OTC) that recapitulate the in vivo metabolic reprogramming of human cancer while retaining native patient tumor microenvironment and 3D architecture 1,2. The matched pairs of cancerous (CA) and non-cancerous (NC) lung OTC from the same patient enable reprogrammed cancer tissue metabolism and on-/off-target drug responses for individual patients to be defined. We have deployed this system along with multiplexed Stable Isotope-Resolved Metabolomics (mSIRM) to probe the efficiency of different substates that fuel de novo synthesis of purine nucleotides in matched patients’ CA versus NC lung OTC 3. We found for seven non-small cell lung cancer (NSCLC) patients that 13C6-glucose was the preferred substrate over D3-serine, D2-glycine, or 13C2-glycine in supporting purine synthesis in CA tissues but not or less so in matched NC tissues. Kinetic modeling of the tracer data along with gene/protein expression data suggests that cytoplasmic activation and dynamic compartmentation of the glucose-to-serine pathway as well as reversal of mitochondrial serine to glycine fluxes can account for this preference for glucose. In all seven patients’ CA tissues, c-MYC was overexpressed and its suppression in NSCLC PC9 cells blocked de novo serine synthesis from glucose, enhanced serine-glycine exchanges, and reduced the efficiency of glucose versus serine incorporation into ATP/GTP. However, serine rather than glucose was the preferred substrate for purine synthesis in NSCLC cell lines but c-MYC could alter this preference for serine towards glucose in fueling purine synthesis. This tissue and cell line difference should be considered in designing serine starvation-based cancer therapy. To track metabolism that modulates epigenetic regulation, we employed a fast, sensitive, and robust Fourier transform-mass spectrometric method to analyze S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels in A549 cells under anti-cancer methylseleninic acid (MSA) and selenite treatments. We found that SAM/SAH levels were reduced by both treatments and MSA but not selenite increased the SAM to SAH ratio. These changes were accompanied by reduced proliferation, central metabolism, and H3K27Me3 levels in MSA and less so in selenite-treated A549 cells. Thus, the tool for tracking SAM/SAH metabolism along with the SIRM approach opens the opportunity for interrogating epigenetic metabolism and its regulation of growth-promoting central metabolic events. Funding: This work was supported in part by grants: 1R01ES022191-01 (to TWMF and RMH), 1P01CA163223-01A1 (to ANL and TWMF), and 1U24DK097215-01A1 (to RMH, TWMF, and ANL). Refs: 1 Sellers, K. et al. Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation. The Journal of Clinical Investigation 125, 687-698, doi:10.1172/JCI72873 (2015). 2 Fan, T. W., Lane, A. N. &amp; Higashi, R. M. Stable Isotope Resolved Metabolomics Studies in ex vivo Tissue Slices. Bio-protocol 6, e1730 (2016). 3 Fan, T. W. M. et al. De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues. The Journal of biological chemistry 294, 13464-13477, doi:10.1074/jbc.RA119.008743 (2019). Citation Format: Teresa W-M Fan, Andrew N. Lane, Jason A. Brandon, Joonseon Yang, Chi V. Dang, Richard M. Higashi. Tracking metabolic compartmentation and epigenetic metabolism in human lung cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA22.

Abstract PO-164: Neighborhood disparities in timeliness of treatment for early stage lung cancer patients

Abstract Disparities in receipt of appropriate and timely cancer treatment continue. While there has been ample research identifying disparities by unmodifiable factors such as race/ethnicity, modifiable mechanisms, such as a neighborhood’s social and built environment, that drive such disparities are poorly understood. Minority neighborhoods enduring the impact of residential segregation often have less access to resources to maintain health and little control over their environments. The objective of this study is to better understand the importance of neighborhood racial/ethnic composition on racial/ethnic disparities in timely treatment for early- stage non-small cell lung cancer (NSCLC) patients. We studied 22,903 stage I/II NSCLC (2006-2015) patients in the California Cancer Registry. Appropriate treatment was defined as receipt of guideline concordant therapy (GCT) according to the 2016 NCCN guidelines, and timeliness as initial treatment within 45 days and adjuvant therapy within 6 months. The exposure was neighborhood racial/ethnic concordance, defined by the racial/ethnic composition of a neighborhood being predominately concordant, mixed, or discordant from a patient’s race/ethnicity. Multivariable hierarchical regression models were used to estimate the effect of neighborhood racial/ethnic concordance on GCT and timely GCT, independently and jointly with patient race/ethnicity. Overall, 81.4% of patients received GCT; 57.7% of them in a timely manner. Non-Hispanic blacks (NHBs) (76.9%) had the lowest rate of GCT and Filipinos (49.7%) and NHBs (50.0%) had the lowest rate of timely GCT. Patients living in concordant neighborhoods had the highest rate of GCT (83.0%) and timely GCT (61.0%). Most patients lived in white (32.9%) and mixed white and Hispanic (34.4%) neighborhoods, and the percentage of patients living in concordant neighborhoods (33.7%) were the highest among non-Hispanic whites (NHWs; 41.0%) and Hispanics (28.7%). Compared to patients in concordant neighborhoods, patients in mixed (undertreatment: RR=1.09, 95% CI=1.02-1.17; treatment delay: RR=1.10, 95% CI=1.05-1.16) and discordant (undertreatment: RR=1.15, 95% CI=1.04-1.27; delay: RR=1.12, 95% CI=1.04-1.21) neighborhoods were at increased risk for undertreatment and delay. This association does not hold for all race/ethnicities. However, compared to NHWs living in concordant neighborhoods, NHBs (undertreatment: RR=1.41, 95% CI=0.96-2.09) and Hispanics (undertreatment: RR=1.48, 95% CI=1.25-1.74; treatment delay: RR=1.26, 95% CI=1.10-1.44) living in concordant neighborhoods were also at increased risk. Early stage lung cancer has a high rate of survival when treated appropriately and in a timeline matter. Neighborhoods are key determinants of health. Understanding the role that neighborhoods play in healthcare utilization can help craft individual- or policy-level interventions that may include additional health care resources and targeted health care interventions. Citation Format: Chelsea A. Obrochta, Joseph Gibbons, Caroline A. Thompson. Neighborhood disparities in timeliness of treatment for early stage lung cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-164.

Dose adjustment for tyrosine kinase inhibitors in non‑small cell lung cancer patients with hepatic or renal function impairment (Review).

In recent years, a number of tyrosine kinase inhibitors (TKIs) have been approved for the treatment of non-small cell lung cancer. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. TKIs are administered orally, which has the advantages of improved flexibility and convenience for the patients. However, challenges have arisen in the use of these novel agents. Prescribing drugs for patients with hepatic or renal function impairment poses a challenge for clinicians due to the large pharmacokinetic variability in each individual patient. Moreover, several TKIs have been shown to cause laboratory test abnormalities normally associated with hepatic or renal injury. The aim of the present review was to discuss the effects of hepatic and renal function impairment on the pharmacokinetic variability of 17 TKIs and their potential hepatotoxicity and nephrotoxicity, and to recommend dose adjustment for patients with hepatic or renal impairment.

Effects of reduced platelet count on the prognosis for patients with non-small cell lung cancer treated with EGFR-TKI: a retrospective study

BackgroundProgressive lung cancer is associated with abnormal coagulation. Platelets play a vital part in evading immune surveillance and angiogenesis in the case of tumor metastasis. The study aimed to analyze the predictive and prognostic effects of platelet count on non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).MethodsThis study retrospectively analyzed the prognostic effects of platelets on 52 NSCLC patients with epidermal growth factor receptor (EGFR) mutant following EGFR-TKI treatment. Related data, together with the progression-free survival (PFS) and overall survival (OS) were collected before and after 2 cycles of treatments (60 days).ResultsThe anti-EGFR treatment markedly reduced the platelet count in 33 (63.5%) patients after 2 cycles of treatment. Multivariate Cox analysis revealed that, the decreased platelet count was closely correlated with the longer OS (HR = 0.293; 95%CI: 0.107-0.799; p = 0.017). Besides, the median OS was 326 days in the decreased platelet count group and 241 days in the increased platelet count group (HR = 0.311; 95%CI: 0.118-0.818; P = 0.018), as obtained from the independent baseline platelet levels and other clinical features.ConclusionsThe platelet count may predict the prognosis for EGFR-TKI treatment without additional costs. Besides, changes in platelet count may serve as a meaningful parameter to establish the prognostic model for NSCLC patients receiving anti-EGFR targeted therapy.

Benefit of dosimetry distribution for patients with multiple brain metastases from non-small cell lung cancer by a Cyberknife stereotactic radiosurgery (SRS) system

BackgroundIn order to obtain a high dose conformal index of tumor and steep dose fall-off in healthy tissues for brain metastasis stereotactic radiosurgery (SRS), the aim of this study was to investigate SRS planning optimization by comparing one multiple-lesions plan (MLP) with multiple single-lesion plans (SLPs) for patients with multiple brain metastases using the Cyberknife (CK) system.MethodsFifty non-small cell lung cancer (NSCLC) patients (28 males and 22 females) with 2–4 brain metastases, inter-tumour distances less than 3 cm, were retrospectively replanned with the original prescription dose (12–32 Gy) in the original fractions (1–3). Two different clinical CK SRS plans (SLPs and MLP) were generated for the same patients with the same collimator and prescription isodose line (62–68%) by the CK Multiplan System. Both SLPs and MLP were able to achieve > 95% PTV volume covered prescription dose and met the Timmerman 2011 organs at risk (brainstem, optic nerve and pituitary) constraints.ResultsCompared with those in the SLPs, the maximum dose (Dmax) and mean dose (Dmean) of brainstem in the MLP were reduced 0.22–3.13% (2.62%) and 2.71–12.56% (5.57%), respectively, all P < 0.05. Meanwhile, the volumes of the whole brain minus the tumors that received a single dose equivalent of 8–16 Gy (V8Gy-V16Gy) were effectively reduced in the MLP. The treatment time parameters, the total number of beams and monitor units, of the MLP were reduced by 3.31 and 1.47% (P < 0.05), respectively. Although there were a few differences in the conformity index (CI) and homogeneity index (HI) between the two treatment plans, the differences were not statistically significant (P = 2.94 and 1.08 > 0.05).ConclusionOne multiple-lesions plan for brain metastases could achieve higher precision in the target and lower doses in healthy tissue while shortening the treatment time and improving the treatment efficiency over multiple single-lesion plans.

Video-assisted thoracoscopic surgery lobectomy might be a feasible alternative for surgically resectable pathological N2 non-small cell lung cancer patients.

BackgroundThe majority of previous studies of the clinical outcome of video‐assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non‐small cell lung cancer (pN2 NSCLC) have been single‐center experiences with small patient numbers. The aim of this study was therefore to investigate these procedures but in a large cohort of Chinese patients with pathological N2 NSCLC in real‐world conditions.MethodsPatients who underwent lobectomy for pN2 NSCLC by either VATS or thoracotomy were retrospectively reviewed from 10 tertiary hospitals between January 2014 and September 2017. Perioperative outcomes and overall survival of the patients were analyzed. Cox regression analysis was performed to identify potential prognostic factors. Propensity‐score analysis was performed to reduce cofounding biases and compare the clinical outcomes between both groups.ResultsAmong 2144 pN2 NSCLC, 1244 patients were managed by VATS and 900 by open procedure. A total of 305 (24.5%) and 344 patients died during VATS and the thoracotomy group during a median follow‐up of 16.7 and 15.6 months, respectively. VATS lobectomy patients had better overall survival when compared with those undergoing the open procedure (P < 0.0001). Multivariate COX regression analysis showed VATS lobectomy independently favored overall survival (HR = 0.75, 95% CI: 0.621–0.896, P = 0.0017). Better perioperative outcomes, including less blood loss, shorter drainage time and hospital stay, were also observed in patients undergoing VATS lobectomy (P < 0.05). After propensity‐score matching, 169 patients in each group were analyzed, and no survival difference were found between the two groups. Less blood loss was observed in the VATS group, but there was a longer operation time.ConclusionsVATS lobectomy might be a feasible alternative to conventional open surgery for resectable pN2 NSCLC.Key points Significant findings of the study: VATS lobectomy has comparative OS in pN2 NSCLC versus open procedure in resectable patients.What this study adds: VATS lobectomy might be feasible for pN2 NSCLC.

Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer patients with EGFR or HER2 exon 20 insertions.

BackgroundInsertions in exon 20 (Ex20ins) of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are relatively insensitive to first‐ and second‐generation EGFR‐tyrosine kinase inhibitors (TKIs) in non‐small cell lung cancer (NSCLC). This study aimed to investigate the immune microenvironment features and efficacy of PD‐1/PD‐L1 blockade of NSCLC with EGFR and HER2 Ex20ins.MethodsClinical characteristics, coexisting mutations, and outcomes to EGFR‐TKIs and immune checkpoint blockade were reviewed for NSCLC patients with exon 20 mutations of EGFR or HER2. Data obtained included the molecular spectrum (extended genotyping for mutations in 324 cancer‐related genes), as well as tumor mutational burden (TMB), PD‐L1 protein expression, and the abundance of CD4+ and CD8+ tumor‐infiltrating lymphocytes (TILs).ResultsA total of 1270 NSCLC patients were identified. Of these, 504 (39.7%) cases had EGFR mutations and 6.9% (35/504) of them had EGFR Ex20ins. Meanwhile, 21 (1.7%) cases with HER2 Ex20ins were detected. Comprehensive genomic profiling identified A767_V769dup variant (25.0%) was the most common type in tumors with EGFR Ex20ins. Co‐occurring mutations were not uncommon including TP53 (45%), PIK3CA (20%), CDKN2A (10%), and EGFR amplification (20%). The average TMB was 3.3 mutations/megabase. PD‐L1 expression in patients with EGFR Ex20ins was significantly higher than for those with HER2 mutations (48.6% vs. 19.0%, P = 0.027). High TMB and PD‐L1 expression was independently associated with significantly poor prognosis (P = 0.025, P = 0.045, respectively) while there was no association between CD4+/CD8+ TILs and prognosis in EGFR or HER2 mutant NSCLC. Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD‐1/PD‐L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins.ConclusionsNSCLC patients with EGFR/HER2 Ex20ins had similar genomic characteristics and distinct immune features. Patients with EGFR Ex20ins had significantly higher PD‐L1 expression than those with HER2 mutations, which may be the potential reason for the different responses to PD‐1/PD‐L1 blockage.