Resected Early-stage Non-small Cell Lung Cancer Research Articles

Time trends and predictors of survival in surgically resected early-stage non-small cell lung cancer patients.

The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS). We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS. There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS. The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.

Closing the gap: Contribution of surgical best practices to outcome differences between high- and low-volume centers for lung cancer resection.

BackgroundClinical outcomes for resected early‐stage non‐small cell lung cancer (NSCLC) are superior at high‐volume facilities, but reasons for these differences remain unclear. Understanding these differences and optimizing outcomes across institutions are critical to the management of the increasing incidence of these cases. We evaluated the extent to which surgical best practices account for resected early‐stage NSCLC outcome differences between facilities according to case volume.MethodsWe performed a retrospective cohort study for clinical stage 1 or 2 NSCLC undergoing surgical resection from 2004 to 2013 using the National Cancer Database (NCDB). Surgical best practices (negative surgical margins, lobar or greater resection, lymph node (LN) dissection, and examination of > 10 LNs) were compared between the highest and lowest quartile volumes.ResultsA total of 150,179 patients were included in the cohort (89% white, 53% female, median age 68 years). In a multivariate model, superior overall survival (OS) was observed at highest volume centers compared to lowest volume centers (hazard ratio (HR) = 0.89; 95% CI, 0.82‐0.96; P = .002). After matching for surgical best practices, there was no significant OS difference (HR = 0.95; 95% CI, 0.87‐1.05; P = .32). Propensity score‐adjusted HR estimates indicated that surgical best practices accounted for 54% of the numerical OS difference between low‐volume and high‐volume centers. Each surgical best practice was independently associated with improved OS (all P ≤ .001).ConclusionQuantifiable and potentially modifiable surgical best practices largely account for resected early‐stage NSCLC outcome differences observed between low‐ and high‐volume centers. Adherence to these guidelines may reduce and potentially eliminate these differences.

EP1.17-15 Comparison of Long-Term Outcome of Wedge Resection, Anatomical Segmentectomy and Lobectomy in Stage I-II Non-Small Cell Lung Cancer

In patients with early stage non-small cell lung cancer (NSCLC) lobectomy is still considered the treatment of choice, whereas sublobar resection is more frequently performed in patients with reduced lung function and high perioperative risk. We investigated long term outcome of patients undergoing either lobectomy or anatomical segmentectomy or wedge resection for early stage NSCLC. In this retrospective cohort study patients with early stage NSCLC who underwent either lobectomy or anatomical segmentectomy or wedge resection at our center between 2006 and 2018 were analyzed. Primary endpoint was overall survival (OS) and disease-free survival (DFS). 383 patients with peripherally located stage I or II NSCLC (TNM 8) who underwent curative intent surgery were identified. Patients undergoing neoadjuvant or adjuvant treatment or with centrally located tumors were excluded. 325 patients (84.8%) received lobectomy, 26 patients (6.8%) anatomical segmentectomy and 32 patients (8.4%) wedge resection. Pathological stage was IA 221 (57.7%), IB 93 (24.3%), IIA 48 (12.5%), IIB (3.9%). Histology revealed adenocarcinoma in 285 (74.4%), squamous cell lung cancer 98 (25.6%). There was no significant difference regarding OS and DFS between all three groups. Interestingly, in patients with tumors larger than 2cm there was also no significant difference in OS and DFS between all groups. The relevance of sublobar resection in early stage NSCLC patients is still controversial. In our cohort study the long-term outcome of anatomical segmentectomy and wedge resection was comparable to outcome after lobectomy. However, well-designed prospective randomized studies are necessary to confirm the value of sublobar resections for stage I and II NSCLC.

Comment suivre un patient opéré ?

After surgery for non-small cell lung cancer (NSCLC), most guidelines recommend a follow-up including clinic visits and chest CT-scans. The IFCT-0302 study is the only phase III trial to have evaluated the impact of a chest CT-scan-based follow-up on overall survival. Two surveillance strategies were compared: clinic visits and chest X-rays vs clinic visits, chest X-rays, thoraco-abdominal CT-scans and fiberoptic bronchoscopies. Follow-up was planned every 6 months for 2 years and annually between years 3 and 5. Among the 1775 included patients, 82 % had undergone surgery for a stage I-II NSCLC. There was no difference in overall survival, with 5-year survival rates of 66.7 % in the control arm and 65.8 % in the CT-scan-based follow-up arm (HR=0.95; 95%CI=0.82-1.09; p=0.37). Exploratory analyses suggest that, after 2 years, early detection of second primary lung cancers might have an interest. A comprehensive approach of surveillance, including smoking cessation programs and treatment of comorbidities can be proposed after resection for early-stage NSCLC.

P1.17-30 Sex and Age-Associated Survival Following Resected Early Stage Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the most common malignant tumour, and a leading cause of mortality worldwide. Rising rates of NSCLC have been observed among females, but nonetheless females also are often observed to possess better prognosis across all stages of disease. We aimed to assess the impact of biological sex along with age at diagnosis on the outcome of NSCLC patients with resected early-stage disease. A 15-year population-based retrospective analysis was conducted on de novo early stage (AJCC 7th edition, Stage I or II) patients between 1999-2014, whose primary tumor was surgically resected. Demographic, clinical characteristics, treatment modalities and outcome data were extracted from the institutional Glans-Look Lung Cancer Database, and univariate analysis, including Kaplan-Meier survival, alongside multivariate Cox regression was performed to compare outcomes by sex and determine prognostic factors associated with survival. 872 early-stage resected NSCLC patients were identified. Median age at diagnosis 65.9 years (IQR: 59.1-72.6), 56% female, 76% ‘ever’ smokers, 68% Stage I, 91% oncologic resection (9% wedge resection). Median overall survival (mOS) for all early-stage resected cases was 93 months (95% CI: 81.9 – 105.4) with a 5-year survival rate of 62.5%. Females exhibited superior survival outcomes to males (105.4 months vs. 77.5 months, log-rank p=0.002), as did those <75 years at diagnosis compared to those ≥75 years (103.9 vs. 76.2 months, log-rank p <0.001). Best and worst survival outcome was observed in females under age 75, and males over age 75, respectively (mOS 114.3 vs. 64.5 months; 5-year survival: 67.9% vs. 50.5%). No difference in rate of recurrence (overall) or rate of metastatic recurrence between males and females was identified (39% vs. 36%, p=0.214; 19% vs. 16%, p=0.591). After controlling for confounding variables, a reduced risk of mortality was found for females (HR: 0.8, p=0.016), age under 75 years at diagnosis (HR: 0.6, p <0.001) and stage I presentation (HR: 0.6, p<0.001). Females experience significantly longer mOS, in particularly females under the age of 75 years at diagnosis. After adjusting for confounding factors, we found significantly reduced mortality risk for females aged under 75 years at diagnosis, and Stage I disease. Despite possessing the poorest outcomes among this cohort, males ≥75 years still possessed a 5-year survival rate of 50%, suggesting that surgical resection is a highly effective treatment option for suitable NSCLC patients, regardless of age.

Current status of immune checkpoint inhibition in early-stage NSCLC.

Immune checkpoint inhibition (ICI) immunotherapy has revolutionized the approach to metastatic non-small-cell lung cancer (NSCLC). In particular, antibodies blocking the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand (PD-L1) are associated with higher response rates, improved overall survival and better tolerability as compared with conventional cytotoxic chemotherapy. Recently, ICI has moved from the second-line to the first-line setting for many patients with non-oncogene-addicted NSCLC, either alone or in combination with chemotherapy. The next logical step is to examine this therapy in patients with non-metastatic NSCLC to improve long-term overall survival and cure rates. For patients with unresectable stage III NSCLC, ICI with durvalumab after concurrent chemoradiotherapy has brought a major improvement in 2-year progression-free and overall survival, which holds promise for an improved cure rate. As the relapse pattern in patients with completely resected early-stage NSCLC is predominantly systemic, high expectations rest on the integration of ICI therapy in their treatment approach. A large number of studies with adjuvant or neo-adjuvant ICI are ongoing and will be discussed here. The advent of stereotactic ablative radiotherapy has brought a valid alternative treatment of patients unfit for or not willing to undergo surgery. Data on combining systemic therapy and stereotactic ablative radiotherapy are virtually non-existent, but there is a strong biological rationale to combine radiotherapy and ICI therapy. Early findings in small feasibility studies are promising and now need to be explored in well-designed phase III trials.

Disparities in the surgical management of early stage non-small cell lung cancer: how far have we come?

It is currently estimated that nearly one-third of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage I-II disease on clinical evaluation. Curative-intent surgical resection has been a cornerstone of the therapeutic management of such patients, offering the best clinical and oncologic outcomes in the long-term. In 1999, Peter Bach and colleagues brought attention to racial disparities in the receipt of curative-intent surgery in the NSCLC population. In the time since this seminal study, there is accumulating evidence to suggest that disparities in the receipt of definitive surgery continue to persist for patients with early stage NSCLC. In this review, we sought to provide an up-to-date assessment of 20 years of surgical disparities literature in the NSCLC population. We summarized common and unrecognized disparities in the receipt of surgical resection for early stage NSCLC and demonstrated that demographic and socioeconomic factors such as race/ethnicity, special patient groups, income and insurance continue to impact the receipt of definitive resection. Additionally, we found that discrepancies in patient and provider perceptions of and attitudes toward surgery, access to invasive staging, distance to treatment centers and negative stigmas about lung cancer that patients experience may act to perpetuate disparities in surgical treatment of early stage lung cancer.

Prognostic Role of Circulating miRNAs in Early-Stage Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of 84 circulating microRNAs (miRNAs) in 182 patients with resected early-stage NSCLC (99 adenocarcinoma (ADC), 83 squamous cell carcinoma (SCC)) from whom peripheral blood samples were collected pre-surgery. miRNA expression was analyzed in relation to disease-free survival (DFS) and overall survival (OS). In univariable analyses, five miRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p) were significantly associated with DFS in SCC, and four (miR-130b-3p, miR-26a-5p, miR-126-3p, and miR-205-5p) remained significantly associated with OS. In ADC, miR-222-3p, miR-22-3p, and mir-93-5p were significantly associated with DFS, miR-22-3p remaining significant for OS. Given the high-dimensionality of the dataset, multivariable models were obtained using a regularized Cox regression including all miRNAs and clinical covariates. After adjustment for disease stage, only miR-126-3p showed an independent prognostic role, with higher values associated with longer DFS in SCC patients. With regard to ADC and OS, no miRNA remained significant in multivariable analysis. Further investigation into the role of miR-126 as a prognostic marker in early-stage NSCLC is warranted.

Validation of the 12-gene Predictive Signature for Adjuvant Chemotherapy Response in Lung Cancer.

Response to adjuvant chemotherapy after tumor resection varies widely among patients with non-small cell lung cancer (NSCLC); therefore, it is of clinical importance to prospectively predict who will benefit from adjuvant chemotherapy before starting the treatment. The goal of this study is to validate a 12-gene adjuvant chemotherapy predictive signature developed from a previous study using a clinical-grade assay. We developed a clinical-grade assay for formalin-fixed, paraffin-embedded (FFPE) samples using the NanoString nCounter platform to measure the mRNA expression of the previously published 12-gene set. The predictive performance was validated in a cohort of 207 patients with early-stage resected NSCLC with matched propensity score of adjuvant chemotherapy. The effects of adjuvant chemotherapy were significantly different in patients from the predicted adjuvant chemotherapy benefit group and those in the predicted adjuvant chemotherapy nonbenefit group (P = 0.0056 for interaction between predicted risk group and adjuvant chemotherapy). Specifically, in the predicted adjuvant chemotherapy benefit group, the patients receiving adjuvant chemotherapy had significant recurrence-free survival (RFS) benefit (HR = 0.34; P = 0.016; adjuvant chemotherapy vs. nonadjuvant chemotherapy), while in the predicted adjuvant chemotherapy nonbenefit group, the patients receiving adjuvant chemotherapy actually had worse RFS (HR = 1.86; P = 0.14; adjuvant chemotherapy vs. nonadjuvant chemotherapy) than those who did not receive adjuvant chemotherapy. This study validated that the 12-gene signature and the FFPE-based clinical assay predict that patients whose resected lung adenocarcinomas exhibit an adjuvant chemotherapy benefit gene expression pattern and who then receive adjuvant chemotherapy have significant survival advantage compared with patients whose tumors exhibit the benefit pattern but do not receive adjuvant chemotherapy.

Immunotherapy in patients with early stage resectable nonsmall cell lung cancer.

'Early-stage' nonsmall cell lung cancer (NSCLC) refers to stage I and stage II disease, and selected cases of stage IIIA disease where complete tumor resection is feasible. Surgery is the standard treatment for early NSCLC, but the overall 5-year survival remains below 50%. The addition of adjuvant cisplatin-based chemotherapy to surgery improved 5-year survival rates by 5-10%, but no significant therapeutic innovation has been established thereafter. We review recent and ongoing studies looking how immunotherapy may improve the outcome of these patients. Antigen-specific immunotherapy (cancer vaccination) did not fulfill its promise in a large phase III randomized trial in completely resected early-stage NSCLC. Over the past few years, immunotherapy with immune checkpoint inhibition (ICI) has led to remarkable progress in nononcogene addicted metastatic NSCLC. We review ongoing clinical investigations that want to translate these benefits to earlier stages of NSCLC. Both adjuvant and neoadjuvant large randomized controlled trials with ICI are ongoing. Although from a mechanistic perspective the neoadjuvant administration may be preferred, it is crucial that both adjuvant and neoadjuvant trials are recruited as planned, to have a balanced view how ICI therapy may ultimately improve cure rates in these patients.

P3.01-59 Comparison of Lobectomy, Segmentectomy and Wedge Resection for Early Stage NSCLC: A Direct and Network Meta-Analysis

Aim: The purpose of this study was to compare the effect of lobectomy, segmentectomy and wedge resection for early stage non-small cell lung cancer (NSCLC) treatment. Surgical section is a first choice for surgical treatment of early stage NSCLC (5). However, it is not applied for most NSCLC with advanced stages owing to its high metastasis and recurrence rates. In addition, video-assisted thoracoscopic surgery (VATS) as a less invasive surgical method is widely used for clinical stage I NSCLC during lobectomy, segmentectomy, and wedge resection. Lobectomy is a traditionally gold standard for early stage NSCLC treatment. In recent years, segmentectomy and wedge resection as alternative sublobar resection to lobectomy are recommended. Many studies have indicated that sublobar resection results in equivalent outcomes in patients with stage I NSCLC in comparison with lobectomy, and it is gradually considered that pneumonectomy is unnecessary. However, sublobar resection for NSCLC treatment remains controversial due to an increased risk in local recurrence and poorer long-term survival compared to lobectomy, thus additional local therapy is recommended to patients undergoing sublobar resection. Eligible studies were retrieved from PubMed, Embase, and Cochrane Library. The 1, 2 or 5-year overall survival (OS) and disease-free survival (DFS), and complications rates were used as outcomes indictors. The pooled results for comparison indicators were measured by odds ratios (ORs) with 95% confidence interval (CI) as dichotomous variables. The random effects model was used for all test models in the present study. The consistency assessment in this network meta-analysis was conducted by Node-splitting analysis. A total of 23 studies encompassing 13406 early stage NSCLC patients were included into this network meta-analysis. The results revealed that although 1, 2 and 5-year OS and DFS of lobetomy was superior to segmentectomy and wedge resection, and segmentectomy was better than wedge resection, except for 2-year OS, only result of 5-years OS between groups (wedge resection vs. segmentectomy, OR= 0.56, 95%CI: 0.36-0.87; wedge resection vs. lobetomy, OR= 0.51, 95%CI: 0.33-0.79) were significant difference. On the contrary, the complications rate in wedge resection was significant lower than that of lobetomy (lobetomy vs. wedge resection, OR= 1.73, 95%CI: 1.05-2.72) and segmentectomy (segmentectomy vs. wedge resection, OR= 1.66, 95%CI: 1.02-2.74), and it was highest in lobetomy. Segmentectomy might be recommended as a reasonable alternative to lobectomy with lower complications rate for early stage NSCLC treatment.

Quels suivis après la chirurgie du cancer du poumon ? Pour quels malades ?

After surgery for non-small cell lung cancer (NSCLC), most guidelines recommend a follow-up including clinic visits and chest CT-scans. The IFCT-0302 study is the only phase III trial to have evaluated the impact of a chest CT-scan-based follow-up on overail survival. Two surveillance strategies were compared: clinic visits and chest X-rays vs clinic visits, chest X-rays, thoraco-abdominal CT-scans and fiberoptic bronchoscopies. Follow-up was planned every 6 months for 2 years and annually between years 3 and 5. Among the 1775 included patients, 82% had undergone surgery for a stage I-II NSCLC. There was no difference in overall survival, with 5-year survival rates of 66.7% in the control arm and 65.8% in the CT-scan-based follow-up arm (HR=0.95; 95% CI=0.82-1.09; p=0.37). Exploratory analyses suggest that, after 2 years, early detection of second primary lung cancers might have an interest. A comprehensive approach of surveillance, including smoking cessation programs and treatment of comorbidities can be proposed after resection for early-stage NSCLC.

Meta-analysis of segmentectomy versus wedge resection in stage IA non-small-cell lung cancer.

BackgroundAlthough limited resection was once considered the surgical treatment for patients with Phase IA non-small-cell lung cancer (NSCLC), there has been an ongoing controversial surgical indication for wedge resection and segmentectomy in recent years. The objective of this study was to compare overall survival (OS) and disease-free survival (DFS) of segmentectomy and wedge resection for early stage NSCLC, using a meta-analysis.MethodsSystematic research was conducted using four online databases to search for studies published before 2017. The DFS and OS for early stage NSCLC after segmentectomy and wedge resection were compared. The studies were selected according to rigorous predefined inclusion criteria, and meta-analyzed using the log (hazard ratio; ln[HR]) and its standard error (SE) calculations.ResultsIncluded in this meta-analysis were nine studies, published from 2006 to 2017, with a total of 7,272 patients. Survival outcome of segmentectomy was comparable to wedge resections for stage IA lung cancer because of OS (similar hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.83–1.05, P=0.26) and DFS (similar HR: 0.81, 95% CI: 0.60–1.09, P=0.17). Nevertheless, for stage IA NSCLC with tumor size ≤2 cm, segmentectomy was superior to wedge resection (combined HR: 0.82, 95% CI: 0.70–0.97, P=0.02). However, there were no significant differences in OS rates, 1.07 (95% CI: 0.78–1.46, P=0.68), between segmentectomy and wedge resection for IA NSCLC with a tumor size of ≤1 cm.ConclusionThis study concluded that segmentectomy could achieve better OS than wedge resection for stage IA NSCLC with a tumor size of ≤2 cm. However, surgeons could conduct segmentectomy and wedge resection for NSCLC ≤1 cm according to patient profile and the location of tumor. These results should be confirmed by further randomized clinical trials.

Preoperative Pulmonary Function Tests (PFTs) and Outcomes from Resected Early Stage Non-small Cell Lung Cancer (NSCLC).

Preoperative pulmonary function tests (PFTs) predict operative morbidity and mortality after resection in lung cancer. However, the impact of preoperative PFTs on overall outcomes in surgically-resected stage I and II non-small cell lung cancer (NSCLC) has not been well studied. This is a retrospective study of 149 patients who underwent surgical resection as first-line treatment for stage I and II NSCLC at a single center between 2003 and 2014. PFTs [forced expiratory volume in 1 sec (FEV1), Diffusing Capacity (DLCO)], both absolute values and percent predicted values were categorized into quartiles. The Kaplan-Meier method and Cox regression analysis were used to determine whether PFTs predicted for overall survival (OS). Logistic regression was used to estimate the risk of postoperative complications and length of stay (LOS) greater than 10 days based on the results of PFTs. The median age of the cohort was 68 years. The cohort was predominantly males (98.6%), current or ex-smokers (98%), with stage I NSCLC (82.76%). The majority of patients underwent a lobectomy (n=121, 81.21%). The predominant tumor histology was adenocarcinoma (n=70, 47%) followed by squamous cell carcinoma (n=61, 41%). The median follow-up of surviving patients was 53.2 months. DLCO was found to be a significant predictor of OS (HR=0.93, 95% CI=0.87-0.99; p=0.03) on univariate analysis. Although PFTs did not predict for postoperative complications, worse PFTs were significant predictors of length of stay >10 days. Preoperative PFTs did not predict for survival from resected early-stage NSCLC, but did predict for prolonged hospital stay following surgery.

Effect of the number of lymph nodes examined on the survival of patients with stage I non–small cell lung cancer who undergo sublobar resection

ObjectivesEarly stage lung cancer is being detected at a higher frequency with the implementation of screening programs. At the same time, medically complex patients with multiple comorbidities are presenting for surgery, with a concomitant rise in rates of sublobar resection. We sought to examine the effect of sampling lymph nodes on the outcomes of patients who undergo sublobar resection for small (<2 cm) stage I non–small cell lung cancer (NSCLC). MethodsAll patients in the Surveillance, Epidemiology, and End Results database from 2004 to 2013 with small (<2 cm) stage I NSCLC who underwent sublobar resection (wedge/segmentectomy) and no other cancer history were included. The association of the number of lymph nodes examined (LNE; categories none, 1-3, 4-6, 7-9, >9) with the overall survival as well as disease-specific survival were examined using univariate as well as multivariate analyses while controlling for covariates such as age, size (<1 cm, >1 cm), grade, histology (adenocarcinoma vs others), and extent of resection (wedge/segmentectomy). ResultsData from 3916 eligible patients were analyzed. Seven hundred fifteen patients (18.3%) had segmentectomy. No lymph nodes were examined in 49% and 23% of wedge resection and segmentectomy patients, respectively. Among all eligible patients, 1132 (29%), 474 (12%), 228 (6%), and 328 (8%) patients had 1 to 3, 4 to 6, 7 to 9 and >9 LNE, respectively. Univariate analyses showed significant associations between overall and disease-specific survivals with age, grade, histology, sex, extent of surgery, and LNE. The association between the number of LNE and survival remained significant even after adjusting for significant covariates including extent of sublobar resection (hazard ratio for groups with LNE 1-3, 4-6, 7-9, and >9 compared with 0 LNE were 0.79, 0.77, 0.68, and 0.45 for overall survival; P < .001) and 0.85, 0.77, 0.71, and 0.44 for disease-specific survival (P < .05), respectively. In multivariate modeling, LNE was retained as a significant variable and extent of resection was not. In patients in whom at least 1 lymph node was examined, extent of resection was not predictive of outcome. ConclusionsMany patients having sublobar resection for early stage NSCLC in the United States do not have a single lymph node removed for pathologic examination. The number of LNE is associated with improved survival, presumably due to avoidance of mis-staging. This association seems greater than the association with extent of resection (segmentectomy vs wedge resection). Appropriate lymph node examination remains an important part of resection for lung cancer even if the resection is sublobar.

A preclinical study of tumor-infiltrating lymphocytes in NSCLC.

161 Background: Multiple clinical studies have shown that adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) is remarkably effective in melanoma patients. Non-small cell lung cancer (NSCLC) shares similarities with melanoma in terms of mutational burden and sensitivity to immune checkpoint inhibitors. We therefore sought to test whether TIL ACT may represent a viable option for the treatment of NSCLC patients. We utilized tissue collected from patients enrolled on the prospective ImmunogenomiC prOfiling of Non-small cell lung cancer (ICON) study. Methods: TIL and tissue-infiltrating lymphocytes were expanded ex vivo from 97 freshly resected early-stage localized NSCLC tumors and 39 matched uninvolved lung tissues. Growth and functional characteristics of TIL were assessed via flow cytometry, TIL-tumor reactivity assays, and analysis of TCRβ sequencing data. Results: NSCLC showed an increased proportion of CD3+ lymphocytes within the tumor-infiltrating leukocyte component as compared to matched normal lung tissue. The TIL compartment included a suppressed CD8+ T cell subset expressing significantly higher levels of PD-1 and lacking cytolytic potential compared to T cells expanded from normal tissue. TIL contained a higher proportion of proliferating (Ki67+) CD8+CD103+ tissue-resident memory (TRM) cells expressing activation markers such as CTLA4, LAG3, PD1 and ICOS, and increased CD4+ Tregs. Despite a highly immunosuppressive environment, TIL expansion was achieved with a success rate of 68% (n = 97) but appeared hindered in patients undergoing neoadjuvant chemotherapy treatment prior to surgery (56.2%, n = 16 vs 72.5% success rate in therapy-naïve patients). In addition, expansion efficiency (number expanded and time of culture) of TIL and matched lung residing lymphocytes were significantly associated (r = 0.379, p = 0.017, n = 39). Importantly, expanded CD8+ TIL products were oligoclonal and showed reactivity toward autologous tumors. Conclusions: Although NSCLC TIL are functionally inhibited in vivo they can be successfully expanded ex vivo and demonstrate recognition of autologous tumor cells. These data suggest that TIL can potentially be used for adoptive T cell-based immunotherapy in NSCLC.

PUB019 EGFR Mutation Correlates with Uninflamed Phenotype and Weak Immunogenicity, Causing Impaired Response to PD-1 Blockade in NSCLC

Patients with EGFR mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, two pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10-2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression. Furthermore, patients with EGFR mutation showed a lack of T-cell infiltration (P = 0.003) and shrinking proportion of PD-L1+/CD8+ TIL (P = 0.005). Importantly, patients with EGFR mutations, especially the sensitive subtype (exon 19Del, L858R, L861Q, G719X, S768I), showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with EGFR wild-type did (HR = 0.73, P < 0.00001). Three cases treated with PD-1 inhibitor in our center also supported that EGFR mutation was unfavorable to PD-1 blockade even when those with strong positive of PD-L1 and CD8+ TIL. This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.

Prognostic impact of a ground glass opacity component in the clinical T classification of non–small cell lung cancer

ObjectiveTo determine whether solid component size and the presence of a ground glass opacity (GGO) component are independently associated with survival outcomes in patients with early-stage non–small cell lung cancer (NSCLC) using the eighth edition Lung Cancer Stage Classification. MethodsWe retrospectively evaluated 1029 surgically resected early-stage NSCLCs. T categories were assigned based on solid component size using the eighth classification. All tumors were classified into 1 of 2 groups: the GGO group or the solid group. We evaluated the prognostic impact of several clinicopathological variables in clinical T classification using a Cox proportional hazard model. ResultsOn multivariable analysis, the presence of a GGO component (hazard ratio [HR], 0.314; 95% confidence interval [CI], 0.181-0.529: P < .001) and solid component size (HR, 1.021; 95% CI, 1.006-1.036; P = .006) were identified as independently significant prognostic factors of overall survival. However, after accounting for the presence of a GGO component, neither maximum tumor size nor solid component size added to the prediction of long-term survival. Moreover, tumor size significantly affected survival outcome only in the solid group (HR, 1.020; 95% CI, 1.006-1.034; P = .004). Survival was excellent at ≥90% despite the revised T categories, provided that the tumor had a ground glass appearance. Meanwhile, tumor size significantly affected survival only in the solid group (P < .001). ConclusionsThe presence of a GGO component is a significant prognostic factor in early-stage NSCLC. External validation is required to assess whether it should be adopted as a novel factor in clinical T staging.

Survival Outcome after Stereotactic Body Radiation Therapy and Surgery for Early Stage Non-Small Cell Lung Cancer: A Meta-Analysis

ABSTRACTObjective: Treatment modalities in medically compromised patients with early-stage non-small cell lung cancer (NSCLC) are controversial. Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has been increasingly recognized as a favorable alternative to surgical resection for early-stage NSCLC. Many retrospective analyses compared the efficacy of stereotactic body radiotherapy (SBRT) with surgery for early-stage non-small cell lung cancer (NSCLC). However, the efficacy between SBRT and surgery regimens for patients with early-stage NSCLC remains unclear. This study aimed to investigate the efficacy between SBRT and surgery. Methods: Publications on comparison SBRT with Surgery in treatment of early stage non-small cell lung cancer (NSCLC) from 2011 to 2017 were collected. Retrospective trials analyzed the summary hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS), local control survival (LC), regional control survival (RC), loco-regional control survival (LRC), and distant control survival (DC) between SBRT and Surgery. The major outcomes measures were hazard ratios (HRs). Meta-analysis Revman 5.3 software was used to analyze the combined Pooled HRs using fixed- or random-effects models according to the heterogeneity. Result: A systematic literature search was conducted including14 studies. In this meta-analysis, patients with SBRT achieved inferior OS, DFS, LC, RC, LRC and DC, compared with surgery. Conclusion: In this study we found more favorable outcomes with stage I NSCLC treated with SBRT. The surgery had no obvious advantages in this meta-analysis. Although surgery has become the recommended treatment at present, SBRT has potential to be an alternative treatment as a novel non-invasive radiation therapy modality in patients with stage I-II NSCLC.

Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer.

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early stage resectable NSCLC remains unclear. Here, we studied PD-L1 expression and tumor infiltrating lymphocytes (TILs) in surgically resectable NSCLC and correlate the finding with clinicopathological features and patient outcomes. Total of 170 archival samples of resectable NSCLC were probed for PD-L1 expression using the clone 22C3 pharmDx kit. The PD-L1 expression was determined by the Tumor Proportion Score (TPS) and classified into TPS <1%, TPS 1 to 49% and TPS ≥50%. The scoring of TILs was from hematoxylin & eosin stained tissue sections using a system for standardized evaluation of TILs in breast cancer. PD-L1 expression was compared with clinical pathological characteristics and survival outcome. Expression of PD-L1 scores of TPS ≥50%, TPS 1 to 49% and TPS <1% were observed in 10.6%, 24.7% and 64.7% of the 170 archival samples, respectively. Positive PD-L1 expression was significantly higher in patients with squamous carcinoma, in those with higher TNM stage and with the presence of TILs. Neither the PD-L1 expression, TIL status, nor their combination was an independent prognosis biomarker of survival when the data was subjected to either univariate or multivariate analysis. The incidence of PDL1 expression appears to be lower in patient with early stage resectable lung cancer. PD-L1 expression and TILs are not prognostic indicators of survival outcome in this population.